IntroductionMesenchymal stromal cells (MSCs), designated mesenchymal stem cells by some investigators [1Pittenger M.F. Mackay A.M. Beck S.C. et al.Multilineage potential of adult human mesenchymal stem cells.Science. 1999; 284: 143-147Crossref PubMed Scopus (10190) Google Scholar], are a heterogeneous population of spindle-shaped, plastic-adherent cells isolated from bone marrow, adipose tissue, and many other tissue sources [2Horwitz E. Le Blanc K. Dominici M. et al.Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement.Cytotherapy. 2005; 7: 393-395Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar, 3Dominici M. Le Blanc K. Mueller I. et al.Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.Cytotherapy. 2006; 8: 315-317Abstract Full Text Full Text PDF PubMed Scopus (2795) Google Scholar]. These intriguing cells have been widely studied for many disorders in both hematopoietic cell transplantation and regenerative medicine.Although MSC research continues along many avenues, this article will focus on the MSCs in close relation to hematopoietic cell transplantation (HSC). To assist the nonexpert, we have divided the article into 3 sections discussing (I) the current view of the MSC mechanisms of action for most applications, (II) MSCs as adjunct therapy to foster HSC engraftment and hematopoietic reconstitution, and (III) MSCs for prophylaxis and therapy of graft-versus-host disease (GVHD).Section I: A New View of MSCsMesenchymal stromal cells (MSCs) were originally identified by Friedenstein et al. [4Friedenstein A.J. Petrakova K.V. Kurolesova A.I. Frolova G.P. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues.Transplantation. 1968; 6: 230-247Crossref PubMed Scopus (1629) Google Scholar] as the stromal cells of the marrow microenvironment that support hematopoiesis. Soon thereafter, MSCs were shown to differentiate into bone and have an immense capacity for growth in cell culture in vitro. Friedenstein et al. [5Friedenstein A.J. Deriglasova U.F. Kulagina N.N. et al.Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method.Exp Hematol. 1974; 2: 83-92PubMed Google Scholar] further showed that a subset of the cells had a high proliferative potential, generating clonal colonies when plated in tissue culture at low density, the so-called fibroblast colony-forming cells (CFU-F). It was then discovered that MSCs could differentiate in vitro into fat and cartilage as well as bone. At that time, the only widely recognized stem cells were the HSCs, and based largely on that model, adult stem cells were generally defined as cells that could undergo self-renewal and differentiation into at least 2 lineages. As there was no clear distinction between in vivo and in vitro differentiation capacity, MSC seemed to fulfill those criteria. Owen [6Owen M. Friedenstein A.J. Stromal stem cells: marrow-derived osteogenic precursors.Ciba Found Symp. 1988; 136: 42-60PubMed Google Scholar] then proposed the existence of stromal stem cells, analogous to the HSCs, that could reconstitute the hematopoietic microenvironment, and suggested the CFU-F may represent such cells. Later, Caplan [7Caplan A.I. Mesenchymal stem cells.J Orthop Res. 1991; 9: 641-650Crossref PubMed Scopus (3412) Google Scholar] noted that MSCs fulfilled the self-renewal and multilineage differentiation criteria and proposed that these cells were actually MSCs, with the capacity to differentiate into a wide variety of mesenchymal tissues. According to this concept, these MSCs could serve as a broadly applicable stem cell source for regenerative medicine, repopulating injured tissues and clinically ablated diseased tissues with healthy, terminally differentiated, tissue-specific cells [8Caplan A.I. Bruder S.P. Mesenchymal stem cells: building blocks for molecular medicine in the 21st century.Trends Mol Med. 2001; 7: 259-264Abstract Full Text Full Text PDF PubMed Scopus (946) Google Scholar, 9Prockop D.J. Marrow stromal cells as stem cells for nonhematopoietic tissues.Science. 1997; 276: 71-74Crossref PubMed Scopus (4101) Google Scholar].The New Paradigm of the MSC Mechanism of ActionIt has now been 15 years since the first report of MSC infusion into humans [10Lazarus H.M. Haynesworth S.E. Gerson S.L. Rosenthal N.S. Caplan A.I. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use.Bone Marrow Transplant. 1995; 16: 557-564PubMed Google Scholar]. Several thousand patients have received systemically infused MSCs for various indications. Interestingly, in all of these studies, the documented engraftment of donor cells at the presumed site of activity is low or even completely absent. Even in preclinical models, the engraftment is exceedingly low. Despite our preconceived notions, the most appropriate conclusion seems to be that, after systemic infusion, there is no definitive evidence of a therapeutic effect being mediated by engraftment and terminal differentiation of MSCs to the cells of the resident tissue. In other words, there is no evidence of MSCs acting as “building blocks” to rebuild tissue after systemic infusion. Given their feeble and transient engraftment, nevertheless resulting in substantial clinical benefit, what molecular and cellular mechanism may account for the striking biologic activity of MSCs? An emerging body of data suggests that soluble factors released by the MSCs are key elements in their mechanism of action for most, if not all, of the systemic effects [11Horwitz E.M. Dominici M. How do mesenchymal stromal cells exert their therapeutic benefit?.Cytotherapy. 2008; 10: 771-774Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar].MSCs secrete stromal-derived factor-1 I. et of the stromal-derived factor-1 human stem cell PubMed Scopus Google Scholar], a in HSC to the in the marrow microenvironment I. et of human stem cell engraftment and of on 1999; PubMed Scopus Google Scholar]. In MSCs secrete and stem cell MSCs are to further and M. Gerson S.L. and of of marrow-derived mesenchymal stem cells (MSCs) and stromal cells.J PubMed Scopus Google Scholar]. MSCs secrete and M. Le M. I. A.M. bone marrow stromal cells a of 2006; PubMed Scopus Google Scholar].The for soluble by MSCs is an of and will a of These with the that engraftment and is an a for MSC therapeutic infused MSCs exert a therapeutic effect the of soluble that on and tissues. as stem cells to serve as cellular to the of tissues or the microenvironment to foster of the New are 2 key implications to the that the mechanism of biologic activity after systemic infusion of MSCs, in all applications, is the of soluble the tissue source of the MSCs may be in biologic Despite the and that populations of MSCs are heterogeneous et of human mesenchymal stem cell from of and Hematol. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, of in a colony of human mesenchymal stem cells of cell 2001; PubMed Scopus Google Scholar]. MSCs are to be the population of cells of the tissue data that MSC their tissue of that MSC tissue is et of mesenchymal stem cells from human bone marrow, adipose tissue, and Hematol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, K. of mesenchymal stem cells from bone marrow, or adipose 2006; PubMed Scopus Google Scholar]. different tissue sources may MSC with different different MSC tissue sources may be for clinical and culture expansion may and the of the cells. the density, culture and of vivo in to culture may These that the cell be to or of in to the for a clinical are the implications for the of MSCs as adjunct therapy in The 2 are to HSC engraftment and as prophylaxis therapy for The the of MSCs to foster HSCs, will be in the on the cellular of the microenvironment after of MSCs to foster engraftment may a based on the that MSCs may that engraftment and hematopoietic actually the The of MSCs in is in this is of the most widely studied of These are with the and the being are to Mesenchymal (MSCs) and biologic of stromal stem and has been recognized [5Friedenstein A.J. Deriglasova U.F. Kulagina N.N. et al.Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method.Exp Hematol. 1974; 2: 83-92PubMed Google Scholar, and the and the of hematopoietic stem cell Full Text Full Text PDF PubMed Scopus Google Scholar]. A variety of in vitro have of hematopoietic stem cell expansion with MSCs, with from factors and as well as from cellular in stromal stem cells and their may a for HSC growth and expansion [1Pittenger M.F. Mackay A.M. Beck S.C. et al.Multilineage potential of adult human mesenchymal stem cells.Science. 1999; 284: 143-147Crossref PubMed Scopus (10190) Google Scholar, M. Gerson S.L. and of of marrow-derived mesenchymal stem cells (MSCs) and stromal cells.J PubMed Scopus Google Scholar, S.E. Caplan A.I. by human marrow-derived mesenchymal progenitor cells in effects of and PubMed Scopus Google Scholar, A.I. Mesenchymal stem cells as 2006; PubMed Scopus Google Scholar, Mesenchymal stem Med. 2005; PubMed Scopus Google Scholar]. expansion have been with expansion most the of these cells the bone marrow et mesenchymal stem cells support and from hematopoietic progenitor cells.J PubMed Scopus Google to be is be in vivo by of MSC in the human et of mesenchymal stem cells in 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, et therapeutic for multipotent mesenchymal stromal Hematol. PubMed Scopus Google Scholar]. has on the effect of stromal stem cells on the HSCs, with to the various growth factors and that have effects on HSC growth and differentiation as well as cellular expansion [1Pittenger M.F. Mackay A.M. Beck S.C. et al.Multilineage potential of adult human mesenchymal stem cells.Science. 1999; 284: 143-147Crossref PubMed Scopus (10190) Google Scholar, M. Gerson S.L. and of of marrow-derived mesenchymal stem cells (MSCs) and stromal cells.J PubMed Scopus Google Scholar, S.E. 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In there have been isolated in MSC infusion may have therapeutic et al. et of mesenchymal stem cells for the of engraftment stem cell Scholar] a stem cell transplantation for growth in Even after an of 2 years had infusion of MSCs from was with of the in hematopoiesis. not evidence of MSC engraftment was patients with hematopoietic after transplantation were infused with MSC only I. et of mesenchymal stromal cells hematopoietic hematopoietic stem cell a Scopus Google Scholar]. It was a that 2 of the patients of donor the other to such as these have to in MSCs being for as therapy for hematopoietic have been to that of MSC with of HSC after to of the with and M. et and therapy effects of mesenchymal stem cells in with PubMed Scopus Google Scholar, The of cell transplantation in and 2005; PubMed Google Scholar]. 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The International Society for Cellular Therapy position statement.Cytotherapy. 2006; 8: 315-317Abstract Full Text Full Text PDF PubMed Scopus (2795) Google Scholar]. no that stromal stem cell populations have been isolated from tissue sources and at differentiation and of bone marrow stromal PubMed Scopus Google Scholar]. may between these various MSC to have not been has been or not or MSCs will be has been is that be all that to tissue have not been stem cell 2008; 2: Full Text Full Text PDF PubMed Scopus Google Scholar], and that effects such as a effect on the a M. et between of mesenchymal stem cells and a in of a clinical 2008; PubMed Scopus Google Scholar]. this not be an if MSC are to be in the or as a for an in the of we that these will be the that will the that the of will close to and of MSCs and stromal cells (MSCs) are a population of heterogeneous cells by an of hematopoietic and of and that differentiate in vitro into and et of mesenchymal stem cells from adult PubMed Scopus Google Scholar, M. Le Blanc K. Mueller I. et al.Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.Cytotherapy. 2006; 8: 315-317Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, E.M. Le Blanc K. Dominici M. et al.Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement.Cytotherapy. 2005; 7: 393-395Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, M.F. Mackay A.M. Beck S.C. et al.Multilineage potential of adult human mesenchymal stem cells.Science. 1999; 284: 143-147Crossref PubMed Scopus Google Scholar]. MSC do not or and for cell and is not for therapeutic effect Blanc K. Haynesworth S.E. Mesenchymal stem cells and and of the PubMed Scopus Google Scholar]. may and to M. 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These MSC a to for the of graft-versus-host disease in and hematopoietic cell transplantation that are not broadly and Mesenchymal stem cells in and 2008; 8: PubMed Scopus Google Scholar, stromal cell therapy in hematopoietic stem cell and Marrow Transplant. Scholar]. the of MSC cell and cells are for cells, and are in donor cell 7: PubMed Scopus Google Scholar]. MSC differentiation of to and and Mesenchymal stem cells in and 2008; 8: PubMed Scopus Google Scholar]. MSCs cell and and could their effects on cells Mesenchymal stem cell evidence that cells are of MSCs, MSCs 2006; PubMed Scopus Google Scholar]. 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These were in a by the and Marrow MSC a expansion for the cells and Blanc K. et stem cells for of graft-versus-host a 2008; Full Text Full Text PDF PubMed Scopus Google Scholar]. and adult patients were with or bone marrow-derived MSC for A MSC infusion, with was infused into patients and the patients were with 2 or The was The from infusion of first MSC to was with patients with at infusion. with a had a at and at 2 years to and human adipose mesenchymal stem cells as therapy for graft-versus-host disease Full Text Full Text PDF PubMed Scopus Google Scholar]. 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Full Text Full Text PDF PubMed Scopus Google Scholar] the of a for patients with adult patients received 2 of MSC at a of 2 or in with a to prophylaxis with or patients were with noted of were for at least or tissue were The was not to a between the 2 different MSC no were E. et human mesenchymal stem cells to therapy for the of graft-versus-host Marrow Transplant. Full Text Full Text PDF PubMed Scopus Google from 2 clinical for and have been In both or MSC were for with at 2 the the the of patients with or were to have was noted with to or et in patients with disease the and of a in Society of Marrow Scholar]. with MSCs for the of is patients were with MSC for with after infusion of 3 at and at I. et of multipotent mesenchymal stromal cells in patients stem cell Mol 2008; PubMed Scopus Google Scholar]. with was with at with no M. I. et stem cells for of graft-versus-host 2006; PubMed Scopus Google Scholar]. both this and of the patients in the of M. I. et stem cells for of graft-versus-host 2006; PubMed Scopus Google Scholar, I. et of multipotent mesenchymal stromal cells in patients stem cell Mol 2008; PubMed Scopus Google the clinical with MSC for the of is the culture and of as well as potential and for clinical be to the and of MSC that MSC are most IntroductionMesenchymal stromal cells (MSCs), designated mesenchymal stem cells by some investigators [1Pittenger M.F. Mackay A.M. Beck S.C. et al.Multilineage potential of adult human mesenchymal stem cells.Science. 1999; 284: 143-147Crossref PubMed Scopus (10190) Google Scholar], are a heterogeneous population of spindle-shaped, plastic-adherent cells isolated from bone marrow, adipose tissue, and many other tissue sources [2Horwitz E. Le Blanc K. Dominici M. et al.Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement.Cytotherapy. 2005; 7: 393-395Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar, 3Dominici M. Le Blanc K. Mueller I. et al.Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.Cytotherapy. 2006; 8: 315-317Abstract Full Text Full Text PDF PubMed Scopus (2795) Google Scholar]. These intriguing cells have been widely studied for many disorders in both hematopoietic cell transplantation and regenerative medicine.Although MSC research continues along many avenues, this article will focus on the MSCs in close relation to hematopoietic cell transplantation (HSC). To assist the nonexpert, we have divided the article into 3 sections discussing (I) the current view of the MSC mechanisms of action for most applications, (II) MSCs as adjunct therapy to foster HSC engraftment and hematopoietic reconstitution, and (III) MSCs for prophylaxis and therapy of graft-versus-host disease
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