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• W2004994175 abstract "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 [12Ponomaryov T. Peled A. Petit I. et al.Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function.J Clin Invest. 2000; 106: 1331-1339Crossref PubMed Scopus (514) Google Scholar], which plays a vital role in HSC homing to the niche in the marrow microenvironment [13Peled A. Petit I. Kollet O. et al.Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.Science. 1999; 283: 845-848Crossref PubMed Scopus (1452) Google Scholar]. In vitro, MSCs constitutively secrete interleukin (IL)-6, IL-7, IL-8, IL-11, IL-12, IL-14, IL-15, macrophage-colony-stimulating factor, Flt-3 ligand, and stem cell factor. Upon IL-1a stimulation, MSCs are induced to express further IL-1a, leukemia inhibitory factor (LIF), granulocyte-colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) [14Majumdar M.K. Thiede M.A. Mosca J.D. Moorman M. Gerson S.L. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells.J Cell Physiol. 1998; 176: 57-66Crossref PubMed Scopus (786) Google Scholar]. Finally, MSCs can secrete several chemokine ligands, including CCL2, CCL4, CCL5, CCL20, CX3CL1, and CXCL8 [15Honczarenko M. Le Y. Swierkowski M. Ghiran I. Glodek A.M. Silberstein L.E. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors.Stem Cells. 2006; 24: 1030-1041Crossref PubMed Scopus (587) Google Scholar].The search for soluble mediators generated by MSCs is an active area of investigation and will probably reveal a new array of important secreted signaling molecules. These observations, together with the finding that local engraftment and differentiation, is an uncommon event, suggest a new general paradigm for MSC therapeutic activity. Systemically infused MSCs exert a therapeutic effect primarily through the release of soluble mediators that act on local and distant target tissues. Rather than serving as stem cells to repair tissues, they serve as cellular factories secreting mediators to stimulate the repair of tissues or modulate the local microenvironment to foster requisite beneficial effects.The Impact of the New ParadigmThere are 2 key implications to the idea that the principal mechanism of biologic activity after systemic infusion of MSCs, in virtually all applications, is the secretion of soluble mediators. First, the tissue source of the MSCs may be critically important in determining biologic activity. Despite the uniform morphology and cell-surface marker expression, gene expression studies show that populations of MSCs are heterogeneous [16Wagner W. Feldmann Jr., R.E. Seckinger A. et al.The heterogeneity of human mesenchymal stem cell preparations—evidence from simultaneous analysis of proteomes and transcriptomes.Exp Hematol. 2006; 34: 536-548Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 17Tremain N. Korkko J. Ibberson D. Kopen G.C. DiGirolamo C. Phinney D.G. MicroSAGE analysis of 2,353 expressed genes in a single cell-derived colony of undifferentiated human mesenchymal stem cells reveals mRNAs of multiple cell lineages.Stem Cells. 2001; 19: 408-418Crossref PubMed Scopus (265) Google Scholar]. Whereas MSCs are often considered to be the same general population of cells regardless of the tissue source, recent data suggest that MSC gene expression reflects their tissue of origin, indicating that MSC tissue heterogeneity is biologically relevant [18Wagner W. Wein F. Seckinger A. et al.Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood.Exp Hematol. 2005; 33: 1402-1416Abstract Full Text Full Text PDF PubMed Scopus (1066) Google Scholar, 19Kern S. Eichler H. Stoeve J. Kluter H. Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue.Stem Cells. 2006; 24: 1294-1301Crossref PubMed Scopus (2496) Google Scholar]. Thus, different tissue sources may generate MSC products with different cytokine expression profiles. Hence, different MSC tissue sources may be especially suited for specific clinical applications. Second, isolation and culture expansion conditions may significantly affect gene expression, and therefore the bioactivity, of the cells. Such conditions include the seeding density, culture media, serum supplementation, and extent of ex vivo expansion. Furthermore, bioreactors, in contrast to conventional plastic culture flasks, may affect gene expression. These observations suggest that the cell processing protocols can be modified to enhance or repress expression of specific genes in order to optimize the cytokine profile for a given clinical indication.What are the implications for the use of MSCs as adjunct therapy in HCT? The 2 principle applications are to enhance HSC engraftment and as prophylaxis and/or therapy for GVHD. The work investigating the use of MSCs to foster HSCs, which will be discussed in the next section, initially focused on repairing the cellular constituency of the microenvironment after radiochemotherapy conditioning. Use of MSCs to foster engraftment may merit a reexamination based on the idea that MSCs may release mediators that facilitate engraftment and hematopoietic reconstitution without actually rebuilding the microenvironment. The use of MSCs in GVHD, which is also discussed later in this article, is currently 1 of the most widely studied applications of MSCs. These studies are consistent with the secreted mediator proposal, and the approaches being studies are likely to yield optimal results.Section II: Mesenchymal Stem Cells (MSCs) and HematopoiesisThe biologic relationship of stromal adherent stem cells/MSCs and hematopoiesis has been long 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, 20Garrett R.W. Emerson S.G. Bone and blood vessels: the hard and the soft of hematopoietic stem cell niches.Cell Stem Cell. 2009; 4: 503-506Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar]. A variety of in vitro analyses have clearly demonstrated augmentation of hematopoietic stem cell (HSC) expansion upon coculture with ex vivo-expanded MSCs, with contributions from trophic factors and secreted cytokines as well as from direct cellular interaction in which stromal stem cells and their specific progenitors may provide a scaffold 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, 14Majumdar M.K. Thiede M.A. Mosca J.D. Moorman M. Gerson S.L. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells.J Cell Physiol. 1998; 176: 57-66Crossref PubMed Scopus (786) Google Scholar, 21Haynesworth S.E. Barber M.A. Caplan A.I. Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha.J Cell Physiol. 1996; 166: 585-592Crossref PubMed Scopus (580) Google Scholar, 22Caplan A.I. Dennis J.E. Mesenchymal stem cells as trophic mediators.J Cell Biochem. 2006; 98: 1076-1084Crossref PubMed Scopus (2273) Google Scholar, 23Väänänen H.K. Mesenchymal stem cells.Ann Med. 2005; 37: 469-479Crossref PubMed Scopus (167) Google Scholar]. All lineages including lymphocyte expansion have been observed, with megakaryocyte expansion most heralded given the relative scarcity of these cells within the bone marrow environment [24Cheng L. Qasba P. Vanguri P. et al.Human mesenchymal stem cells support megakaryocyte and pro-platelet formation from CD34(+) hematopoietic progenitor cells.J Cell Physiol. 2000; 184: 58-69Crossref PubMed Scopus (125) Google Scholar].What remains to be determined is whether hematopoiesis can truly be augmented in vivo by application of MSC in the human transplant setting [25Dazzi F. Ramasamy R. Glennie S. et al.The role of mesenchymal stem cells in haemopoiesis.Blood Rev. 2006; 20: 161-171Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 26Caimi P.F. Reese J. Lee Z. et al.Emerging therapeutic approaches for multipotent mesenchymal stromal cells.Curr Opin Hematol. 2010; 17: 505-513Crossref PubMed Scopus (43) Google Scholar]. Significant effort has focused on exploiting the paracrine effect of stromal adherent stem cells on the HSCs, with particular attention to the various secreted growth factors and matrix components that have agonistic effects on promoting 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, 14Majumdar M.K. Thiede M.A. Mosca J.D. Moorman M. Gerson S.L. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells.J Cell Physiol. 1998; 176: 57-66Crossref PubMed Scopus (786) Google Scholar, 21Haynesworth S.E. Barber M.A. Caplan A.I. Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha.J Cell Physiol. 1996; 166: 585-592Crossref PubMed Scopus (580) Google Scholar, 22Caplan A.I. Dennis J.E. Mesenchymal stem cells as trophic mediators.J Cell Biochem. 2006; 98: 1076-1084Crossref PubMed Scopus (2273) Google Scholar, 24Cheng L. Qasba P. Vanguri P. et al.Human mesenchymal stem cells support megakaryocyte and pro-platelet formation from CD34(+) hematopoietic progenitor cells.J Cell Physiol. 2000; 184: 58-69Crossref PubMed Scopus (125) Google Scholar]. Additionally, the immune suppressive potential of MSCs has also been highlighted, not only for therapeutic interventions, but also for providing immune protection to potential targeted HSCs [27Aggarwal S. Pittenger M.F. Human mesenchymal stem cells modulate allogeneic immune cell responses.Blood. 2005; 105: 1815-1822Crossref PubMed Scopus (1607) Google Scholar, 28Li N. Feugier P. Serrurrier B. et al.Human mesenchymal stem cells improve ex vivo expansion of adult human CD34+ peripheral blood progenitor cells and decrease their allostimulatory capacity.Exp Hematol. 2007; 35: 507-515Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 29Lazarus H.M. Koc O.N. Devine S.M. et al.Cotransplantation of HLA-identical sibling culture expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients.Biol Blood Marrow Transplant. 2005; 11: 389-398Abstract Full Text Full Text PDF PubMed Scopus (713) Google Scholar, 30Frassoni F.L.M. Bacigalupo A. Gluckman E. et al.Expanded mesenchymal stem cells (MSC), co-infused with HLA identical hemopoietic stem cell transplants, reduce acute and chronic graft versus host disease: a matched pair analysis.Bone Marrow Transplant. 2002; 29: 75Crossref PubMed Scopus (25) Google Scholar, 31Ringdén O. Uzunel M. Rasmusson I. et al.Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease.Transplantation. 2006; 81: 1390-1397Crossref PubMed Scopus (968) Google Scholar, 32Parekkadan B. Milwid J.M. Mesenchymal stem cells as therapeutics.Annu Rev Biomed. Eng. 2010; 12: 87-117Crossref PubMed Scopus (588) Google Scholar]. Recent demonstration that adherent stromal stem cells can modulate inflammatory cytokine-mediated tissue injury suggests that hematopoiesis augmentation by MSC may not be confined to growth promotion but also include injury protection processes [33Kim J. Hematti P. Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages.Exp Hematol. 2009; 37: 1145-1453Abstract Full Text Full Text PDF Scopus (587) Google Scholar, 34Maggini J. Mirkin G. Bognanni I. et al.Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile.PLoS One. 2010; 5: e9252Crossref PubMed Scopus (438) Google Scholar, 35Hemeda H. Jakob M. Ludwig A.K. et al.Interferon-gamma and tumor necrosis factor-alpha differentially affect cytokine expression and migration properties of mesenchymal stem cells.Stem Cells Dev. 2010; 19: 693-706Crossref PubMed Scopus (134) Google Scholar, 36Pulavendran S. Vignesh J. Rose C. Differential anti-inflammatory and anti-fibrotic activity of transplanted mesenchymal vs. hematopoietic stem cells in carbon tetrachloride-induced liver injury in mice.Int Immunopharmacol. 2010; 10: 513-519Crossref PubMed Scopus (49) Google Scholar]. Increased levels of tumor necrosis factor (TNF)-α or interferon (INF)-γ associated with the inflammatory state have been known to hinder HSC growth and expansion, as has been demonstrated within the Fanconi anemia model of bone marrow failure [37Rathbun R.K. Faulkner G.R. Ostroski M.H. et al.Inactivation of the Fanconi anemia group C gene augments interferon-gamma-induced apoptotic responses in hematopoietic cells.Blood. 1997; 90: 974-985Crossref PubMed Google Scholar, 38Pang Q. Keeble W. Christianson T.A. et al.FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity.EMBO J. 2001; 20: 4478-4489Crossref PubMed Scopus (115) Google Scholar]. This potential novel mechanism of MSC impact on hematopoiesis has not yet been scrutinized to any significant degree and remains a subject of intense investigation.Despite the encouraging observations of augmented hematopoiesis by MSCs in vitro with confirmation of these principles with multiple preclinical animal models [39Almeida-Porada G. Flake A.W. Glimp H.A. et al.Cotransplantation of stroma results in enhancement of engraftment and early expression of donor hematopoietic stem cells in utero.Exp Hematol. 1999; 27: 1569-1575Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 40Anker P.S. Noort W.A. Kruisselbrink A.B. et al.Nonexpanded primary lung and bone marrow-derived mesenchymal cells promote the engraftment of umbilical cord blood-derived CD34(+) cells in NOD/SCID mice.Exp Hematol. 2003; 31: 881-889Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar, 41Maitra B. Szekely E. Gjini K. et al.Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation.Bone Marrow Transplant. 2004; 33: 597-604Crossref PubMed Scopus (416) Google Scholar, 42Angelopoulou M. Novelli E. Grove J.E. et al.Cotransplantation of human mesenchymal stem cells enhances human myelopoiesis and megakaryocytopoiesis in NOD/SCID mice.Exp Hematol. 2003; 31: 413-420Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 43Fricke S. Ackerman M. Stolzing A. et al.Allogeneic non-adherent bone marrow cells facilitate hematopoietic recovery but do not lead to allogeneic engraftment.PLos One. 2009; 4: e6157Crossref PubMed Scopus (13) Google Scholar], there still remains a dearth of human studies that clearly document successful clinical augmentation of hematopoiesis by MSCs. Clinical application of MSCs could target enhancement of primary engraftment, or conversely, for application in patients experiencing or at risk for graft failure, recently shown in a retrospective analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) to be associated with over 90% mortality [44Schriber J. Agovi M.A. Ho V. et al.Second unrelated donor hematopoietic cell transplantation for primary graft failure.Biol Blood Marrow Transplant. 2010; 16: 1099-1106Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. The first studies of interest were first published over 15 years ago, and subsequently, several small studies have been completed that confirm safety of MSC infusion and perhaps demonstrate some utility, but as of yet, no phase III randomized trials have materialized. In patients undergoing peripheral blood stem cell transplantation (PBSCT) for rescue after high-dose myeloablative chemotherapy for breast cancer, coinfusion of autologous, ex vivo expanded MSC was found to be safe, and interestingly, demonstrated both neutrophil engraftment at a median of 8 days and platelet engraftment at 8.5 days [45Koc O.N. Gerson S.L. Cooper B.W. et al.Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy.J Clin Oncol. 2000; 18: 307-316PubMed Google Scholar]. MSC were also used specifically to target enhanced engraftment in a study reported by LeBlanc et al. [46LeBlanc K. Samuelsson H. Gustafsson B. et al.Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells.Leukemia. 2007; 21: 1733-1738Crossref PubMed Scopus (368) Google Scholar]. Seven patients, 3 of whom had already experienced graft failure/graft rejection, and 4 patients for whom hematopoietic engraftment were targeted for enhancement, were transplanted with HSCs and haploidentical MSCs, and all 7 achieved 100% donor chimerism with a median time to both neutrophil and platelet engraftment of 12 days. Subsequently, several other small studies in haploidentical HSC transplantation and of cord blood transplantation cotransplanted with MSC have suggested engraftment benefit, although this has not been universally confirmed [47Ball L.M. Bernardo M.E. Roelofs H. et al.Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation.Blood. 2007; 110: 2764-2767Crossref PubMed Scopus (434) Google Scholar, 48MacMillan M.L. Blazar B.R. DeFor T.E. et al.Transplantation of ex-vivo culture-expanded parental haploidentical mesenchymal stem cells to promote engraftment in pediatric recipients of unrelated donor umbilical cord blood: results of a phase I-II clinical trial.Bone Marrow Transplant. 2009; 43: 447-454Crossref PubMed Scopus (194) Google Scholar, 49Baron F. Lechanteur C. Willems E. et al.Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning.Biol Blood Marrow Transplant. 2010; 16: 838-847Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar].What is intriguing is whether or not MSC transplantation by itself can provide therapeutic benefit. Certainly, this approach is being highlighted in the field of regeneration medicine using MSC both for immunomodulatory therapeutics as well as for assisting in tissue repair [32Parekkadan B. Milwid J.M. Mesenchymal stem cells as therapeutics.Annu Rev Biomed. Eng. 2010; 12: 87-117Crossref PubMed Scopus (588) Google Scholar]. In HSCT, there have been isolated reports in which solitary MSC infusion may have provided therapeutic benefit. Specifically, Fouillard et al. [50Fouillard L. Chapel A. Bories D. et al.Infusion of allogeneic-related HLA mismatched mesenchymal stem cells for the treatment of incomplete engraftment following autologous haematopoietic stem cell transplantation.Leukemia. 2007; 21: 569-570Google Scholar] reported a single patient who underwent autologous stem cell transplantation for acute myelogenous leukemia (AML) who subsequently experienced partial graft failure, requiring ongoing growth factor in transfusion support. Even after an interval of over 2 years had passed, infusion of haploidentical MSCs from her brother was associated with reversal of the defect in hematopoiesis. Short-term but not long-term evidence of MSC engraftment was identified. Additionally, 6 patients with poor hematopoietic recovery after allogeneic transplantation were infused with donor-expanded MSC only [51Meuleman N. Tondreau T. Ahmad I. et al.Infusion of mesenchymal stromal cells can aid hematopoietic recovery following allogeneic hematopoietic stem cell myeloablative transplant: a pilot study.Stem Cell Dev. 2009; 18: 1249-1252Crossref Scopus (63) Google Scholar]. It was a suggestive result that 2 of the 6 patients experienced rapid recovery of donor hematopoiesis, although the other 4 failed to demonstrate benefit. Observations such as these have led to great interest in MSCs being considered for use as primary therapy for hematopoietic injury. There have been animal studies to suggest that cotransplantation of MSC with limiting doses of HSC after radiation injury can lead to enhanced survival of the animals associated with more rapid platelet and neutrophil recovery [52Hu K.X. Sun Q.Y. Guo M. et al.The radiation protection and therapy effects of mesenchymal stem cells in mice with acute radiation injury.Br J Radiol. 2010; 83: 52-58Crossref PubMed Scopus (66) Google Scholar, 53Dainiak N. Ricks R.C. The evolving role of haematopoietic cell transplantation in radiation injury: potentials and limitations.BJR Suppl. 2005; 27: 169-174Crossref PubMed Google Scholar]. Given these considerations, MSC therapy has emerged as a potential therapeutic maneuver for treatment of acute radiation syndrome, in the event of nuclear accidents or potential nuclear terrorist events, with a plan to stockpile for the Department of Defense large quantities of cryopreserved MSC. If FDA approval for MSC for treatment of acute radiation syndrome is eventually obtained, a staggered plan for delivery of 20,000 cryopreserved doses for the United States Emergency Preparedness Network has been put in place (Osiris, Inc., Website, announcement, 1/3/08).Significant work remains to be performed to actually confirm that MSCs should be utilized routinely to support hematopoiesis with enough efficiency to demonstrate a therapeutic benefit. Many questions remain regarding efficacious dose, optimized and targeted delivery, and relevant efficacy measurements. Recently, there have been interesting observations that umbilical cord HCT directly transplanted within the medullary cavity has been associated with improved engraftment [54Kimura T. Asada R. Wang J. et al.Identification of long-term repopulating potential of human cord blood-derived CD34-flt3-severe combined immunodeficiency-repopulating cells by intra-bone marrow injection.Stem Cells. 2007; 25: 1348-1355Crossref PubMed Scopus (37) Google Scholar, 55Frassoni F. Gualandi F. Podestá M. et al.Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study.Lancet Oncol. 2008; 9: 831-839Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 56Ramirez P.A. Wagner J.E. Brunstein C.G. Going straight to the point: intra-BM injection of hematopoietic progenitors.Bone Marrow Transplant. 2010; 45: 1127-1133Crossref PubMed Scopus (21) Google Scholar]. Certainly, many of the regeneration medicine efforts surrounding neurologic or cardiac repair have focused on issues of direct implantation versus systemic intravenous delivery. Trafficking of MSCs to relevant target areas is clearly confounded by pulmonary vascular bed retention, and whether augmentation of efficacy within the HSCT arena can be improved upon by direct implantation within the marrow cavity needs to be studied. A single case report provides tantalizing data on this subject [57Resnick I. Stepensky P. Elkin G. et al.MSC for the improvement of hematopoietic engraftment.Bone Marrow Transplant. 2010; 45: 605-606Crossref PubMed Scopus (15) Google Scholar]. A 3-year-old child with Wiscott-Aldrich syndrome underwent haploidentical HSCT from his mother with direct intraosseous injection of preexpanded, donor MSCs unilaterally into the iliac crest at 6 different sites. No clinical benefit could be documented, although posttransplant assessment at day 60 with bilateral bone marrow biopsies revea" @default.
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• W2004994175 title "MSCs in Hematopoietic Cell Transplantation" @default.
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