text:
|Publication number
|Publication type
|Application number
|Publication date
|Dec 14, 2010
|Filing date
|Apr 27, 2010
|Priority date
|Jun 1, 2000
|Fee status
|Also published as
|Publication number
|Jonathan Strietzel
|Original Assignee
|Network Directory Sciences LLC
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (32), Non-Patent Citations (7), Referenced by (8), Classifications (11), Legal Events (3)
|External Links: USPTO, USPTO Assignment, Espacenet
The present application claims the benefit, as a continuation under 35 U.S.C. 120, of U.S. patent application Ser. No. 12/364,940 entitled, "Method and Apparatus for Telecommunications Advertising," filed Feb. 3, 2009, which is in turn a continuation of U.S. patent application Ser. No. 09/585,460, now U.S. Pat. No. 7,489,768, entitled, "Method and Apparatus for Telecommunications Advertising, filed Jun. 1, 2000, the entirety of which are incorporated by reference herein as is set forth in their entirety.
The present invention relates generally to telecommunications and, more particularly, to a method and apparatus for telecommunications advertising.
Currently, the area of telecommunications is rapidly expanding. As a result, new products and services are constantly coming into the market, which promise more information, of more relevance to an individual user, and presented in a more timely fashion. It is an exciting time for consumers interested in such products and services; however, such products and services can be very costly. For example, Personal Digital Assistants (FDA's) and cellular phones can cost hundreds of dollars depending on the features and functions included. Moreover, sending a megabyte of data content over a wireless network can cost hundreds of times what it costs to send the same data over a fixed network. Obviously, consumers would prefer that the costs come down, before they start using many of these new telecommunications products and services. Unfortunately, the providers of these products and services need more users before they can bring the costs down significantly. Advertising is one way to subsidize the costs of new products and services, thus making them more affordable for the consumer.
It has been suggested that in a telecommunications network, advertising messages could be applied to a calling party's line in between rings of the ringback signal. For example, such a system is disclosed in U.S. Pat. No. 4,811,382 issued to Sleevi (the Sleevi patent). The Sleevi patent further suggests that a message could be associated with the calling party based on the calling party's phone number, the called party's phone number, or the long distance carrier of either party. In addition, messages could be changed based on the time of day, or the day of the week or month. One drawback to these suggestions, however, is that only the calling party is targeted and the association of messages is based on a limited number of criteria. Moreover, only using the period in between the ringback signals limits the type and number of messages that can be played to the caller. Another drawback is that the suggestions above only contemplate a fixed analog telecommunications network. New telecommunications systems, however, provide expanded opportunity to provide advertisers with highly targeted advertising and to subsidize the costs to the consumer of the products and services associated with these new systems.
A telecommunications advertising means is disclosed. The telecommunication advertising means includes an advertisement database coupled to a processing means. The advertisement database stores subscriber specific or third party advertisements that are selectively associated with communications in a telecommunications network. The selective association is carried out by the processing means. In one embodiment, a router is coupled to the advertisement database. The router routes communications from source to destination within the telecommunications network. The router also routes advertisements that have been associated with the communications to the sources and destinations of the communications.
A telecommunications system is also disclosed. The telecommunications system comprises a network subsystem, which includes a telecommunications advertising means. The telecommunications advertising means comprises an advertisement database and a processing means.
A method of telecommunications advertising is also disclosed as well as various other embodiments of the telecommunications advertising means. These other embodiments and further features and advantages of the invention are described in detail below.
In the figures of the accompanying drawings, like reference numbers correspond to like elements, in which:
Router 106 receives incoming communication 108 and connects it to the appropriate destination 112. Router 106 may, for example, be part of a fixed-line telecommunications network, such as a PSTN or ISDN, which generally connect ordinary telephone sets together via switching centers. In this case, telecommunications advertising means 100, and therefore router 106, may be included in such a switching center. In the typical fixed telecommunications network example, the switching center is normally a telephone company facility called a central office, but the switching center may be a toll office, a private branch exchange (PBX), or the like.
A typical process by which router 106 would function within a switching center is illustrated by the steps in
In step 204, the switching center will apply a dial tone to the calling party's line and wait for the calling party to dial a number. In step 206, the number is dialed and the switching center interprets the digits making up the number. Some portion of the number, typically the first three digits, will indicate whether the call is an inter-office call or a same office call, i.e., whether the call needs to be routed through a second central office or not. Therefore, in step 208 the switching center determines if the call is an inter-office call, in which case an idle connection or trunk to the other central office is selected (step 210). In step 212, once the trunk is seized, or if no trunk was necessary because it is a same office call, the switching center determines the status of the called party's line. As best seen in
Thus, in the fixed telecommunications network example, router 106 forms an integral part of the circuits and systems of the switching center. Processing means 104 may also be integrated into the circuits and systems making up the switching center. In fact, in some implementations processing means 104 may be merged with router 106. Advertisement database 102 may be a standalone database or may be integrated into the resources present within a particular switching center. Moreover, the components that makeup telecommunications advertising means 100 can actually be distributed throughout the network.
The following implementations are described in order to further illustrate the above possibilities. In one implementation, telecommunications advertising means 100 may be included in a switching center such as a central office. Depending on the particulars of the implementation, each component of means 100 may standalone within the central office or may be integrated into the circuits and systems that make up the central office. Alternatively, in another implementation the components comprising telecommunications means 100 may be distributed throughout central offices within the network. In other words, a router 106 may be present in each of a plurality of central offices making up the fixed telecommunications network. Advertisement database 102 and processing means 104 may, however, be contained within one particular central office, or distributed along with router 106.
Although source 110 has been described above as a telephone set, source 110 of incoming communication 108 is not limited to a telephone set. In other implementations, for example, source 110 is a desktop computer, a laptop, a fax machine, or an interface to an entirely different communications system. With regard to the latter, traditional fixed networks are interfaced to a variety of modem telecommunication networks from which incoming communication 108 may be generated. Thus, for example, source 110 may also be a wireless network, a local loop, a paging network, or a Local Area Network (LAN). As will be discussed in relation to further embodiments, each of these networks contains at least one interface to a fixed network. Therefore, each of these network types may act as source 110 of incoming communication 108 in various implementations of means 100.
The switching center itself is not limited to a typical PSTN or ISDN type of network switching center. For example, telecommunications advertising means 100 may be integrated into a wireless system or the Internet. In these implementations, the method of identifying destination 112 and of connecting source 110 thereto are different, but the basic approach is the same. In implementations involving the Internet, telecommunications advertising means 100 may be included within a router or plurality of routers used to route traffic across the Internet. In this case, the Internet address or domain name is used to identify source 110 and destination 112, instead of the digits of the telephone number dialed. It will be apparent to those skilled in the art, therefore, that incoming communication 108 is not limited to voice communications, but may also include data communications. In fact, depending on the implementation, incoming communication 108 may be a video communication, a paging communication, an email communication, or any combination of the above. Other than what type of advertisements may be sent, the type of communication does not impact the functionality of telecommunication advertising means 100.
In addition to connecting source 110 with destination 112, router 106 also routes advertisements associated with source 110 to source 110 and any advertisements associated with destination 112 to destination 112. Because the user is captive, the user must hear or observe the message. In this way, it can be assured that the advertising message reaches its intended target.
Looking at
Alternatively, the message can actually replace the dial tone. This is possible because a dial tone alerts the user to the fact that the user is connected to the network and may dial a number. Thus, this implementation would use the advertisement to alert the user of the network connection. Once the advertisement finishes playing, the user dials the desired number.
In an alternative implementation, a short advertisement replaces the ringback signal in step 218. Typically, the ringback signal consists of short rings every few seconds. In this implementation, therefore, a short advertisement is played in place of the rings. In another implementation, once the called party's telephone goes off hook in step 220, a short advertisement is played to the calling party. The playing of the short advertisement indicates to the calling party that the called party has answered and that the calling party may begin the conversation after the advertisement has played.
An advertisement may also be associated with the called party (destination 112). In this implementation, the advertisement is routed to the called party when the called party's telephone goes off hook. The calling party preferably continues to receive the ringback signal, or substitute advertisements, until the advertisement is finished on the called party's side, at which point the conversation may begin. Alternatively, when the called party's line goes off hook a short advertisement may be played for both parties, so that the conversation may begin after the advertisements are complete. Ideally, the advertisements would last the same amount of time, to avoid any feeling of disconnect by one of the parties.
In additional variations, the implementations described above may be further combined. For example, an advertisement in place of the dial tone may be combined with short advertisements in place of the ringback signal, which may be further combined with an advertisement played to one or both parties when the called party's telephone goes of hook. In a slightly different implementation, instead of the ringback signal or substitute advertisements, a continuous advertisement may be played to the calling party after the calling party dials the number. When the called party's telephone goes off hook, the advertisement will stop, and conversation can then begin. This continuous advertisement may be combined with an advertisement played before or in place of the dial tone. In addition, it may be combined with an advertisement played for the called party, when the called party picks up. Those skilled in the art will appreciate, therefore, that the implementations discussed can be combined in a variety of ways in order to deliver to each party a variety of different messages of different lengths, and at different times during the call initiation process. In this respect, the calling party may receive the same advertisement or advertisements as the called party, or the advertisements may be different. It can be assured, however, that each party will hear or observe the advertisement or advertisements, just as it is assured that each party would hear the dial tone or ringback signal. This is because the parties must pay attention at the specific times such advertisements would be playing in order to complete the call.
In order to ensure that the advertisements are well targeted to the particular called or calling party, processing means 104 preferably associates advertisements stored in advertisement database 102 based on information about the parties. As mentioned previously, advertisements stored in advertisement database 102 may be subscriber specific advertisements or third party advertisements. In particularly preferred implementations, a specific advertisement is associated based on the specific subscriber. For example, a certain subscriber may want a specific message played for any outgoing call, incoming call, or both. This type of implementation will be particularly advantageous for business subscribers. By way of illustration, a business subscriber may want to have a specific short message, such as the business name or jingle of the business, routed back to the source of each incoming call. Alternatively, a business may want a specific message or messages played each time an outgoing call or interoffice call is originated on one of the business' lines. This concept may be extended in order to allow third party advertisers to target specific users or groups of users for specific advertising messages. For example, a particular advertiser may pay the telecommunications provider to play an advertising message to each party placing a call in the telecommunication provider's network.
Money collected from advertisers or from business subscribers to play their advertising messages is preferably used to offset the cost of the service to each regular subscriber to the telecommunications network. Alternatively, the system 100 may be set up so that money collected from advertisers and businesses is used to offset the cost of subscribers that have agreed to receive advertising messages as part of the call process.
The implementations, as described so far, have not involved highly targeted advertising. Means 100 may be used, however, to facilitate highly targeted advertising. For example, a certain advertiser may want to limit the playing of his advertisement to subscribers in certain geographic areas. Further, the advertiser may have advertising messages in multiple languages and would therefore want to play a different message depending on the primary language of the targeted subscriber. These types of implementations may be achieved by programming processing means 104 to selectively associate advertisements stored in advertisement database 102 to the calling and/or called parties based on predetermined criteria. One example of selective association has already been discussed, i.e., playing a message specific to a certain business to callers calling the business. Other example criteria, in addition to language and geography, that can be employed to increase the selectivity of the advertising message played are the source 110 of incoming communication 108, the type of incoming communication 108, the time of day of communication 108, and the destination 112 of incoming communication 108. With respect to source 110 and destination 112, a wide variety of factors can be used, including, for example, area code, account type, average monthly phone bill, frequent phone numbers called, address, etc.
Information associated with source 110 of incoming communication 108, such as the corresponding number, is preferably used to determine if source 110 is initiating a same office call, an inter-office call, or a call originating in a different type of network such as a cellular network, a LAN, a local loop, or a paging network. Third party advertisements can then be associated with incoming communication 108 based on the source, and in a manner that increases the selectivity of the advertising so as to produce a better return on the advertising dollars spent. Similarly, the type of communication can play a useful role in increasing the selectivity of the advertisement. As mentioned previously, the type of communication is not limited to telephone calls, but may include data communication, video communication, paging communication, email, voice/audio communication, or any combination. Thus, by taking into account the source and type of the communication, a more selective approach may be employed to associate specific advertisements from specific advertisers with specific communications.
Similar information about the destination of incoming communication 108 may also be advantageously integrated into the message association process. In a further implementation, information related to preferences for products and services, as well as personal data, is gathered for each subscriber and used to make the association even more highly targeted. It should be noted that these criteria used in the association process apply to both advertisements sent to source 110 of incoming communication 108 and advertisements sent to destination 112 of incoming communication 108.
Of course, the basic principles are the same for implementations that involve other than the traditional fixed telecommunications network implementations. For example, networks relying in whole or in part on wireless communication lines would still operate in the same manner. In the case of the Internet, the selectivity can be even more beneficial in that the Internet brings together a host of communication methods and devices. Thus, there is an even broader range of selection criterion that can be used in the association of advertisements with communications. Additionally, the advertisement can be in a variety of formats. For example, the advertisement may be an audio advertisement, it may be a jingle, a textual message, a video message, a graphic message, or a combination of these messages, depending on the desired implementation. Thus, in an implementation involving the Internet, where multimedia capable computers are usually used to access the network, each of these message types would be applicable. But even in the traditional telecommunications network, video conferencing is possible, wherein text, video, or graphical advertisements are employed. New digital technologies for fixed networks, such as ISDN, also make implementations involving a variety of advertisement types possible. The advantage of certain types of advertisement messages in relation to certain types of networks will be discussed more fully in relation to further embodiments discussed below.
An alternative embodiment of the invention is now described in connection with
The general situation is illustrated in
Network subsystem 304 further comprises an advertisement database 102 and a processing means 104. Like the previous embodiment, advertisement database 102 stores advertisements that are played to users of terminals 302 at appropriate times based on appropriate criteria. Processing means 104 associates at least one advertisement from advertisement database 102 with each communication within network 300. In the embodiment illustrated in
In network 300, incoming communications are analyzed to determine the source, destination, type of communication, time of day, etc., then processing means 104 selectively associates at least one advertisement with the source and/or destination of the communication based on the information determined. The advertisement or advertisements are advertisements unique to a specific subscriber, or a third party advertisement. For example, when a terminal to terminal communication is initiated, processing means 104 may associate an advertisement with the source and route it back to the source terminal 302. Additionally, an advertisement from advertisement database 102 may be associated with the destination terminal 302 and routed to that terminal. The advertisement may be the same for both source and destination or it may be different depending on the implementation. If the communication is initiated with a fixed network user, then this may cause the advertisements associated with either the source, or destination, or both to be different than in the terminal to terminal situation.
When communication is established between a terminal 302 and a fixed network user, special considerations may arise. This is because the fixed network may also comprise a telecommunications advertising means 100. Therefore, processing means 104 must be capable of resolving which advertising means 100 will associate an advertisement or advertisements with the communication. Looking at specific implementations in the discussion below will further develop the embodiment depicted in
Network subsystem 404 comprises mobile switching center (MSC) 412 as well as a plurality of administrative registers 416 and advertisement database 418. Network subsystem 404, of which MSC 412 is the main part, performs the switching of calls between the mobile users and between mobile and fixed network users. MSC 412 acts like a normal switching node of a fixed network, but additionally provides the functionality needed to handle a mobile subscriber, such as registration, authentication, location, updating, handoffs, and call routing. MSC 412 also provides the connection to a fixed network through network interface 414. In the implementation shown, MSC 412 also performs the functions of selectively associating advertisements in advertisement database 418 with communications within network 400. In alternative implementations, a separate processing means may be used to perform this function. Administrative registers 416 contain all the administrative information of each subscriber registered in network 400, along with the current location of each MS 406. It should be noted that some or all of registers 416 may also be implemented as part of MSC 412. Alternatively, each register 416 and MSC 412 may be implemented as independent units. Administrative registers 416, together with MSC 412, provide call routing and roaming capabilities.
When a MS 406 places a call to another MS 406, the call is routed through MSC 412. Unlike the fixed network embodiment, the caller initiating the call does not usually receive a dial tone indicating connection to the network. A caller will dial the number desired and then place MS 406 to their ear. MSC 412 will determine, based on the number dialed, that the destination of the call is another MS 406. If the called party is using their MS 406, or if the called party's MS 406 is turned off, then a busy tone or a message indicating the unavailability of the called party is routed back to the calling party. If, on the other hand, the called party's MS 406 is on and is idle, then a ring signal is applied to the called party's MS 406 and a ringback signal is applied to the calling party's MS 406. When the called party answers, the ring and ringback signals are terminated and the conversation can begin.
Because there is typically no dial tone, an advertisement from advertisement database 418 cannot be played prior to or in place of the dial tone. But an advertisement or advertisements from advertisement database 418 can be, depending on the implementation, substituted for the rings in the ringback signal, played in between the rings of the ringback signal, or substituted for the ringback signal entirely, i.e., one long advertisement or series of short advertisements is played for the caller until the called party picks up as opposed to the traditional ringback signal. In a preferred implementation, once the called party picks up, an advertisement is played for one or both parties after which, the conversation can begin. In addition, implementations may combine, in different ways, the playing of messages at these various points during the call.
MSC 412, or a standalone processing means in those implementations that include one, selectively associates advertisements in advertisement database 418 based on, for example, information related to the caller, or source of the call, and/or the destination. As in the fixed network example, advertisements may also be selectively associated based on the time of day, geographic location, primary language, or the identity of the specific caller or called party. In one implementation, the message associated comprises billing information for one or both parties. For example, the party's balance and minutes remaining for the month are played for the party. In another implementation, a specific party or subscriber specifies the message or messages to be played under certain circumstances. For example, a business may pay to have the business' jingle played to any caller using a MS 406 to call the business. In yet another implementation, the network advertises new calling plans or special promotions are played. In particularly preferred implementations, third party advertisers may pay to have advertisements related to their products and services played during the call. Money generated from this type of advertising may be used to subsidize the cost of products and services for subscribers to network 400.
Unlike routing in the fixed network example, where a terminal is semi-permanently wired to a central office, a mobile user can roam nationally and even internationally. Therefore, the directory number associated with a particular MS 406 usually contains a country code as well as identification of the associated home network 400. When a fixed network subscriber initiates a call to a mobile user, the fixed network switching center interfaces with one or several MSC's 412 in order to connect the call. As a result, the steps are very similar to the ones illustrated in
It should be noted that MS's 406 used in cellular systems present unique possibilities for communicating advertisements to subscribers. For example, one implementation takes advantage of the fact that the ring the called party hears is completely programmable. Therefore, in this implementation the ring is replaced by an advertisement. This can be accomplished by storing potential advertisements in each MS 406. When MSC 412 associates a particular advertisement, it sends a command to a called party's MS 406 to play that advertisement in place of the ring. MS 406, accesses the stored advertisements and plays the appropriate one at the appropriate time. The ability to program a MS 406 over the air to constantly update which advertisements are stored in MS 406 may also be taken advantage of in this implementation.
Another unique method of communicating messages to mobile users that may be employed in the present embodiment takes advantage of the fact that a large number of MS's 406 are equipped with a display device. Therefore, the present embodiment also contemplates the use of graphic or text advertisements that are displayed on the user's display device. For example, a company may pay to have its trademark flashed on the screen of each MS 406 whenever there is an incoming call, or whenever a user pushes send to initiate a call, or a combination thereof. The use of graphic or text advertisements is also incorporated in implementations involving a second example type of network 300 as illustrated in
The process involved in completing a page is illustrated in
Two way paging, pagers with multiple programmable ring indicators, and pagers equipped with voice audio capabilities, however, expand the possible methods of implementing a telecommunications advertising means 100 within a paging network 600 to many of the various implementations described above in connection with prior embodiments. In pagers with voice audio capabilities or voicemail, for example, an audible advertisement, such as a jingle or slogan, may be selectively added by switching center 606 to the beginning of each voice page received.
It will be apparent to those skilled in the art that other implementations of network 300 will involve other network systems, such as local loops, wireless local loops, or LAN's. Moreover, the type of communication involved, in addition to calls and pages, incorporates video and text communication depending on the system implementation. Each of the implementations discussed may also incorporate a means to acquire more information about a product or service advertised during the communication. For example, a calling or called party in a telephone network, a cellular network, or a paging network can stay on after the communication transaction is over and receive options or a menu allowing the party to select to receive more information about a particular product or service. In certain other implementations, the user can actually select to be connected directly to the company offering the products or service.
There is also provided a method of telecommunications advertising comprising the steps illustrated in
In step 804, an advertisement or advertisements are associated with a source of a communication within the telecommunications network. For example, an advertisement may be associated based simply on the identity of the source as determined by the number or address associated with the source. Preferably, however, the identity is combined with the user information in order to selectively associate a highly targeted advertisement, such as an advertisement for a particular product, with the source. In step 806 the advertisement is played for the user associated with the source of the communication.
An advertisement is also preferably associated with the destination of the communication. This step is illustrated as optional step 812 in
It is contemplated that the users of networks including a telecommunication advertising means 100 would be billed at a lower rate for the communication service due to the fact that the advertisements are included in the communication. Further, as illustrated by step 816 in
In an alternative embodiment, the users are given the option to receive more information prior to the connection between source and destination. For example, after the advertisements are played for the user associated with the source, the user is given the option to receive more information relating to the advertised products or services. Depending on the implementation, the user may choose to receive the information immediately or to wait until after the communication transaction. In other sample embodiments, similar options are provided to the destination user as well. In alternative embodiments, one or both users are given the option to receive more information at various points during the communication transaction.
As illustrated in
Once the user has gained access, the user has the option to change the preferences and user information contained in the record. This step is illustrated as step 904 in
In step 908, the new information is automatically updated and stored in the record, which is automatically updated and stored in the database. In an additional sample embodiment, the record is accessed via telephone. The user again uses a password to access the information and is then provided with menu options to select new or updated information.
After the new information is updated and stored in step 908, the updated record is used, in step 910, to automatically update associations of advertisements to be played to the user. For example, the telecommunications advertising means is part of a telecommunications network. When the user initiates or receives a communication within the network, the user information is used to associate advertisements that are played to the user before, during, or after the communication. In step 910, the updated user information automatically updates which advertisements are associated with, and played to, the user.
While various embodiments of the invention have been presented, it should be understood that they have been presented by way of example only and not limitation. It will be apparent to those skilled in the art that many other embodiments are possible, which would not depart from the scope of the invention. For example, certain telecommunications network systems are described. Telecommunications technology, however, is constantly evolving, resulting in new systems and means for communicating. The present invention anticipates that changes in technology will occur, but the basic invention will continue to apply to newly developed systems.
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Owner name: NETWORK DIRECTORY SCIENCES, LLC, TEXAS
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:MOUNT HAMILTON PARTNERS, LLC;REEL/FRAME:024555/0406
Effective date: 20100617
|Mar 1, 2011
Owner name: CALLERTONE INNOVATIONS, LLC, TEXAS
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NETWORK DIRECTORY SCIENCES, L.L.C.;REEL/FRAME:025877/0937
Effective date: 20110210
|Jun 16, 2014
|Fee payment
Year of fee payment: 4


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Business \ Modify \ Download \ Bleeds \ Please \ Watching \ Readme \ Printready
Print Template - Fresh and Evil Business Card 224384 by threebytes @ GraphicRiver
Photoshop \ Print Template \ Business Cards \ Creative
This is a fresh and evil business card. The design communicates all the necessary information and is the right choice for people are looking for something evil yet playful.
The files are easy to modify in CMYK and printready.
With your Download you get.
2 PSD files layered and easy to modify ЁC dimensions: 2"x3.5" (2.25"x3.75" bleeds)
readme.txt with links to download the free fonts
Free Fonts used: Museo Sans, Evilz
Thank you for watching.
Please rate my file, if you like the business card!
Layered: Yes; Graphics Files Included: Photoshop PSD; Minimum Adobe CS Version: CS; Print Dimensions: 3.5x2.5.
Keywords: business, business card, card, clean, evil, fresh, halloween, mask, modern, purple, shop, store.

subset: commoncrawl


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Just found out VBAC is banned at my current hospital.. (Xposted)
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November 8th, 2013, 08:46 PM
Mega Super Mommy
Join Date: Jun 2009
Posts: 4,398
Also posted in February 2014 DDC..
Just found that out thanks to google. No wonder my OB was trying to pull the vbac bait and switch thing. When he was talking about there even being an option to vbac, I kind of assumed it was allowed in the hospital, but vbac websites have the place listed as banned. You'd think that would be worth mentioning at some point in all the vbac conversations we've had. If I showed up at that hospital ready to push or close to it, it's not like they can turn me away. I'm wanting to move forward with switching. Now I just need to start researching individual OBs in the other hospital that allows vbac. On the lists I'm reading, some hospitals are listed as banned and others as de facto banned. What's the difference and what will it mean for me?
My OB did well on my csection though, I just strongly disliked it the experience. I like what he did when he closed me up. He used skin glue stuff and steri-strips, no staples or stitches, so didn't need to have anything removed which is good because I would have wigged out. I'm going to request that glue stuff if I need a csection again with whatever new OB I choose, if I can. Please tell me if this fear is unfounded, but I guess I'm afraid of making the switch only to end up with an OB who messes up my possible csection as silly as that sounds.
Mom to a 2 year old baby girl, 2 week old baby boy, and one in Heaven.
In loving memory of our angel baby, with us for 4 weeks. Baby went to be with God July 24th, 2009.
Last edited by SkyBaby; November 8th, 2013 at
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- Details
Details9.0 Wireless:~ Current speed, speed comparator, ride time, trip distance, dual odometer (for 2 wheel sizes), average speed, maximum speed, clock, and temperature. 4-line MacroMonitorª LCD displays up to 5 pieces of data at a glance. Digital wireless technology eliminates messy wires. Fits 25.4-31.8mm handlebars. Magnet fits up to 4mm bladed spokes.


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Micah Dickson wants to
It bring awareness to the corporate hold has on cable television pricing.
Apple TV, a digital media player introduced in 2007, offers users access to iTunes movies on the larger screen of a television as well as streaming video from Netflix, Hulu and other online services. However, Apple TV's appeal to consumers as an alternative TV device has been limited by a paucity…Read More
If you like some pointers on the best ways of streaming, this video made by Brian Cooley will definitely shows you the ins and outs, pro's…Read More
Since the commencement of the internet highway, people has fancied watching programs online. This underhandedly gave us a new source of freedom of choice. Who says democracy don't work. Because of alternatives like, XBOX One, Apple TV, Roku, and the growing popularity of Smart TVs, cable and…Read More


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How to: Use the MAPI Crash Recovery API
Last modified: June 25, 2012
Applies to: Outlook
This topic contains a code sample in C++ that shows how to call the MAPICrashRecovery function from the UnhandledExceptionFilter function. The MAPICrashRecovery function checks the state of the Personal Folders file (PST) or Offline Folders file (OST) shared memory. If the memory is in a consistent state, the MAPICrashRecovery function moves the data to disk and prevents further read or write access until the process is terminated. By ensuring that the PSTs or OSTs are in a consistent state before the process is terminated, you can prevent Microsoft Outlook 2010 or Microsoft Outlook 2013 from displaying the following error message and avoid performance problems.
A data file did not close properly the last time it was used and is being checked for problems. Performance might be affected while the check is in progress.
LONG WINAPI UnhandledExceptionFilter(__in EXCEPTION_POINTERS* pep) { // Let the OS terminate the process upon return. LONG retval = EXCEPTION_EXECUTE_HANDLER; switch (pep->ExceptionRecord->ExceptionCode) { case EXCEPTION_BREAKPOINT: case EXCEPTION_SINGLE_STEP: // Ignore debugging exceptions. retval = EXCEPTION_CONTINUE_SEARCH; break; default: // The process is going to be terminated, so disconnect the MAPI database. MAPICrashRecovery(MAPICRASH_RECOVER); // Optionally, you can display a crash reporting dialog box here. // If the user chooses to debug, // call MAPICrashRecovery(MAPICRASH_CONTINUE). break; } return retval; }


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Applications are open for the Ca' Foscari – Harvard Summer School organized in collaboration with one of the world's most prestigious Ivy League Universities: Harvard University in Boston, Massachusetts. This programme, unique to Ca' Foscari, is designed to give students and teachers from both sides of the world to study, teach, interact and grow through curricula of excellence and a wide range of cultural activities.
The programme for CFHSS 2017 will be presented to prospective students in Aula Baratto on March 27th, at 4:30pm through testimonials from former Faculty and students involved in the programme throughout the past 12 years.
All courses allow students to accumulate University credits (6 CFU / ECTS) per course, thereby accelerating their tertiary study during the summer period, and students have the opportunity to take part in numerous cultural activities aimed at encouraging interaction between the two sides of the Atlantic. The CFHSS provides a truly unforgettable experience through the opportunity to become immersed in a new method of learning and to engage in an international cultural exchange right here in Venice.
The Ca' Foscari – Harvard Summer School offers numerous courses in a range of interdisciplinary areas such as economics, labour law, international law, mathematics, literature, history, philosophy and environmental science. There are up to 70 places available for Ca' Foscari students, and as one of the numerous advantages of the programme, all credits obtained are reciprocally recognised at Harvard University. Undergraduate students will also gain 2 bonus points when they graduate.
Applications close April 3rd


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Outre Quick Weave Half Wig Big Beautiful Hair 4C-Coily
Color Shown On Model: 1B
MATERIAL: Synthetic - Heat resistant fiber
TYPE: Half wig
LENGTH: Medium
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Step 4: When the hair is completely dry, just finger comb to style the curls.
Tips & Tricks:
- Finger comb the curls from the tips to the roots. Avoid brushing or combing your curly wig.
- Avoid heavy styling products. Products like gel, cream and mousse will weigh down the hair and cause tangling and matting issues.
- Before going to bed, take your wig off and put it on a wig stand to maintain the hair's curls and the wig's shape.


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We will help you find a private study skills teacher in Bathgate and anywhere in the UK. Private study skills tuition is an excellent way to boost confidence as well as improving grades and doesn't have to be boring! Please use our service to find Bathgate study skills tutors and select the one who best fits your requirements.
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kaitlyn pham
I'm a beginner and just interested in trying the voice over career. I'm 27 but can easily sound and look 16 years old
English (North American), English
Child, Teen, Young Adult
Payment Terms
Hire kaitlyn as a voice actor. Payment is made through Voices.com SurePay, an escrow service that guarantees your work is done to your satisfaction. Send payment securely by Visa, Mastercard or PayPal through Voices.com then download your files from the website.
Watch a video to see how to make a payment
Next Steps
To contact kaitlyn pham about your project, request a quote today. We'll walk you through the process step-by-step. It's fast and easy.
This talent has not uploaded any demos yet.
Hire kaitlyn pham as a voice actor. Working with kaitlyn pham is fast and easy. We'll walk you through the process step-by-step.
Request a quote for your project today.


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GraphicRiver Premium Stylization Photoshop Action 8431306
Script & Plugin \ Add-on \ Photoshop \ Actions \ Photo Effects
Unsplash \ Action \ Download \ Effect \ Stylization \ Photshop \ Unbeatable
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Script & Plugin \ Add-on \ Photoshop \ Actions \ Photo Effects
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Complexity: Well-labeled 'ACTION' operation and easy to modify to suit your need.
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Last Update: ; Add-on Files Included: Photoshop ATN; Works With: JPG; Minimum Adobe CS Version: CS4.
Silver surfer Photo Effect Set v1; Retro Style Photo Effect Set v.1; Simple Creative Business Card; Smart Company Business Card v.2; Transparent Image Shape Ps Action; Smart Company Business Card; Creative Business Card v. 03.
Keywords: action, effect, effect action, photo effect, photshop, photshop stylization, style, styliz.


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|Home | About | Journals | Submit | Contact Us | Français
Stem cell niches are dynamic microenvironments that balance stem cell activity to maintain tissue homeostasis and repair throughout the lifetime of an organism. The development of strategies to monitor and perturb niche components has provided insight into the responsive nature of the niche and offers a framework to uncover how disruption of normal stem cell niche function may contribute to aging and disease onset and progression. Additional work in the identification of genetic factors that regulate the formation, activity, and size of stem cell niches will facilitate incorporation of the niche into stem cell-based therapies and regenerative medicine.
Stem cell niches are discrete and dynamic functional domains that influence stem cell behavior to govern tissue homeostasis under diverse physiological (development and aging) and pathological (injury and disease) conditions. The niche must be flexible in order to coordinate stem cell behavior with homeostasis and repair; however, the plasticity of a niche may be co-opted in cancer and chronic disease. Here, we review experimental data highlighting the relationships between stem cells and their niches, advances in imaging technologies that permit characterization of niches in vivo, and factors regulating niche involvement in tissue regeneration and cancer.
In 1978, R. Schofield proposed that proliferative, hematopoietic cells derived from the spleen (spleen colony-forming cells, CFU-S) displayed decreased proliferative potential when compared to hematopoietic stem cells from the bone marrow because they were no longer in association with a complement of cells, a "niche," which supports long-term stem cell activity (Schofield, 1978). This idea that specialized environments within tissues can preserve proliferative potential and block maturation of adult stem cells was the first description of the stem cell niche hypothesis. Implicit in this model is the prediction that removal of stem cells from the niche results in loss of stem cell identity, self-renewal capacity, and the onset of differentiation. As such, the niche would provide a mechanism to precisely balance the production of stem cells and progenitor cells to maintain tissue homeostasis. Therefore, a stem cell niche is not defined solely by the presence of stem cells but also by the ability to regulate stem cell behavior.
Characterization of somatic support cells that produce factors necessary for the maintenance of germline stem cells (GSCs) in C. elegans and Drosophila provided examples of discrete "niches" (Kiger et al., 2001; Kimble and White, 1981; Tulina and Matunis, 2001; Xie and Spradling, 2000) and, consequently, paradigms for the identification and characterization of stem cell niches in vertebrates. Development of functional assays to verify stem cell identity, characterize niche support cells, and technologies to visualize stem cell-niche cell interactions in vivo have enabled a better understanding of how stem cell niche dynamics are regulated in physiological and pathological processes.
Lineage-tracing techniques and serial transplantation assays have confirmed the presence of stem cell populations in many tissues. Consequently, these methods have also aided in characterizing putative niches. In Drosophila, clonal analysis relies upon mitotic recombination to initiate marker expression in a random mitotic cell and all of its subsequent daughter cells (Harrison and Perrimon, 1993; Lee and Luo, 1999). This method has been used to identify a number of stem cell populations in tissues as diverse as the nervous system, gonads, and digestive tract (Figure 1) (Decotto and Spradling, 2005; Fox and Spradling, 2009; Gönczy and DiNardo, 1996; Margolis and Spradling, 1995; Micchelli and Perrimon, 2006; Nystul and Spradling, 2007; Ohlstein and Spradling, 2006; Singh et al., 2007).
Within mammalian tissues, uptake and long-term retention of bromo-deoxyuridine (BrdU) or incorporation of fluorescently labeled histone H2B during DNA synthesis have been used as a marker for slowly cycling ("label-retaining") putative stem cells. However, improved lineage-tracing strategies utilizing Cre re-combinase have facilitated locating stem/progenitor cell populations in vivo (Table 1), providing insight into ongoing debates regarding the nature of stem cell populations within tissues such as the digestive system and skin.
For example, intestinal stem cells in mammals had been proposed to reside at the +4 position (four cells above Paneth cells), based on the observation that these cells incorporated and retained BrdU (Potten et al., 1974). However, recent lineage-tracing analysis and in vitro culturing techniques provided convincing evidence that crypt base columnar cells (CBCs) that express leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) behave as stem cells in intestinal crypts (Barker et al., 2007; Sato et al., 2009). In the murine small intestine, CBCs are intercalated between Paneth cells and are in direct contact with a basement membrane at the base of the intestinal crypt (Chang et al., 1974).
Using a Cre-inducible knockin allele of Lgr5, lineage tracing demonstrated that Lgr5+ cells were responsible for the maintenance of the entire villus and capable of long term (>12 month) self-renewal (Barker et al., 2007). In addition, single dissociated Lgr5+ crypt cells cultured in vitro generated cryptvillus organoid structures resembling intestinal epithelium and contained the appropriate differentiated cell types (Sato et al., 2009). Lgr5 is a Wnt target gene, and components of the Wnt signaling pathway are required for intestinal stem cell maintenance (Korinek et al., 1998). Mutations in APC or β-catenin are sufficient to induce colon carcinoma (Korinek et al., 1997), and deletion of Apc in Lgr5+ cells specifically led to transformation within days, suggesting that Lgr5+ CBC cells are a likely cell-of-origin of intestinal cancer (Barker et al., 2009). However, lineage-tracing analysis using a Cre-Bmi1 strategy supported the +4 position as another putative position for stem cells (Sangiorgi and Capecchi, 2008). Bmi1 and Lgr5 label cells at different locations within the intestinal crypts with distinct cellular morphologies; therefore, it is possible that these cell types may constitute overlapping stem cell populations.
It was long assumed that neighboring myofibroblasts acted as support cells within the crypts to provide a stromal niche for the intestinal stem cells. However, the ability of isolated stem cells to generate organized, crypt-like structures in vitro suggests that the stem cells are not absolutely dependent upon these fibro-blasts for maintenance (Sato et al., 2009). Given the proximity of Paneth cells to Lgr5+ CBC cells and the fact that they are a likely source of Wnt (Gregorieff et al., 2005), this cell type could easily act to support the adjacent stem cell population. If so, the ability of CBC cells to generate differentiated cells that then act as a niche component (Sato et al., 2009) would be similar to ability of somatic stem cells in the Drosophila testis, which give rise to differentiated cells that are an integral component of the testis niche (Voog et al., 2008). As Lgr5 appears to be a marker for epithelial stem cells in a number of tissues (Barker et al., 2010; Jaks et al., 2008), it will be interesting to determine whether cells that are functionally equivalent to Paneth cells exist within these niches.
Genetic labeling experiments have also aided in the identification of stem cell populations within the skin. The epidermis, hair follicles, and sebaceous glands are maintained by stem cell populations that reside in at least three distinct microenvironments: the basal layer of the interfollicular epidermis (IFE), the follicular bulge, and the base of the sebaceous gland. Epidermal stem cells in the IFE, which normally contribute to epidermal homeostasis, reside in nests near the basement membrane (Jones and Watt, 1993) and have been identified using clonal marking strategies (Clayton et al., 2007; Ghazizadeh and Taichman, 2005). The complete nature of the epidermal niche is not known, although the basement membrane likely provides positional information and proliferative cues (Lechler and Fuchs, 2005).
Stem cells residing in the bulge region of the outer root sheath of the hair follicle have been identified using long-term label retention (Cotsarelis et al., 1990; Tumbar et al., 2004) and lineage-tracing strategies (Jaks et al., 2008; Levy et al., 2005; Nowak et al., 2008; Zhang et al., 2009). These slow-cycling stem cells are specified early in development and are capable of contributing to the epidermis upon injury, as well as the sebaceous gland (Nowak et al., 2008). Based on molecular markers and proliferation capacity, bulge-derived stem cells are distinct from cells that reside in the hair germ (Greco et al., 2009), which are activated prior to each new hair cycle and are also capable of contributing to the bulge (Ito et al., 2004). Due to the dynamic nature of the stem cell niche in the hair follicle, both temporal (hair cycle stage or time after injury) and spatial information (location of stem cell population in relation to bulge or near wound edge) likely coordinate interactions between the distinct populations of stem cells in the bulge and hair germ (Greco et al., 2009). Dermal papilla (DP) cells are specialized, mesenchymal cells that lie at the base of the hair follicle and are marked by expression of the serine protease, Corin (Enshell-Seijffers et al., 2008). DP cells are capable of promoting hair follicle formation in skin epidermis in vitro (Jahoda et al., 1984) and clearly provide signals to activate the hair germ, as well as bulge stem cells (Greco et al., 2009); therefore, DP cells are likely a component of the hair follicle stem cell niche.
In addition to lineage tracing strategies, single-cell transplantation assays have confirmed stem cell identity and function in a number of tissues (Table 1). Isolation of prospective stem cells is accomplished using fluorescence-activated cell sorting (FACS) based upon expression of cell surface marker combinations and/or dye-exclusion properties, followed by transplantation of these cells into live tissues, typically manipulated so as to be devoid of endogenous stem cells. The fluid nature of the hematopoietic system has aided in the isolation of hematopoietic stem cells (HSC) that can be identified by numerous cell surface markers (Wilson et al., 2008) (reviewed in Wagers, 2005; Weissman et al., 2001). However, isolation of cells by FACS in conjunction with transplantation has also led to the identification of stem cells from solid tissues, including those from testis, muscle, breast, and prostate (Cerletti et al., 2008; Lawson et al., 2007; Leong et al., 2008; Shackleton et al., 2006; Sherwood et al., 2004; Shinohara et al., 2000; Stingl et al., 2006). Thus, optimized techniques for the isolation and characterization of putative stem cell populations have confirmed the multilineage differentiation capacity of stem cells at single-cell resolution, as well as shed light on the environmental influences that regulate their behavior.
Given the dynamic nature of the stem cell-niche relationship, the ability to continuously observe and analyze stem cell behavior in vivo, rather than at specific time points in fixed specimens, is essential for understanding the regulation of stem cell behavior by the niche (Rieger et al., 2009; Rieger and Schroeder, 2008) (reviewed in Schroeder, 2008). Advanced imaging strategies, enhanced fluorescent probes, and increased data analysis methods have given the field unprecedented access to observe the dynamics of stem cell behavior in a number of systems. For example, within the well-defined stem cell niche of the Drosophila gonad, time lapse imaging in explanted Drosophila testes have complemented observations that proper orientation of the mitotic spindle within GSCs is essential for asymmetric division of male GSCs (Cheng et al., 2008; Sheng et al., 2009; Yamashita et al., 2007). Asymmetric localization/inheritance of cell-fate determinants and niche support cells have also been visualized live in Drosophila ovaries and neuroblasts (Cabernard and Doe, 2009; Fichelson et al., 2009).
Much like lineage-tracing strategies, improved live imaging techniques have also provided direct evidence to support established hypotheses regarding the behavior of mammalian stem cells. Insight into cell types capable of influencing both adult hematopoietic stem/progenitor cells (HSPCs) and leukemic cells has been provided by elegant intravital microscopy studies using two-photon video imaging and high-resolution confocal optics (Lo Celso et al., 2009; Sipkins et al., 2005; Xie et al., 2009). Live imaging within the mouse calvarium indicated that HSPCs reside within perivascular sites near osteoblasts in close contact with endothelial vasculature. In these studies, HSPCs were observed to localize significantly closer to osteoblasts that constitutively express the PPR (parathyroid hormone/parathyroid hormone related peptide receptor), confirming that extrinsic factors are capable of regulating HSC/progenitor behavior (Arai et al., 2004; Calvi et al., 2003; Deneault et al., 2009; Essers et al., 2009; Zhang et al., 2003) (reviewed in Garrett and Emerson, 2009).
Within the murine testis, spermatogonia lie along the basement membrane of the seminiferous tubules and are in close contact with Sertoli cells (Tegelenbosch and de Rooij, 1993). Specific markers for spermatogonial stem cells (SSCs) do not currently exist, although a subset of undifferentiated spermatogonia (Aundiff) that express glial cell line-derived neurotrophic factor (GDNF) family receptor 1α and Nanos2 may be enriched for SSCs (Suzuki et al., 2009). In addition, Neurogenin3 (Ngn3+) has been used as a marker for (Aundiff) spermatogonia, which can be functionally identified via transplantation or colony forming assays (Nakagawa et al., 2007). Insights from time-lapse microscopy followed by three-dimensional reconstruction have provided an unprecedented view into putative SSC niches within the mouse testis. Here, Ngn3-GFP+ Aundiff spermatogonia preferentially localized to sites where vasculature lies close to adjacent seminiferous tubules (Yoshida et al., 2007). Signals from neighboring interstitial cells and vasculature likely influence SSCs within the Aundiff spermatogonial population, as differentiating spermatogonia migrate along the basement membrane away from localized regions of branching vessels (Yoshida et al., 2007). In addition, alterations in the vasculature due to surgical transplantation resulted in a relocalization of Aundiff, spermatogonia providing strong in vivo evidence that the putative SSC niche in the testis is remarkably flexible.
Vasculature has been implicated as contributing to the stem cell niche in other tissues, including the hematopoietic system (Kiel et al., 2005; Sugiyama et al., 2006) and regions of the hippocampus and lateral ventricles of the brain (Palmer et al., 2000; Shen et al., 2004, 2008; Tavazoie et al., 2008; Wurmser et al., 2004). Therefore, the vasculature may serve a conserved support role for stem cells throughout the body. In addition to providing key nutrients, the ability of the vasculature to provide circulating, systemic factors that regulate stem cells and/or the niche would provide a mechanism to coordinate stem cell activity in dynamic fashion in response to metabolic flux or other whole-organism changes, such as aging (Conboy et al., 2005; Mayack et al., 2010; Ryu et al., 2006).
Paramount to niche characterization are sensitive and specific tools to perturb and monitor stem cell activity and niche function to determine causal relationships. Experimental gain- and loss-of-function studies in cell types likely to influence stem cell behavior are necessary to rigorously define the niche. Two general classes of stem cell niches have been proposed based on the physical relationship of stem cells with neighboring niche components (Morrison and Spradling, 2008). Stromal niches can be thought of as discrete anatomical sites containing niche support cells that physically contact adjacent stem cells and influence stem cell behavior via close range signaling (e.g., Drosophila germline stem cell niches). In contrast, epithelial niches are depicted as those that lack specific niche support cells and typically consist of stem cells directly in contact with a basement membrane, as well as more mature cells of the lineage (e.g., mammalian muscle fiber). Monitoring niche size and function after genetic manipulation or after tissue injury suggest that both spatial and temporal restrictions regulate the activity and number of niches.
Laser ablation of the distal tip cell (DTC) in the C. elegans gonad resulted in loss of adjacent germline stem cells, indicating that the DTC is required for niche function (Kimble, 1981). Subsequent genetic analysis demonstrated that short range signaling via the Notch pathway from the DTC is a key molecular determinant of regulating stem cell behavior within this stromal niche (Austin and Kimble, 1987; Henderson et al., 1994). Interestingly, work in this model has revealed the presence of cells that can support germ line proliferation that are not normally found in contact with the stem cell population (McGovern et al., 2009). The presence of such a "latent niche" is quite provocative, as it presents an interesting model for investigating how distant niches could provide an environment conducive to stem cell maintenance and proliferation, such as in the case of metastasis.
In the Drosophila ovary, germline stem cells (GSCs) directly contact somatic cells, known as cap cells, which act as key support cells by secreting the self-renewal factor Decapentaplegic (Dpp) (Xie and Spradling, 1998, 2000). Notch signaling from the germ line to the soma influences the number of cap cells, and hyperactivation of Notch signaling leads to an increase in the number of cap cells with a concomitant expansion of GSCs (Song et al., 2007; Ward et al., 2006). In addition to directing the symmetric division of stem cells to maintain full occupancy of the niche (Xie and Spradling, 2000), the GSC niche is competent to direct the proliferation of nearby somatic stem cells that enter the niche upon depletion of endogenous GSCs. These data indicate that empty niches can regulate the behavior of "foreign" stem cells not normally found in that location (Kai and Spradling, 2003). Furthermore, GSCs that are unable to differentiate can outcompete normal GSCs for niche occupancy (Jin et al., 2008). Such findings underscore the flexibility of niche size and function and present an intriguing model for how stem cells that have accumulated mutations over time may evolve to predominate in their endogenous niche or thrive in distant niches in other tissues.
In the Drosophila testis, a cluster of 10–15 somatic support cells, known as the hub, contribute significantly to the stem cell niche in the testis (Kiger et al., 2001; Tulina and Matunis, 2001). Hub cells are specified during development (Boyle and DiNardo, 1995; Le Bras and Van Doren, 2006) and are maintained by an adjacent population of pluripotent somatic stem cells (Voog et al., 2008). Absence or depletion of GSCs during development leads to proliferation of the somatic stem cells, which appear to take on hub characteristics (Flatt et al., 2008; Gönczy and DiNardo, 1996), suggesting that the germ line may negatively regulate somatic stem cell proliferation, thereby influencing formation of the niche during development. Consistent with a role in hub maintenance, loss of the somatic stem cells led to subsequent loss of the hub and adjacent GSCs, providing indirect evidence that the hub is indeed necessary for promoting GSC maintenance (Voog et al., 2008). In addition, the adult testis niche is competent to support the dedifferentiation of spermatogonia into self-renewing stem cells to facilitate stem cell replacement, providing another paradigm for how niches may function in normal tissue homeostasis or endow differentiated cells with self-renewal capacity (Brawley and Matunis, 2004; Cheng et al., 2008; Sheng et al., 2009).
Gain and loss-of-function studies have indicated that mammalian hematopoietic stem/progenitor cells (HSPCs) receive inputs from multiple sources, including endosteal, endothelial, and advential cells, as well as adipocytes (Adams et al., 2006; Calvi et al., 2003; Essers et al., 2009; Fleming et al., 2008; Katayama et al., 2006; Naveiras et al., 2009; Stier et al., 2005; Sugiyama et al., 2006; Zhang et al., 2003). Directed expression of parathyroid hormone receptor (PTH) or deletion of BMPR1α specifically in osteoblasts led to an expansion of osteoblasts and a corresponding increase in putative HSCs, providing evidence that osteoblasts may be a crucial support cell within the HSC niche in the bone marrow (Calvi et al., 2003; Zhang et al., 2003). Consistent with this model, selective ablation of osteoblasts using a collagen α1 type I (Col1α1) promoter to express thymidine kinase resulted in a dramatic loss of bone marrow cellularity and loss of HPSCs (Visnjic et al., 2004). In contrast, biglycan-deficient mice that have reduced osteoblast populations showed no defects in hematopoiesis, HSC frequency, or function, indicating that fewer osteoblasts do not necessarily lead to reductions in HSCs (Kiel et al., 2007). As discussed above, the vasculature also contributes to the hematopoietic niche in the bone marrow, as putative HSCs clearly associate with sinusoidal endothelium, in addition to the endosteum (Kiel et al., 2005). Therefore, the hematopoietic niche includes several types of support cells that are involved in regulating HSC behavior; however, the degree to which each contributes under normal or pathological conditions or during transplantation is not clear (reviewed in Garrett and Emerson, 2009).
Radiation and cytotoxic therapies result in concomitant loss of hematopoietic, endothelial, and osteoblastic cells (Amsel and Dell, 1971; Shirota and Tavassoli, 1991). Recovery of HSPCs is dependent upon angiogenic and osteoblastic regeneration. Sinusoidal endothelial cells, which express VEGFR2/3 and are lost during radiation-induced injury, are capable of regeneration and necessary for the recruitment and maintenance of HSC pools (Hooper et al., 2009). Conditional deletion of VEGFR2 within endothelial cells resulted in inefficient sinusodial endothelial cell regeneration and hematopoietic recovery. Similarly, restoration and reversible expansion of the osteoblastic niche was observed after total body irradiation due, in part, to proliferation of osteoblasts with subsequent hematopoietic recovery (Dominici et al., 2009). Upon injury, megakaryocytes were found in close contact with osteoblasts and could facilitate osteoblast expansion/recovery through the production of TGF-β1 and PDGF-β (Dominici et al., 2009). In addition, genetic and in vitro studies have identified the chemokine CXCL12 (SDF-1), and its cognate receptor CXCR4, as important components that regulate neovascularization, mobilization of hematopoietic cells, and survival of megakaryocytes and osteoblast progenitors (Hodohara et al., 2000; Jin et al., 2006; Kortesidis et al., 2005). Conditional ablation of CXCL12 (and a host of other HSPC maintenance factors) from vascular and endosteal cells would be needed before definitive conclusions can be drawn regarding the dynamic nature of the hematopoietic niche. However, interactions between both vascular and endosteal niches are likely necessary for proper hematopoietic function and recovery.
Intestinal stem cells (ISCs) in the Drosophila midgut were originally identified using lineage-tracing strategies and are a prototypical example of stem cells that reside within an epithelial niche (Micchelli and Perrimon, 2006; Ohlstein and Spradling, 2006). ISCs reside along the basement membrane within clusters, or "nests," of 2 to 3 basally located diploid cells, including daughter enteroblasts, that are interspersed between differentiated, polyploid enterocytes. Although all cells in the stem cell-containing nests are positive for the transcription factor Escargot, only the ISC directly contacts the basement membrane and stains positive for the Notch ligand Delta, whereas Notch signaling is activated exclusively in the daughter enteroblast (Micchelli and Perrimon, 2006; Ohlstein and Spradling, 2007).
In response to intestinal injury, stress, or aging, ISC division rate increases (Amcheslavsky et al., 2009; Biteau et al., 2008; Choi et al., 2008; Jiang et al., 2009). Interestingly, facultative stem cells within the Drosophila hindgut also appear to be able to respond to damage to mediate tissue homeostasis (Fox and Spradling, 2009). Recent evidence indicated that differentiated enterocytes signal via the JAK-Stat pathway to stimulate proliferation of ISCs (Jiang et al., 2009; Beebe et al., 2010). Intestinal cell death due to apoptosis, stress, or infection was sufficient to induce the expression of the JAK-STAT ligands Upd/Upd2/Upd3, which stimulated both ISC division and enteroblast differentiation (Jiang et al., 2009). Therefore, signaling from lineage-related differentiated cells to initiate or accelerate stem cell division only when replacement cells are needed may serve as a niche-based mechanism to maintain tissue homeostasis and repair (Figure 2).
Satellite cells (~5% of adult muscle nuclei) are mononuclear cells that reside adjacent to the muscle fiber and are enclosed by basal lamina (Mauro, 1961). Satellite cells represent a heterogeneous population of cells from which skeletal muscle precursors (SMPs) can be isolated based on expression of cell surface markers followed by FACS (Cerletti et al., 2008; Kuang et al., 2007; Sherwood et al., 2004). SMP identity and function has been confirmed based on transplantation assays, which demonstrate the ability of transplanted SMPs to contribute to and repair damaged muscle fibers and replenish the satellite cell pool (Cerletti et al., 2008; Collins et al., 2005; Sacco et al., 2008).
Notch signaling regulates mammalian satellite cell behavior postnatally and in response to injury (Conboy and Rando, 2002). Increases in expression of Delta in myofibers results in satellite cell/muscle stem cell proliferation. In older animals, satellite cells maintain expression of Notch; however, Delta expression is reduced (Conboy et al., 2003). Direct activation of Notch in injured muscle or exposure to young serum via parabiosis with a young animal is sufficient to enhance muscle regeneration (Conboy et al., 2003; Conboy et al., 2005), suggesting that the loss (or gain) of an age-specific systemic factor(s) is responsible for inefficient repair in aged animals. Additional inputs, including Wnt (Brack et al., 2007) and TGF-β (Carlson et al., 2008) signaling, may also regulate the ability of aged satellite cells to respond to Notch and participate in repair of injured muscle fibers. In mammalian muscle, satellite cells proliferate in response to myofiber ablation, suggesting that mature muscle fibers may act as a local niche to regulate satellite cell proliferation (Bischoff, 1990), similar to the way in which enterocytes regulate the proliferation of Drosophila ISCs (Figure 2). The prominent role for differentiated cells in regulating the behavior of nearby stem cells may prove to be prevalent in tissues for which stem cells are involved in acute repair, rather than continual tissue replacement.
In contrast to adult muscle regeneration, early developmental processes are recapitulated to guide tissue and niche regeneration of the epidermis and associated appendages. During normal skin homeostasis, bulge stem cells do not contribute to the epidermis. However, upon injury, bulge stem cells migrate, proliferate, and aid in epidermal regeneration transiently (Ito et al., 2005; Levy et al., 2007; Nowak et al., 2008). Similarly, during wound repair, de novo hair follicle regeneration has been observed that closely parallels embryonic hair development based on the expression profiles of molecular markers and involvement of Wnt signaling (Ito et al., 2007). Using a Cre-inducible Keratin15 labeling strategy, nascent hair follicles and newly generated bulge stem cells were observed to descend from the epidermis and/or upper region of the follicle (Figure 2). These data demonstrated that new stem cell niches could be generated during adulthood. The ability of resident stem cell populations in the epidermis and bulge to adjust fate decisions in the context of wounding suggests that these cells may be exposed to and molecularly competent to interpret alternative nonhomeostatic niche signals to orchestrate appropriate regeneration programs. Therefore, current models suggest that the niche can direct tissue repair via reiteration of developmental programs that specify or expand stem cells, such as Wnt-mediated repair of the epidermis, or distinct adult-specific genetic programs, such as positive feed-forward signals from differentiated cells, to stimulate stem cell proliferation. Regardless, the factors that regulate the transient generation and regression of facultative niches or alert endogenous niches to tissue damage may also be inappropriately utilized in the progression of some pathologies.
As discussed above, the dynamic relationship between stem cells and the niche may be most evident during tissue repair, as a consequence of injury. However, constitutive activation of wound healing programs, including accompanying inflammatory responses, likely lead to permanent changes in the niche that could lead to dysregulation of stem cell behavior and, ultimately, contribute to disease. However, a thorough assessment of the role of the niche in disease initiation and progression is dependent upon a clear understanding of the normal structural and molecular components that constitute each stem cell niche.
Although cell-autonomous changes clearly underlie altered stem cell behavior during aging, recent studies have demonstrated that a decline in niche function, including decreased production of local self-renewal factors, also contributes to reduced tissue homeostasis and repair in a number of systems (Boyle et al., 2007; Conboy et al., 2003; Hsu and Drummond-Barbosa, 2009; Pan et al., 2007; Ryu et al., 2006). In addition, changes in circulating, systemic factors also lead to decreased stem cell activity (Conboy et al., 2003; Hsu and Drummond-Barbosa, 2009; Mayack et al., 2010). However, restoration of niche function can counter aging-related changes in stem cell behavior (Boyle et al., 2007; Conboy et al., 2005; Mayack et al., 2010; Pan et al., 2007), indicating that strategies to rejuvenate or expand the niche may enhance stem cell-based therapies in regenerative medicine.
Aging may be perceived as systemic stress; however, the changes in stem cell-niche cell relationships in older animals could also be a consequence of chronic damage and wound repair. For example, wounding, infection, and aging all lead to an increase in ISC proliferation in the Drosophila midgut. During aging, normal stress response pathways are engaged; however, the ability of the daughter enteroblasts to differentiate appropriately into enterocytes or enteroendocrine cells, which is regulated by the Notch pathway, is disrupted (Biteau et al., 2008; Ohlstein and Spradling, 2007). The insulin-signaling pathway has been shown to regulate the proliferation of ISCs in response to intestinal damage (Amcheslavsky et al., 2009), as well as aging of the Drosophila ovarian niche, by modifying Notch function in support cells (Hsu and Drummond-Barbosa, 2009). Thus, it is possible that changes in the integration of systemic signals with local signaling pathways elicit different stem cell responses to normal stress and aging.
Recent insights into mechanisms involved in regulating stem cell behavior can be directly applied to the study of cancer biology, including the role of the niche. Involvement of the local microenvironment in tumor initiation or metastasis has been postulated for over 100 years (Paget, 1889). Similar to the manner in which support cells, secreted factors, the extracellular matrix, and vasculature all contribute to the regulation of stem cell behavior, analogous components are easily identified in the tumor microenvironment. Irrespective of whether the tumor-initiating cell is a transformed tissue stem cell or a differentiated cell that has acquired the ability to self-renew, the local microenvironment could influence cancer initiation through a number of mechanisms.
Experimental evidence has demonstrated that normal niches can support the reversion of differentiated cells back to a stem cell state (Brawley and Matunis, 2004; Cheng et al., 2008; Kai and Spradling, 2004; Sheng et al., 2009) and can become occupied by cells that outcompete normal stem cells for residence (Issigonis et al., 2009; Jin et al., 2008). In addition, niches can undergo changes that promote proliferation and maintenance of cancer cells (reviewed in Coussens and Werb, 2002; Tlsty and Coussens, 2006). "Premetastatic" niches can be generated by cancer cell proliferation or tumor-released factors that are capable of supporting the seeding and proliferation of migratory tumor-initiating cells in secondary and tertiary sites (reviewed in Wels et al., 2008). Lastly, wound healing or morphological damage can result in cells positioned near a signaling source that inappropriately directs proliferation (Kai and Spradling, 2003; McGovern et al., 2009) (Figure 3).
Basal cell carcinoma (BCC) is the most common cancer in the United States (800,000 cases/year). BCC can be recapitulated in transgenic human explants that overexpress Sonic Hedgehog in keratinocytes, and stroma associated with human BCC is critical for tumor progression (Fan et al., 1997; Van Scott and Reinertson, 1961). Within murine skin, signaling via the Bone Morphogenetic Protein (BMP) pathway is required for proper progenitor cell differentiation (Kobielak et al., 2003), and BCC cells express high levels of BMPs 2 and 4 (Sneddon et al., 2006). However, transcriptional profiling of human BCCs also demonstrated that the underlying tumor stroma expressed high levels of the BMP antagonist Gremlin1 de novo, which would block differentiation of the adjacent tumor cells (Sneddon et al., 2006). Isolation and culture of BCCs demonstrated that Gremlin1 suppresses BMP-mediated keratinocyte differentiation, suggesting that Gremlin1 expression promotes BCC proliferation in a localized, transformed niche (Sneddon et al., 2006).
Similarly, in invasive breast carcinomas, cancer-associated fibroblasts (CAFs) and the underlying stroma clearly promote tumor initiation and progression (Finak et al., 2008; Hu et al., 2008) (reviewed in Bissell, 2007). For example, expression of CXCL12 (SDF-1) by breast cancer-associated CAFs acts directly on the CXCR4 receptor expressed by the breast cancer cells and induces angiogenesis through the recruitment of endothelial progenitor cells (Orimo et al., 2005). CAFs phenotypically resemble myofibroblasts, cell types often associated with wound healing and tissue remodeling. While the origins of tumor-associated stroma and fibroblasts are not completely understood, genetic factors and a chronic inflammatory environment can contribute to the generation of a modified niche that supports tumor growth (Coppé et al., 2008; Rodier et al., 2009; Sneddon et al., 2006; Trimboli et al., 2009) (reviewed in Coussens and Werb, 2002; Tlsty and Coussens, 2006).
In addition to transformed niches that may influence a primary tumor, genetic approaches have identified niches induced by primary tumors located at distant sites within the body. Soluble factors secreted from primary tumors can induce "premetastatic" niches capable of recruiting cells that subsequently promote tumorigenesis at defined anatomical locations (reviewed in Wels et al., 2008). Factors such as VEGFA, TGFβ, and TNFα, which are secreted from primary tumors, can recruit support cells to and induce expression of inflammatory chemoattractants within tumor-specific premetastatic sites to facilitate the formation of secondary and tertiary tumors (Hiratsuka et al., 2006; Kaplan et al., 2005). Tumor-induced niches have also been shown to recruit normal progenitor cells and affect normal progenitor cell behavior in a leukemic xenograph mouse model. Intravital microscopy studies of Nalm-6 pre-B acute lymphoblastic leukemia (ALL) demonstrated that malignant cells metastasize to specific regions of the bone marrow that express CXCL12 (SDF-1) (Sipkins et al., 2005). In addition, leukemic cell proliferation resulted in the generation of malignant niches that downregulated CXCL12 (SDF-1) production and recruited normal hematopoietic progenitor (CD34+) cells. These malignant niches had high levels of stem cell factor (SCF) and negatively affected normal (CD34+) progenitor cell number and activity (Colmone et al., 2008).
The origin of a cancer cell and its internal transcriptional signature are important determinants of site-specific metastasis (Bos et al., 2009). Access to circulation and the ability to survive at distant locations also influence the metastatic potential of cancer cells (reviewed in Nguyen et al., 2009). To this end, certain cancer cell types appear to be capable of utilizing endogenous niches or aiding in the generation of malignant niches that can influence both normal and cancerous cells. Therefore, malignant niches may act as immune-evasive or antiapoptotic sanctuaries that harbor tumor-initiating cells throughout the course of standard therapeutic treatments.
Stem cell niches are physiologically dynamic domains that will continue to aid in both experimental and conceptual models of development, tissue maintenance, and disease. The stem cell niche hypothesis provided an initial framework within which to define cell types and factors responsible for regulating stem cell behavior, and advances in lineage-tracing techniques, single cell isolation and manipulation, and imaging technologies will continue to expand our knowledge of the nature of stem cell-niche cell interactions. A symbiotic relationship is present within the niche under homeostatic conditions; however, the involvement of the stem cell niche in the response to tissue injury and during aging and disease progression is less well understood. Additional work in the identification of genetic factors that regulate the formation, activity, and size of stem cell niches will be necessary in order to incorporate the niche into stem cell-based therapies and regenerative medicine. Furthermore, in cases where a modified niche accompanies disease progression, targeting the niche (niche ablation) could be considered an alternative, powerful therapeutic approach to accompany current drug regimes and treatments.
We would like to thank V. Greco, A. Wagers, and three anonymous reviewers for comments on the manuscript, and we apologize to those colleagues whose work could not be referenced directly due to space constraints. D.L.J. is funded by the ACS, NIH, CIRM, the Emerald Foundation, and the G. Harold and Leila Y. Mathers Charitable Foundation.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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