biologic interest in mesenchymal stem cells ( mscs ) , which were first described by friedenstein and colleagues in 1966 , has risen dramatically over the last decade . as expected , clinical application of human mscs is also evolving rapidly for a variety of diseases . although umbilical cord ( uc ) rich with mscs and uc - derived mscs ( ucmscs ) has been shown to be easy to isolate and culture , data available focusing on clinical application of ucmscs are quite limited . in this paper , we address the characteristics of mscs , including ucmscs , and their clinical application in hematopoietic stem cell transplantation ( hsct ) . we share our clinical experience in the successful use of in vitro expanded ucmscs [ 24 ] . we also describe several issues related to the clinical use of mscs . for the near future the defining characteristics of mscs are inconsistent among investigators . according to the minimal criteria of the international society for cellular therapy , mscs are defined by their in vitro growth pattern , the expression of specific surface antigens , and the multipotent differentiation potential . being a member of stem cells , mscs are able to self - renew with a high proliferative capacity . they proliferate as fibroblastic spindle - shaped cells and must be plastic - adherent when maintained in standard culture conditions . mscs can be characterized by a panel of surface markers , which is negative for hematopoietic antigens ( cd34 , cd45 , cd14 , cd11b , cd19 , and cd79 ) , and positive for mesenchymal makers ( cd105 and cd73 ) and cell adhesion molecules ( cd29 , cd44 , cd106 , and cd90 ) [ 57 ] . mscs display a broader differentiation potential , and the most unique property to identify mscs is the capacity for trilineage mesenchymal differentiation , including osteoblasts , adipocytes , and chondroblasts . , msc - derived stromal cells establish an appropriate scaffold and a complex network of cytokines , adhesion molecules , and extracellular matrix proteins [ 8 , 9 ] . in vitro , many studies have reported the promotive effects of mscs for expansion of hematopoietic stem cells ( hscs ) [ 1012 ] . in animal models , mscs have been shown to enhance engraftment of donor hscs after cotransplantation [ 1315 ] . like bm - derived mscs ( bmmscs ) , ucmscs were demonstrated to support engraftment of a limited number of human hscs from cord blood in a nod / scid transplant model . mscs express hla - class i , but not class ii [ 17 , 18 ] . in vitro , several investigations have demonstrated that using mismatched mscs does not trigger proliferative t - cell response in the allogeneic mixed lymphocyte reaction [ 12 , 18 , 19 ] . in vivo , transplanted allogeneic mscs can be detected in recipients at extended time points , indicating a lack of immune recognition and clearance . as for showing low immunogenic properties , many studies have reported that mscs can exert profound immunosuppressive effects via modulation of both cellular and innate immune pathways . mscs suppress the proliferative response of b cells to allogenic antigens through an arrest in the g0/g1 phase of the cell cycle , and the major mechanism appears to be through soluble factors produced by mscs [ 2123 ] . additionally , mscs modify t - cell responses indirectly by blocking the differentiation of monocytes into dendritic cells and impairing the antigen - presenting ability . mscs also inhibit t - cell proliferation and function directly by secreting soluble factors [ 2527 ] . moreover , mscs alter the cytokine secretion profiles of dendritic cells , t cells , and natural killer cells to induce a more anti - inflammatory or tolerant phenotype . taken together , mscs are capable of escaping recognition by the alloreactive immune system and can exert immunomodulatory and anti - inflammatory effects . these properties make them a promising tool in the management of graft failure and in the prevention or treatment of graft - versus - host disease ( gvhd ) after hsct . they can be isolated from different tissues , including bm , peripheral blood , adipose tissue , dental pulp , and a variety of fetal tissues , such as amniotic fluid , amniotic membrane , placenta , cord blood , and uc [ 7 , 8 , 17 , 2830 ] . a great impact on clinical utility though as a traditional source , mscs constitute only a small percentage about one in 3.4  10 cells in adult bm . however , mscs are sparse in full - term infants ' cord blood [ 3133 ] , whereas mscs can be obtained and cultured much more efficiently from uc than from cord blood . the ontological and anatomical origins of mscs have profound influences on their properties , and hence affect their performance in clinical application . many studies have found that mscs derived from various origins share a similar spindle - shaped morphology and reveal a consistent immunophenotypic profile [ 6 , 17 , 30 , 35 ] . whereas compared with adult - type mscs , fetal - type mscs appear to have greater expansion capacity and faster doubling time which may result from their longer telomeres , greater telomerase activity , and higher expression of telomerase reverse transcriptase [ 6 , 17 , 28 , 29 , 3638 ] . ucmscs shares similar properties unique to fetal - type mscs , and we and other authors also demonstrated the higher proliferative potential of ucmscs [ 3 , 39 , 40 ] . fetal - type mscs are less lineage - committed   and express lower levels of hla - class i than adult - type mscs . we found that the reduction in peripheral blood mononuclear cell proliferation activated by phytohemagglutinin stimulation was significantly greater in the ucmsc cocultures than in bmmsc cocultures , suggesting the greater immunosuppressive effects of ucmscs . for example , mscs from uc or cord blood exhibit more robust osteogenic but less adipogenic differentiation than bmmscs [ 6 , 37 , 39 , 41 ] . bm is considered as a traditional source of mscs , and most of the knowledge concerning mscs comes from bm studies . however , several limitations restrict the clinical application of bmmscs . harvesting bmmscs involves an invasive and painful procedure , which can cause infection , bleeding , and chronic pain . , ucmscs are obtained after delivery of a baby from a sample that would be discarded inevitably . the process is noninvasive , painless , and harmless for the mother and the baby . uc contains a significant amount of mscs which can be easily collected and cultured [ 34 , 40 ] . in vitro , ucmscs have greater expansion capability and faster growth rate [ 3 , 17 , 39 , 40 ] , indicating the advantage for rapid expansion and consequent downstream application . ucmscs express a lower level of hla - class i than bmmscs , suggesting the lower immunogenicity and the superiority for clinical use in hsct . ucmscs appear to have greater immunosuppressive effects , indicating their better role in the management of gvhd . therefore , uc represents a good alternative source of mscs and should not be discarded as medical waste . . chemotherapy and radiotherapy prior to hsct damage the bm stroma , and may result in delayed engraftment . in 2000 , ko et al . first reported that coinfusion of autologous bmmscs at the time of hsct can lead to rapid hematopoietic recovery . accordingly , 46 patients received allogeneic hscs and mscs from hla - identical siblings , and most patients had prompt hematopoietic recovery without significant side effects . the beneficial effects of mscs on engraftment may relate to their supportive role in hematopoiesis . bacigalupo et al . demonstrated that bmmscs from patients with severe aplastic anemia were deficient in the ability to inhibit t - cell proliferation and cytokine release , indicating the lack of msc immunoprotection in the bm . we found that bmmscs derived from children with severe aplastic anemia exhibit poor potential of proliferation and differentiation . due to the possibility of bmmsc insufficiency , we cotransplanted ucmscs along with hscs in 2 children with severe aplastic anemia . apart from engraftment promotion , mscs were reported to be also efficient in prevention and treatment of graft failure . in 2007 , le blanc et al . reported cotransplantation of bmmscs with hscs to prevent rejection in 3 patients with previous graft failure or rejection . all the patients achieved hematopoietic engraftment and 100% donor chimerism , suggesting the potential role of mscs in the management of graft failure . as t cell depleted hsct from a hla - haploidentical relative is a feasible option for the patient who needs to undergo allogeneic hsct but lacks a hla - compatible donor , the report of ball et al . provides promising results . while there was a graft failure rate of 15% in 47 historical control patients , no graft failure occurred among the 14 children receiving coinfusion of bmmscs during haploidentical hsct . gvhd involves increased secretion of inflammatory cytokines , activation of a variety of immune cells , and finally host tissue damage . mscs can modulate immune responses and lead to resolving of gvhd . in 2004 , le blanc et al . first reported that a girl with acute lymphoblastic leukemia received infusion of haploidentical bmmscs to treat severe treatment - resistant grade iv acute gvhd after hsct , and the clinical response was striking . thereafter , eight patients with steroid - refractory grades iii - iv gvhd were treated with expanded mscs from hla - identical or mismatched donors , and the survival rate was significantly better than that of 16 comparable controls during the same period but not given mscs . in addition to the promising results of mscs for gvhd , another important issue comes from their study : it is feasible and safe to use mscs even from hla - incompatible donors . to date , clinical application of ucmscs in the treatment of gvhd is very limited . according to our experience , we intravenously infused in vitro expanded ucmscs four times into two recipients with severe steroid - resistant acute gvhd . the clinical manifestations of gvhd dramatically improved after each ucmsc infusion , even without additional immunosuppressive therapies . several studies demonstrated that mscs of the donor can graft into the recipient 's bm after allogeneic hsct [ 43 , 50 , 51 ] . however , the marrow stroma remains host in origin after successful allogeneic hsct [ 47 , 52 ] , suggesting that donor mscs are eliminated in the recipient 's bm after infusion . therefore , more than one times of msc infusion may be needed for patients with severe gvhd . because the number of mscs obtained from the donor is not sufficient and mscs have a great propensity for in vitro expansion , passaged cells are used extensively in experimental and clinical practice . although karyotype analysis is not recommended for routine identification of mscs , transforming events potentially leading to the establishment of a novel cell line may occur . additionally , mscs may gradually lose their properties of early progenitor cells , including the abilities to proliferate and differentiate . thus , the conditions of msc culture are very important for successful clinical use , and mscs within six passages are suggested for clinical application . mscs may suppress host immunity against infectious agents , and it is uncertain whether viruses can be transmitted by mscs from infected donors . demonstrated that no viral dna of cytomegalovirus , herpes simplex virus type 1 and type 2 , epstein - barr virus and varicella zoster virus could be detected in mscs isolated from healthy seropositive individuals . thus , the risk of herpes virus transmission is low when infusion of mscs from healthy seropositive donors . however , cytopathological effects and intracellular viral antigens can be found after infection of cytomegalovirus and herpes simplex virus type 1 in vitro . . coinfusion of in vitro expanded mscs at the time of hsct has been shown to be safe and feasible without immediate or late infusion - related toxicities [ 43 , 47 , 49 ] , and patients given mscs seem not to experience more infections . however , the optimum msc dose , the optimum number of infusions and the appropriate cell passages need to be further evaluated in large well - conducted clinical trials . in addition , ucmscs are more primitive than bmmscs . although ucmscs are easier to obtain without suffering to donors , the safety of these cells in human clinical application is still unclear due to the limited clinical experience . besides , the quality of mscs for human clinical use is crucial , but not all physicians have facilities to guarantee the quality of cells .  off - the - shelf
hematopoietic stem cell transplantation ( hsct ) is becoming an effective therapeutic modality for a variety of diseases . 
 mesenchymal stem cells ( mscs ) can be used to enhance hematopoietic engraftment , accelerate lymphocyte recovery , reduce the risk of graft failure , prevent and treat graft - versus - host disease , and repair tissue damage in patients receiving hsct . 
 till now , most mscs for human clinical application have been derived from bone marrow . however , acquiring bone - marrow - derived mscs involves an invasive procedure . 
 umbilical cord is rich with mscs . compared to bone - marrow - derived mscs , 
 umbilical cord - derived mscs ( ucmscs ) are easier to obtain without harm to the donor and can proliferate faster . 
 no severe adverse effects were noted in our previous clinical application of ucmscs in hsct . 
 accordingly , application of ucmscs in humans appears to be feasible and safe . 
 further studies are warranted .