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J. Clin. Med. 2013, 2(4), 220-241; https://doi.org/10.3390/jcm2040220
An Update on Translating Stem Cell Therapy for Stroke from Bench to Bedside
Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 29 August 2013; in revised form: 16 September 2013 / Accepted: 21 September 2013 / Published: 1 November 2013
With a constellation of stem cell sources available, researchers hope to utilize their potential for cellular repair as a therapeutic target for disease. However, many lab-to-clinic translational considerations must be given in determining their efficacy, variables such as the host response, effects on native tissue, and potential for generating tumors. This review will discuss the current knowledge of stem cell research in neurological disease, mainly stroke, with a focus on the benefits, limitations, and clinical potential.
Keywords:stem cells; stroke; transplantation; translational biomedical research
1. Translational Gating Items of Stem Cell Therapy
With the increasing diversity of stem cell sources emerging for donor cells in transplantation therapy, many laboratory-to-clinic translational factors must first be considered, dynamics such as the source of the cells, ease of extraction, immunogenicity, capacity for proliferation, and cell yield. These concerns may serve as potential limitations respective to the donor cell origin being considered, proving a particular source to be a more suitable therapy for a specific disease.
Harvesting of stem cells may be divided into two domains, allogenic vs. autologous sources (though xenogeneic cells have been previously tested). Autologous stem cells are acquired from the host in which the cells are intended for use, while allogenic cells are procured from an unrelated donor prior to transplantation. As one may expect, the use of allogenic stem cells may predispose an individual to various immunologic complications upon treatment, giving rise to the significant limitation of graft rejection with this method of treatment. Yet, autologous treatments may be limited by their ability for propagation and cell yield.
The immunological barriers, such as graft vs. host or required immunosuppression of the host, are of constant consideration in the therapeutic benefits and limitations of stem cell transplantation. Prior research of immunocompromised stroke animals demonstrated inhibition neurogenesis in the cortex endogenously via a CD4+ T cell, but not CD25+ T cell mechanism, supporting the influence of immunodeficiency in reducing stem cell apoptosis [1]. In another study, upon exposure to cyclosporine A, an immunosuppressant, there was enhanced recovery of cortical injury following stroke secondary to endogenous stem cell activity and migration [2]. These papers support the hypothesis that inflammation following a cerebral event may not only damage tissue, but also further disrupt the endogenous neurogenic pathways of repair involving the migration of stem cells from the lateral ventricle regions of the brain, a topic further discussed in the neural stem cell section. This contrasts the proposed mechanism of action for neurotrophic modulators that are believed to furnish a microenvironment conducive to repair, but do not yield new neurons [2].
Because of the potential immunological host response to the transplanted cells, much research has been conducted investigating specific cell line's prospective immunogenicity. Surmounting evidence suggests that the more naive the cell lineage, the less likely the incidence of immunological reaction following transplantation. For instance, umbilical cord blood, due to its immunological immaturity, is less likely to invoke an immunological response and therefore less likely to require immunosuppression. More so, human leukocyte antigen (HLA) matching may be less stringent in umbilical cord blood transplants compared to bone marrow derived transplants and even whole tissue grafts, leading to higher cell viability [3]. Contrasting immunogenicity, some cell lineages may be more immunosuppressive than bone marrow derived stem cells. HLA-G, a contributing factor of immunosuppression [4], is of higher expression in chorionic plate-derived mesenchymal stem cells compared to bone marrow-derived stem cells and adipocyte tissue-derived mesenchymal stem cells [5], suggesting its usefulness as a prognostic indicator of transplant viability in the presence of host immunity [6]. Additionally, placenta-derived mesenchymal stem cells demonstrate less immunomodulation than bone marrow-derived mesenchymal stem cells, suggesting regenerative transplantation potential to be less efficacious [7].
2. Tailoring Stem Cells for Therapeutic Applications in Stroke
Stroke is a major unmet clinical need with only one current Food and Drug Administration (FDA)-approved drug, the tissue plasminogen activator, efficacy limited to 4.5 h after stroke onset. Accordingly, the challenges of proliferation capacity and cell yield are evident with regards to the optimum delivery time of stem cell therapy. With the current clinical trials of cell therapy for acute stroke mostly targeting a window of 48 h, the potential limitation in generating a sufficient number of autologous cells from freshly harvested tissue for therapy in such a short period is apparent [8]. In view of this limitation, allogeneic transplantation is indicated when contemplating with acute stroke therapy. Alternatively, the extended time required for cell amplification with autologous stem cell transplantation renders it more appropriate for chronic stroke therapy. Nonetheless, regardless of autologous or allogeneic stem cell sources, cell harvesting imparts additional technical challenges. For example, acquiring neural stem cells may require invasive procedures that may be disadvantageous despite the therapeutic potential of the cells.
The following sections aim to outline the different tissue sources available for harvesting stem cells, along with their respective benefits, limitations, and prospective use in clinical application as they pertain mainly to neurological diseases, most notably stroke therapy. A review of current stem cells being investigated in neurorestoration has recently been published [9]. We only briefly discuss embryonic and extraembryonic stem cells and focus this paper on our long-standing research interest in adult stem cells.
3. Searching for Safe and Effective Stem Cell Therapy
Embryonic stem cells are pluripotent cells derived from the inner cell mass of the blastocyst that arguably serve as the foundation by which the properties of "stemness" are measured in other cell lines. With the potential to differentiate into all three germ layers, transplantation of embryonic stem cells (ESCs) into animal stroke models has demonstrated repair in both vascular [10] and neuronal damage [11], improved functional recovery of deficits [12,13,14,15,16] and provision of neurotrophic, angiogenic, and anti-apoptotic effects [13,14,15,16,17]. These benefits may extend well into potential translational therapy following a cerebral event, giving the cell line a plentiful array of therapeutic actions in terms of modulating a number of diseases including stroke. The distribution of these cells has been demonstrated with imaging techniques in both the brain and the periphery following transplantation in animal stroke models [18,19]. Although ESCs possess the potential for vast differentiation, there are two predominant concerns limiting their use. The ethics of harvesting embryonic stem cells is widely debated. However, recent advancements, discussed later in this review, may further develop and refine methods for producing these cells through retrograde manipulation of mature cell lines, alleviating some of the tension surrounding their use. Additionally, their naive lineage aligns with the stem cell tenet of the more naive the cell, the greater the potential for tumorigenicity, a topic that will be expanded upon in subsequent sections. Stem cells have the potential to form tumors after transplantation. This tumorigenicity is mostly associated with embryonic stem cells and pluripotent stem (iPS) cells [20]. Shortly after transplantation, a dysregulated differentiation of ESCs was found to cause the formation of teratomas containing all types of somatic tissues of the early embryo [21], due likely to the presence of oncogenes and trisomies which are known to have roles in cancer cell formation [22]. In view of this stem cell tumorigenicity, strategies have been explored including predifferentiation of cells to remove stemness or genetic modification to activate anti-oncogenic genes such as Nurr1 to abrogate the neoplastic state or render the cells post-mitotic [23,24]. While this tumorigenicity has been closely associated with ESCs and iPS cells, recent evidence suggests that safety precautions should also be taken with adult stem cells due to possible ectopic tissue formation seen in grafted mesenchymal stem cells (MSCs) in the Central Nervous System (CNS) [25]. These studies highlight a major hurdle in stem cell therapy, and emphasize the importance of closely monitoring stemness and tumorigenicity as we translate cell therapy to the clinic [22,24,26].
With the concerns surrounding the use of embryonic tissue to harvest stem cells, researchers have looked to sources external to the embryo to harvest stem cells. Wharton's jelly (within the umbilical cord), amnion, placenta, and umbilical cord are all rich stem cell sources [27]. As seen with the neural stem cells and mesenchymal stromal cells, extraembryonic stem cells also relate to different germinal layers. The amniotic epithelium is of ectoderm origin while the amnion-derived mesenchymal stromal cells are derived from the mesoderm [28]. Yet, the amnion-derived mesenchymal stromal cells exhibit less endothelial propensity conferring cell specificity [29]. Transplantation of placenta-derived mesenchymal stromal cells in animal models of stroke are believed to supply a microenvironment favorable for endogenous neural repair and replace damaged tissue [30,31,32]. Mesenchymal stromal cells derived from umbilical cord lining develop an immunosuppressive effect while demonstrating functional recovery, increased vascular density, increased expression of vascular endothelial growth factor, and basic fibroblast growth factor in rat stroke models [33,34].
Adult stem cells often exist in combination with non-stem cells committed to distinct lineage, creating a heterogeneous environment. Because of this, one challenge in the use of adult-derived stem cells is the purification for the isolation for the particular stem cell of interest. In the following sections we will discuss the variety of adult-derived stem cells (Figure 1), their tissue sources, benefits, limitations, and clinical relevance.
Figure 1. Adult stem sources include umbilical cord blood, placenta, amniotic fluid, bone marrow, menstrual blood, breast milk, dental pup, and skin fibroblasts. Most of these cells have been shown to exert neuroprotective effects in stroke animal models and a few have reached clinical trials in stroke patients.
3.1. A Stem Cell Source with a Long History of Transplant Use: Bone Marrow-Derived Stem Cells
A divergent population stem and blast cells constitute the bone marrow. Thus, these cells may be utilized as an admixture or purified upon harvesting. Emerging research demonstrates the ability of bone marrow-derived stem cells, upon injury, to mobilize from the bone marrow (BM) into the peripheral blood. This feature is very practical for harvesting cells, which is currently employed for many immunologic, hematologic, and oncologic clinical applications. With relation to stroke, once in systemic circulation they may migrate to regions of the central nervous system in response to neuronal injury [35]. Cellular components of bone marrow include: hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like stem cells (VSELs) [36]. Here we will outline the aforementioned cell lines in greater detail.
Hematopoietic stem cells are found primarily in the bone marrow where they give rise to both the myeloid and lymphoid lineages of blood cells. Cytokines produced by the CNS can incite hematopoietic stem cell mobilization into the blood, from the marrow, in response to a cerebrovascular accident (CVA) [37,38,39,40]. This mobilization may also be influenced by neurotransmitters, notably catecholamines, either through a paracrine mechanism signaling directly into the bone marrow or through systemic sympathetic release into circulation [41]. This cytokine-mediated recruitment of HSCs is applied clinically through treatment with granulocyte-colony stimulating factor [39,40].
Abundant mobilization of immature hematopoietic CD34+ colony-forming cells and Long-Term Culture-Initiating Cells (LTC-IC) has been observed from clinical data of acute stroke, with the magnitude of this mobilization correlating with recovery of function. Autologous infusions of bone marrow mononuclear cells in human stroke patients during acute, subacute, and chronic phase of stroke have demonstrated no adverse effects of transplantation [42,43,44,45]. Transplantation of HSCs into animal models of stroke has greatly elucidated the therapeutic benefits of this type of stem cell in regenerative medicine. HSCs intravenously administered were able to increase the survival rate of stroke mice, accompanied by decreased neuronal cell death, and facilitated recovery from paralysis and forelimb weakness [46]. In an effort to reveal the mechanism of action of HSC therapeutic benefit in stroke, HSCs were intravenously administered at 24 h after ischemic stroke in mice which showed grafted cell migration into the spleen and later into ischemic brain parenchyma, expressing microglial but no neural marker proteins [47]. Moreover, transplanted stroke animals displayed significantly smaller infarct volumes and less apoptotic neuronal cell death in peri-infarct areas accompanied by a reduction of invading T cells and macrophages and a downregulated proinflammatory cytokine and chemokine receptor gene transcription within the spleen [47]. These findings indicate that transplanted HSCs exert therapeutic effects in stroke possibly acting via regulation of both central and peripheral (i.e., spleen) inflammation. Bone marrow (BM) derived HSCs are also being considered as potential treatment for diseases affecting cardiovascular tissue, bone, and cartilage among other tissues.
Mesenchymal stromal cells were first isolated in bone marrow, but have since been found in nearly every tissue of the body. Here we address the therapeutic application of mesenchymal stromal cells, as well as non-bone marrow derived stem cells, for treatment of stroke.
Transplantation of mesenchymal stromal cells into stroke models induces functional recovery of neurological deficits following cerebral ischemia [48,49,50]. The limited differentiation capacity of mesenchymal stromal cells suggests that observed transplantation benefits may be afforded through activation of endogenous repair pathways by secretion of neurotrophic factors which include brain-derived neurotrophic factor (BDNF) [51], nerve growth factor (NGF) [51], vascular endothelial growth factor (VEGF) [52], basic fibroblast growth factor (bFGF, FGF-2) [52], hepatocyte growth factor (HGF) [48,53], and insulin growth factor-1 (IGF-1) [54]. MSCs may recruit primary stem cells from the subventricular and subgranular zones of the brain to the site of injury, while also dampening apoptosis in the penumbral zone of the lesion [51,52]. A clinical trial of intravenous infusion of autologous BM-derived mesenchymal stromal cells in ischemic stroke patients shows significant functional improvement in infused patients without adverse effects in comparison with non-infused patients [55]. In a long-term 5 year follow up, patients infused with mesenchymal stromal cells demonstrated increased survival rates and greater functional improvement compared to non-infused patients [56]. However, the current transplantation techniques are plagued by very low graft survival rates, and therefore, mode of delivery remains a significant limitation of mesenchymal stromal cell-based therapies for stroke [57].
Mesenchymal stem cells have recently been the focus of many research endeavors, due in large part to their accessibility when compared to other stem cells. Mesoderm-derived mesenchymal stromal cells may be extracted from almost any mesenchymal tissue of the body including: bone marrow, placenta, teeth and adipose tissue. This abundance of harvest sites makes MSCs a preferred line for autologous transplantation. However, evidence indicates that harvest location may impart a specific role to mesenchymal stromal cells as a function of various methods of extraction, isolation, and proliferation [58,59,60,61,62]. To this extent, one site of tissue derived mesenchymal stromal cells may be better qualified for a specific therapy than cells derived from another tissue site.
Despite their limited differentiation capacity and relatively transient life-span after transplantation, evidence shows that mesenchymal stromal cells promote neurogenesis following ischemic injury [52]. As mentioned previously, benefits may stem from secretion of neurotrophic factors such as BDNF and β-NGF, as well as modulation of vasculature from bone marrow, adipose tissue, skeletal muscle, and myocardium [63].
Laboratory findings indicate that neurotrophic factors are involved in the neuroprotective action of stem cells as evidenced by their trophic effects, but additionally their anti-inflammatory and anti-apoptotic effects in animal models of stroke and other neurological disorders [64,65,66]. That BDNF and NGF have been shown as consistently secreted by transplanted stem cells suggest that targeting these two trophic factors' signaling pathway may further improve the outcome of stem cell therapy. Alternatively, the combination of trophic factor treatment with stem cell transplantation may allow a more robust functional improvement in the clinic. The safety profiles of these trophic factors in the clinic in other disease indications [67,68], and the recognition of their clinical limitations, will guide the clinical trials of this combination therapy for stroke. Of note, BDNF Val(66)Met polymorphism has been implicated in worsened functional outcome in patients with subcortical stroke [69]. Similarly, serum from stroke patients revealed NGF upregulation significantly correlates with clinical and neuroradiological parameters of brain injury [70].
In addition to the many potential benefits of menchymal strem cell-based therapies mentioned above, there are also significant risk factors that must be addressed. As with many types of stem cells, the risk of mesenchymal stem cells developing into tumors must be considered. One study showed that a sarcoma developed in the lungs of mice following transplantation of mesenchymal stem cells [71]. Not only the cells themselves but also their secretions may affect tumors. Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secreted from MSCs increases the migration of breast cancer cell lines [72]. Breast cancer cells stimulate de novo secretion of the chemokine CCL5 from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion, and metastasis [73]. Accordingly, certain types of mesenchymal stem cells may demonstrate greater tendency toward tumorigenicity and promotion of metastasis.
Endothelial progenitor cells (EPCs) represent a small population of cells present in the blood that give rise to mature endothelium that lines blood vessels. While in circulation, these cells can be recruited to produce new blood vessels, a term called vasculogenesis.
The etiology of stroke is multifaceted. One contributing factor includes the compromise of vascular integrity, leaving a region vulnerable to stroke. With the endothelium regulating the permeability of the blood brain barrier (BBB), the role of endothelial progenitor cells in producing the mature lining of blood vessels is integral in maintaining cerebral homeostasis. Preliminary studies demonstrated that transplanted EPCs were integrated into newly vascularized endothelium of the hind limbs in ischemic animal models [74]. Further research specifies that BM-derived endothelial progenitor cells are likely signaled to sites of new vascularization prior to differentiation [75,76].
A correlational study in human ischemic stroke patients indicates that the level of circulating EPCs relates to improvement on the National Institute of Health Stroke Scale [77]. Animal models of stroke show that intravenous transplantation of EPCs reduces cerebral infarcts in stroke diabetic mice [78]. Moreover, EPCs can incorporate to the BBB microvasculature and delay the stroke onset in an ischemic hemorrhagic stroke model [79]. In addition, intravenous infusion of autologous EPCs after stroke in rabbits produces functional improvement, decreases number of apoptotic cells, increases microvessel density in the ischemic boundary area, and reduces infarct area [80].
The current hypothesis of very small embryonic-like stem cells is that these pluripotent stem cells are deposited early in embryonic development from an epiblast source, where they function as a reserve that can be accessed in response to physiological stress [81,82]. Investigation is underway using VSELs for stroke therapy in the brain, a region rich in VSEL phenotypic cells [83,84]. VSELs are a great candidate in therapy for cerebral vascular incident because of their potential to differentiate into neurons, oligodendrocytes, and microglia to regenerate damaged CNS [35].
However, current restrictions present a challenge in moving forward. Very small embryonic-like stem cells are present in limited quantity, producing a low yield from harvesting. Such an obstacle may be overcome with refining methods of proliferation prior to transplant [35]. An additional challenge is the decreasing population of VSELs present in older age, further contributing to the difficulty of sufficient yield upon harvesting [84].
3.2. Harvesting Neural Stem Cells for Neural Repair in Stroke
With endogenous stem cells being located in the subgranular zone (SGZ) of the dentate gyrus, the subventricular zone (SVZ), and the subependymal zone (SEZ) of the spinal cord, the therapeutic potential of NSCs for cerebrovascular accidents seems obvious. Chemokine signals such as stromal-derived factor-1 (SDF-1), vascular endothelial growth factor (VEGF), and angiopoietin are released from ischemic tissue, influencing the course of the SVZ NSCs toward a path along blood vessels to reach the infarcted area [85,86,87,88]. Although endogenous stem cells migrate to the lesion following stroke, there appears to be minimal stem cell survival [89,90,91]. This supports the hypothesis that endogenous neural stem cells may not exert their effects solely by replacement of neuronal tissue, but rather by secreting growth factors that influence repair. Immunological responses may also influence the differentiation of endogenous stem cells. In ex vivo studies, microglia from ischemic brains prompted the maturation of NSCs into neurons [92].
Although endogenous NSCs are shown to migrate in response to cellular injury, their effects may be augmented by the addition of exogenous neural stem cells. The literature describes transplantation of NSCs inducing further endogenous stem cell production at the site of injury [93,94,95,96]. However, another study suggests that intravenous infusion of neural progenitor cells decreased neurogenesis despite increasing dendritic length and the number of branch points [97]. This may further support the hypothesis of neurotrophic factors secreted from stem cells exerting a primary effect.
Neural stem cells are proven in terms of their therapeutic potential; however, they present a few significant limitations. The difficulty of obtaining the cells may be the greatest challenge. Under most circumstances, harvesting neural stem cells would require an invasive procedure for autologous use while allogenic grafts would require a fetal source or manipulation from another cell source. A possibility to circumvent this problem would be harvesting the stem cells for therapy during a surgical procedure already intended for the patient [98], such as during a temporal lobe resection in which subventricular matter, a known source of stem cells, could be harvested. As with many other stem cells, there is constant concern about the potential to illicit aberrant cell growth, producing tumors upon transplantation. Whereas the less differentiated the cell, the less likely it will invoke a host reaction; however, the more naive the stem cell, the greater its propensity for uncontrolled proliferation.
Adult stem cells possess a reduced capacity for proliferation and may be less tumorigenic. However, this presents a problem with producing a sufficient number of cells for transplantation. To traverse these limitations, researchers have developed methods such as: long-term culturing, immortalization, insertion of oncogenes, or even derivation of neural stem cells from other tissues or from pluripotent stem cells.
3.3. Recapitulating Cell Developmental Growth in Other Adult Stem Cells
3.3.1. Mimicking Bone Marrow Therapeutic Transplant Potential: Umbilical Cord Blood (UCB)
With their availability, ease of harvesting, and ability for autologous and allogenic use, the therapeutic potential of umbilical cord blood is expansive. The heterogeneous mixture of cells comprising cord blood includes hematopoietic progenitors, lymphocytes, monocytes, embryonic-like stem cells, and mecenchymal stromal cells. Yet, cord blood is considered immunologically immature and exerts its effects through immune modulation and reducing inflammation [99].
Transplantation of umbilical cord blood-derived stem cells in animal models of stroke has produced encouraging results of functional recovery, reducing infarct size, and higher expression of neuroprotective factors, such as BDNF and VEGF [100,101,102,103]. In other studies, human umbilical cord blood has exhibited protective effects in the rat hippocampus in vitro, while promoting dendritic growth. Additional emerging research is investigating the capabilities of human umbilical cord blood hematopoietic stem cells for functional recovery of dopaminergic neuron morphology of the substantia nigra, caudate, and putamen in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinson's disease mouse model. After intracardioventricular injection, there was an increase in size and density of tyrosine hydroxylase staining cells of the substantia nigra [104].
3.3.2. Shedding the Fat for Stem Cells: Adipose Tissue
Adipose tissue derived stem cells have demonstrated the ability to differentiate into neural, glial, and vascular endothelial cells, and also show higher proliferative activity with greater production of VEGF and hepatocyte growth factor in comparison with bone marrow derived stromal cells [98]. In combination with the accessibility, these features make adipocyte-derived stem cells a desirable source for neurovascular therapy. Transplantation of adipose-derived stem cells in ischemic stroke models demonstrates reduction in damage [98]. Additional studies exhibited reduced infarct size, improved neurological function, reduced level of cerebral inflammation, and chronic degeneration in an intracerebral hemorrhage model, substantiating their therapeutic value [105,106].
Yet, stem cells derived from adipose tissue are also subject to limitations. It was considered that spontaneous mutations occur with extensive passaging that foster tumorigenesis, potentially leading to cancer [107,108]. Follow-up studies suggest adipose-derived stem cells promote pre-existing cancerous cells, but do not initiate tumorigenesis. In a human clinical trial of spinal cord injury patients, none of the eight patients experienced any adverse events within the three-month follow-up [109].
3.3.3. Gender-Specific Stem Cells: Menstrual Blood-Derived Stem Cells
Following many of the factors considered in harvesting stem cells, menstrual blood provides a source with many benefits. With the monthly cycling of the endometrium, the ease and availability for harvesting is a large benefit in the research for therapeutic potential. Stem cells collected from menstrual blood demonstrate multipotency and secrete trophic factors such as VEGF, BDNF, and NT-3 in response to oxygen glucose deprivation (OGD) in an in vitro model of stroke. In such studies, the co-culturing of rat primary neurons with menstrual blood, or its conditioned media, improved survival rate [110]. Further, both intracerebral and intravascular transplantation of menstrual blood-derived stem cells in rat stroke models also enhanced survival and behavioral function [110]. Of note, it has been observed that the adherent fraction of menstrual cells do not lose their karyotypic normality or develop tumorigenic potential even after being expanded through 68 doublings [111].
3.3.4. Mother Knows Best: Breast Milk-Derived Stem Cells
Mammary stem cells (MaSCs) present in tissue of the breast, along with differentiated cells, enter the milk through lactating epithelium. Researchers postulate that these cells enter the breast milk through a combination of migration, cell turnover, and mechanical shearing forces [112,113]. The stem cells of breast milk demonstrate pluripotency similar to that of embryonic stem cell morphology and phenotype and thus allow for differentiation into all three germ layers in vitro [113]. Future research may elucidate therapeutic potentials in line with those of ESCs. Additional benefits results from the noninvasive harvesting of the cells, availability, and potential for autologous transplant. In terms of tumorigenicity of breast milk-derived stem cells, a study has reported that even nine weeks after subcutaneous injection of breast milk-derived stem cells in immunodeficient mice, these cells did not produce tumors [113]. Along this line, subpopulations of pluripotent adult cells and other multilineage stem cells have failed to form teratomas. Further work characterizing breast milk-derived stem cells for any oncogenic activity under different pathological conditions is needed to determine their tumorigenicity.
3.3.5. A Wisdom Tooth: Dental Tissue-Derived Stem Cells
Dental tissue-derived stem cells, such as post-natal dental pulp stem cells (DPSCs) [114], stem cells from exfoliated deciduous teeth (SHED) [115], periodontal ligament stem cells (PDLSCs) [116], stem cells from apical papilla (SCAP) [116,117], and dental follicle precursor cells (DFPCs) [118], which exhibit mesenchymal stromal cell-like capabilities, have been identified (for review, see [119]). Furthermore, dental tissue-derived stem cells have demonstrated differentiation into a variety of cell lines including neural tissue, adipocytes, and odontoblasts [120].
The use of dental tissue-derived stem cells have been utilized in the study of animal model middle cerebral artery occlusion (MCAO), demonstrating improved motor function following transplantation into the dorsolateral striatum [121].
3.3.6. Reverting Differentiated Tissues to Stem Cells: Induced-Pluripotent Stem Cells
Once considered unidirectional, stem cells were thought to progress through a linear maturation process leaving them terminally differentiated. However, current evidence suggests otherwise. Through manipulation, differentiated stem cells may be coerced into a prior state of multipotency. Utilizing the method of transfecting specific transcription factors fibroblasts can be manipulated into their embryonic-like stem cell precursors [122]. This technique has also been applied to umbilical cord blood cells, placental mesenchymal stromal cells, neural stem cells, and adipose-derived precursor cells to increase their potency [123,124]. Further studies in animal models of ischemic stroke demonstrate that some of the benefits in transplanting induced pluripotent stem cells (iPSCs) includes improving sensorimotor functions [125,126], reducing infarct size, reducing pro-inflammatory cytokines, and increasing anti-inflammatory cytokines [125].
As noted above, there is speculation for concern when transplanting less differentiated cells. Of particular apprehension is their potential for tumorigenesis and immunogenicity. The transfection technique used to induce retrograde manipulation utilizes transcription factors of known oncogenicity. The finding that transplantation of iPSCs into ischemic brain tissue produces a higher incidence of tumors than in healthy brain tissue, further supports this notion [127]. Transplantation is also limited by rejection by the host, even when autologous cells are grafted [128].
With the aforementioned concerns in mind, emergent research is demonstrating the therapeutic feasibility of vector-free and transgene-free induced pluripotent cells while reducing their tumor potential. A current study investigates the use of these human iPS cell-derived neural progenitor cells (hiPS-NPCs) in a mouse ischemic stroke model after discovering they differentiated into functional neurons in vitro. There was no evidence of tumor formation for 12 months following in vivo transplantation [129].
4. Stem Cell Therapy is Not a Magic Bullet: Exploring Co-Adjunctive Therapies
Due to distinct therapeutic potential of individual cell lines, the possibility exists to combine their respective benefits in targeting disease. Mounting literature substantiates the potential for synergistic effects on stem cell survival when co-transplanted. One such study established enhanced stem cell survival when delivered with adipose-derived stem cells [130]. Moreover, co-transplantation therapy may also decrease adverse events. The co-transplantation of bone marrow-derived stromal cells with embryonic stem cells reduced the incidence of tumor production and transplanting neural stem cells with epithelial cells enhanced survival while promoting differentiation [131,132].
The ability to enhance therapeutic effects is not limited solely to the use of stem cells. Combination therapy employs the addition of a substrate to enhance the efficacy of the stem cell line being transplanted. Examples include: Combining bone marrow-derived stromal cells with trophic factors to enhance survival and potentiation [133] or providing a scaffold for stem cell adherence [134].
The recognition of immunosuppressant factors secreted by certain cells (such as bone marrow and Sertoli cells) supports the use of co-transplantation with an immune-protective cell to allow better graft survival of the cells [135]. Sertoli cells are the germ cells of the testis and it has been shown that they are able to secrete trophic factors that are highly immunosuppressive, and which serve as neuroprotective factors in different animal models of neurological disorders [135,136,137]. As discussed previously, with unique sets of growth factors secreted by stem cells, co-transplantation of stem cells should generate a cocktail of growth factors to be secreted and delivered to the injured brain, thereby affording much more improved therapeutic outcomes. Furthermore, following brain injury, different cell types die or succumb to neurodegeneration, thus warranting the need to transplant multiple cell types. In this case co-transplantation of cells that could differentiate into these multiple cell types will be a logical approach towards replacement of the variety of cells damaged after brain injury [138]. A recent study has demonstrated that neural progenitor cell (NPC) survival and therapeutic support can be enhanced when co-grafted with other genetically modified doxycycline NPCs that can provide bFGF when activated [139,140,141].
As combinations for therapy continue to surface and demonstrate effectiveness, many variables still persist. Factors including: optimal dose, route of administration, and sex of donor/recipient, all of which are likely to be contingent upon the cell type being investigated. To date, we have investigated many of these parameters with umbilical cord blood for conditions such as Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), and Sanfilippo syndrome [142], however, there is still much to be ascertained in regards to stroke therapy. To this end, the Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS) was initiated to resolve these issues and standardize procedures [143,144,145,146].
5. Conclusions
Throughout this review we discussed how each cell line under investigation has its own unique benefits and limitations associated with use. Some of those limitations are immunogenicity, tumorigenicity, ease of harvesting, and the ability to proliferate cells. Researchers are currently addressing these issues through many of the techniques reviewed; yet there are still limited clinical trials. More so, current research is expanding beyond a single cell line transplant. It is likely that future clinical therapy may include the use of co-transplantation and combination therapy mentioned. Further studies also aim to explore the molecular mechanism of response by native tissue in the presence of stem cells. This may progress the exploration of unique trophic factors produced by the stem cells and their utilization in these novel therapies. In moving forward, research must still be conducted in assessing factors for optimal transplantation parameters and the efficacy of treatment, however, across the literature, it is evident that stem cells provide a promising niche of therapeutic potential.
Conflicts of Interest
Cesario V. Borlongan holds patents in stem cell technologies for the treatment of neurodegenerative disorders. Cesario V. Borlongan is supported by James and Esther King Foundation for Biomedical Research Program 1KG01-33966 and NIH NINDS RO1 1R01NS071956-01.
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© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).


text:
Asperkid's Game Plan
Code: BASP49
Price: $22.00
Quantity in Basket: None
By Jennifer Cook O'Toole ©2014
The Asperkid's Game Plan looks at the learning style of children with Asperger syndrome from the inside and explains how to introduce structured play that engages Asperkids and explicitly addresses ASD weaknesses while exploiting ASD strengths.
Demonstrating how just about anything can be turned into an opportunity for learning and growth, the book is bursting with go-to ideas for making simple play equipment in the home or classroom and using it to develop core skills that Asperkids struggle with, from fine motor and social skills, to planning and organization. Whether it is origami math, fried marbles, or a bug's eye view scavenger hunt, every game, project, and idea in the book is explained with clear directions and learning objectives and illustrated with color photographs.
Jennifer O'Toole's enthusiastic approach and fun lessons will inspire and motivate parents, educators, and therapists to make purposeful play a part of every Asperkid's day. (Hardcover: 248 pages)

subset: commoncrawl


text:
She could not wait longer for CCR to get the money together. She had 13 teeth pulled and the vet said "the inside of her mouth looked like hamburger". On her return to her temporary 'home' she purred and head-butted me, flipped on her back and made her Air Muffin feet. She ate canned food and even tried dry.
Now we really do have to start looking for donors - thank you - thank you - to the many people who have already helped as even $5 counts up! Cali will be at Petco Beaverton on Saturday (February 23rd) to meet with her fans and supporters. Show up to meet with this fabulous kitty!
What's New >


text:
November 16, 2004
NetIQ Announces First Product to Centralize Performance and Availability and Security Event Management Enabling More Effective Service Assurance
New and Enhanced Additions to NetIQ's AppManager Suite Enable Customers to Gain Insight into the Enterprise
Press Release
SAN JOSE, Calif.
NetIQ Corp. (Nasdaq: NTIQ), a leading provider of Systems & Security Management and Web Analytics solutions, announced the AppManager® Connector for NetIQ Security Manager™ (AM-SM Connector), a new addition to NetIQ's AppManager Suite of products.
Rather than maintain separate consoles for performance and availability and security event management, the new AM-SM Connector enables organizations to implement end-to-end service level management controls that can detect and respond to both systems- and security-related events and alerts. The connector notifies systems administrators of security-related events that could impact IT service levels through the AppManager operator console. Systems administrators can then use the connector to access the Security Manager Web console for additional information and data on these events.
"Customers today realize they need a holistic view of their enterprise infrastructure to optimize the overall performance of their organizations," said David Pann, vice president of Product Management and Marketing for the Systems Management products at NetIQ. "Performance management and security must be melded together to achieve such a view. The AM-SM Connector is the first offering from NetIQ that equips IT managers with the tools they need to satisfy both internal and external service level commitments, while enhancing their operational efficiency."
The AM-SM Connector reduces the time needed to detect, diagnose and correct security-related issues affecting system performance, such as denial of service attacks. The connector enables systems administrators to correlate system performance and security issues to make such diagnoses.
"The AM-SM Connector allows us to integrate two essential aspects of our enterprise, systems and security," said Steven Pearce, Senior Systems Analyst (NT/Network) Information Systems and Services Department at Boehringer Ingelheim Ltd. "Through this convergence we are able to reduce our training costs, improve our overall IT service levels, report in real time on network activity and trouble-shoot potential vulnerabilities and areas of weakness, while enhancing our staff operational efficiency."
NetIQ also introduced today AppManager® Analysis Center 2.0 and AppManager® Control Center 6.0. Both expand upon the AppManager Suite and enable IT organizations to satisfy both internal and external service level commitments while enhancing IT operational efficiency.
- AppManager Analysis Center 2.0 - AppManager Analysis Center 2.0 is an enterprise reporting and analysis tool designed specifically for AppManager data, providing administrators with the ability to gain deep insight into the health and performance of IT systems and applications. AppManager Analysis Center turns data into actionable knowledge, enabling effective management of services, business, and infrastructure applications and elements. The advanced reporting capabilities help IT organizations to understand service level requirements while ensuring compliance.
- AppManager Control Center 6.0 - From a single console, AppManager Control Center 6.0 allows users to monitor, manage, and have unified views of servers, events and jobs spanning multiple AppManager repositories. System administrators can quickly access the information and commands they need to be productive with list filtering and grouping capabilities. Service Map Views enable users to create a visual representation of the IT environment allowing them to understand how components relate to each other and visually identify the root cause of problems.
The AM-SM Connector, AppManager Analysis Center 2.0 and AppManager Control Center 6.0 for NetIQ's AppManager Suite together provide the visibility, reporting, and service management capabilities necessary to maintain applications and servers across the enterprise. Each solution puts operational information at the hands of IT in a manner that is easily communicable to business, allowing for the alignment of business with IT goals. Reports are easily generated and customizable, providing IT the information they need to quickly diagnose and rectify an issue, resulting in improved service levels. The AM-SM Connector, AppManager Analysis Center 2.0, and AppManager Control Center 6.0 enhance IT operational efficiency by streamlining IT management processes.
Pricing & Availability
The AM-SM Connector and AppManager Analysis Center 2.0 are scheduled to be generally available this month. AppManager Control Center 6.0 is scheduled to be generally available in December. All applications are priced on a per server basis. AM-SM Connector will be available free of charge to AppManager and Security Manager Customers. AppManager Analysis Center 2.0 pricing will start at $150 per server. AppManager Control Center 6.0 will be licensed with the AppManager Operator Console. For each AppManager Operator Console license purchased, which starts at $2500, customers will receive a license for AppManager Control Center.
About the NetIQ AppManager Suite
NetIQ's AppManager Suite assures the performance and availability of mission-critical servers and applications across Windows, Linux and UNIX platforms through proactive monitoring, quick diagnostics and problem resolution. It also helps optimize the utilization and productivity of IT resources through advanced reporting, analysis and automation. In addition to delivering the broadest and deepest management view into the distributed IT infrastructure, AppManager provides a robust architecture that is easy to use, quick to deploy and capable of scaling to thousands of servers.
About NetIQ
NetIQ Corp. (Nasdaq: NTIQ) is a leading provider of Systems & Security Management and Web Analytics solutions. In addition to managing Windows-based applications, NetIQ delivers cross-platform solutions that enhance business performance resulting in higher returns on infrastructure and Web investments. NetIQ products are sold worldwide, directly and through a network of authorized NetIQ distributors and resellers. The company is headquartered in San Jose, Calif., with development and operational personnel in Houston, Texas; Portland, Ore; Raleigh, N.C.; Bellevue, Wash.; and Galway, Ireland. For more information, please visit the company's web site at www.netiq.com or call (888) 323-6768.
Copyright© 2019 Micro Focus Corporation. All Rights Reserved. Micro Focus and the Micro Focus logo are trademarks or registered trademarks of Micro Focus Corporation in the USA. All other trademarks, trade names, or company names referenced herein are used for identification only and are the property of their respective owners.
Let's Talk
Welcome, Want to talk to someone? Call our Sales team or request a call and we'll get right back to you.
- Sales: (888) 323-6768
For support information, please visit Technical Support.
Amy Sachrison
Media and Analyst Relations
(713) 418-5368
Email: email@example.com


text:
This year I aimed to log a daily word count, and this blog post will place me right above 215,000 for 2016. (I should go home and write a thousand words or so, in order to get 216K for 2016… Obviously!)
The management principle is you can't achieve higher goals without changing what you do, you can't change what you don't measure, and you can't measure what you don't track. Hence the love-hate relationship many office minions have with spreadsheets, trackers, databases, and anything involving counting beans.
215K per day divides up to under 600 words a day. I know there are programs dedicated to encouraging a minimum 500 words per day, so yay, I met that (on average). Of course my goal–realistic or not–was to hit 1K per day, so I'm way off.
The other day, I went to the gym with a couple co-workers, and made a suggestion. "Whatever else we do, let's try a pyramid of push-ups and sit-ups," I said, since those are two of the four components of the Air Force fitness test. If you haven't done a pyramid before, it's one push-up, one sit-up, then two of each, then three… Up to some number (ten, I suggested) and back down to one.
I hadn't done one of these in years, and honestly wasn't sure how well my ponderous flesh-husk could handle the challenge. The answer was "not well." I found out right quick where my limits lay.
In the writing arena, much like that pyramid, maybe I bit off more than I could chew by setting a goal like 1k a day. I don't know, because I never tracked my word count before. Now I have data, so at the end of next year, I can see "Am I doing better? Am I doing about the same? Did I slow down?" To be fair, I understand there can be explanations and reasons for those ups and downs, and I'll take those into consideration. But having some baseline gives me something to compare against.
It's the same reason I do well on a diet or fitness plan when I log what I've been doing and eating. "I walked the other day, and I did a sit-up of sorts when I got out of bed. I only ate half that pizza. Doin' pretty good!" I'm far too kind to myself when I don't have the harsh reality of data challenging me.
Sometimes the word count tracker showed the results of a tough effort. That's great–part of the benefit. NaNoWriMo of course is a good example (58K in November), and when I tried Camp NaNo in April, that momentum carried into May, my second best month (just under 24K). Sadly, those months of "high" effort are offset by too many relaxed months where I barely topped 10K. I'll log word counts again next year, even though there are swaths of blocks with a big angry 0.
I know this is a time for new resolutions and personal commitments. A big part of setting that goal is finding a way to track progress — the 'M' in the SMART goal setting acronym is 'measurable.'
Whether you aim for something new, something familiar but better, or simply contentment with where you are right now in life, I wish you a happy 2017 and thank you for hanging out with me here throughout the year.


text:
On 27 Aug 2009, at 19:09, Toby Inkster wrote: > The spec doesn't specify this. If there were a definitive answer, it > would be step #9 in the processing sequence. Ok. Thanks Toby. Not the answer I was hoping for, but anyway ... > My vote, if this were to be written up as an errata, would be to > specify that if @datatype is non-empty but does not contain a valid > CURIE, (Well, it's a syntactically valid CURIE, it just uses an undeclared prefix.) > to treat it as datatype="" - i.e. the value of the attribute is > ignored but the presence of the attribute is not ignored. This would > be consistent with non-CURIE rel, rev, typeof, etc. Sounds reasonable to me. From practical experience it seems to me that missing namespace prefixes are one of the most common authoring errors -- so it would be good if different parsers did the same thing in that case. Thanks again, Richard > > -- > Toby A Inkster > <mailto:firstname.lastname@example.com> > <http://tobyinkster.co.uk> > > >Received on Thursday, 27 August 2009 19:22:52 UTC
This archive was generated by hypermail 2.3.1 : Tuesday, 6 January 2015 21:50:32 UTC


text:
Zyra's website //// Mobile Phones //// Site Index
Mobile Place
Where Incredible Comes As A Standard
Grab yourself some of the most competitive T-Mobile deals around from the Mobile Place website. They also offer a fantastic range of gifts with new connections and free next day delivery.
Mobile Place:
"Chitter Chatter, an established business with over 15 years trading history, are proud to announce the launch of our new low-cost mobile deals site.
We have some of the most competitive T-Mobile deals around. Customers need look no further for the latest mobile phones and tariffs.
We also offer a fantastic range of gifts with new connections and free next day delivery.
Customer satisfaction is essential to us, so we really do care about giving our customers the best possible service".
If you have been tempted by this, here's the link:
The Link Was Here To Go To The Place!
http://www.mobileplace.co.uk affiliate program was with Affiliate Future. Sadly, the program has now finished and the page has had to be Bunged Up. In the meantime, for alternatives please visit our Mobile Phones page.
If the links and banners on this page work, that's good! Otherwise, here's some help


text:
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text:
Job Description:
Leidos is seeking System Administrators, to support our US Army Corps of Engineers IT (ACE-IT) p rogram.
This is a pipelining requisition, to gather resumes for upcoming task orders.
The assignments could be short-term or long-term, full-time or part-time.
Fairly heavy travel (average 50% of the time) is involved.
Locations vary nationwide, remote/telecommuting work is possible.
The incumbent will provide systems administrative and technical support to the program's EMS (emergency management system) to include but not limited to:
- Serve as Primary POC for local server, network and telecom repair of district infrastructure components
-Manage and monitor local server infrastructure to ensure consistent operation
-Coordinate local response to IAVA vulnerability remediation
-Ensure priority adjustment and supporting emergency situations are covered for all services and requirements
-Escalate local issues to the Leidos Division Manager
-Coordinate Level 3 support to the district technical personnel
-Primary escalation POC for after hours and VIP level support requests
-Responsible for monitoring local Service Delivery ticket queues so that aging tickets are given appropriate follow-up attention
Mainframe, network, and work group server monitoring and management
Coordinate and work with network administrators to ensure smooth operation
Set up of administrator and service accounts
Maintenance of system documentation
Tune system performance
Install system wide software and allocate mass storage space
Evaluate vendor products and make recommendations for procurement of software and hardware
Have oversight of installation and backup recovery
Manage computing resource use policy development and standards for allocation
Ensure data network availability
High School Diploma or equivalent
2-4 years' experience
Current DoD 8570 Certification, IAT Level II (Comptia Security +CE and 1 qualifying Computing Environment certification (For example, Microsoft MCP certified, Comptia A+)
Interim Secret Clearance
Strong analytical and follow through skills.
Strong verbal and written communications skills.
Ability to coordinate and get cooperation from multiple areas within IT to accomplish assignments.
Ability to work well independently on defined tasks.
Ability to work well as part of a team.
Windows Server 2012; Active Directory
Networking Technologies (DNS, DHCP, WINS)
Cisco Telephony /Router Solutions.
Experience maintaining Lexmark, HP, or Ricoh printer devices (i.e. installing maintenance kits).
Prior USACE/ACE-IT experience.
Experience working in a DoD environment.
No two career paths will ever look the same.
At Leidos, we know the most talented and diverse IT and engineering professionals will always have a multitude of career choices; your time at Leidos will be a wise investment in your career and in yourself. We welcome your perspective and ideas, in order to foster collaboration and deliver world-class solutions.
We look for solutions that not only transform businesses, but change the world.
Our Civil business is helping to modernize and manage infrastructure, systems and controls, and cyber security for civilian agencies and commercial clients around the globe. With core competencies in information technology, energy and environment, complex logistics, and specialized engineering, we solve technical challenges and implement newfound efficiencies on a number of programs including those that:
-Power homes and businesses
-Guide air traffic
-Streamline tax returns
-Protect digital footprints
-Contain environmental incidents
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January 12, 2006
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Curtis Andrews recently taught a West African drumming course in the School of Music using instruments that were partially built by students in the naval architecture program at the Marine Institute. For more, click here.
(Photo by Chris Hammond)
© 2005 Memorial University of Newfoundland


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This morning I woke up with a nasty cold. It was bound to happen, everyone in the house has been sick for days. But duty called, so off to work I went. When I got to the Staten Island Ferry I noticed an unusually large number of school-aged children. At first I thought it was a class trip, but then I realized that they were all wearing a similar uniform. Of course, today was the ticker tape parade for the Giants.
Don't misunderstand, I support the team. If it were the Yankees I might just have been out there with them. It's just that I was sick, and I was in no mood to hear a few hundred people screaming "LET'S GO GIANTS" in my ear for 30 minutes. The worst part was that since I was sick I came home early and had to ride the boat with more Giants fans on the way home. Read More »