Concise Review: Mesenchymal Stem Cells: Their Phenotype, Differentiation Capacity, Immunological Features, and Potential for Homing

MSCs are nonhematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. MSCs are rare in bone marrow, representing ∼1 in 10,000 nucleated cells. Although not immortal, they have the ability to expand manyfold in culture while retaining their growth and multilineage potential. MSCs are identified by the expression of many molecules including CD105 (SH2) and CD73 (SH3/4) and are negative for the hematopoietic markers CD34, CD45, and CD14. The properties of MSCs make these cells potentially ideal candidates for tissue engineering. It has been shown that MSCs, when transplanted systemically, are able to migrate to sites of injury in animals, suggesting that MSCs possess migratory capacity. However, the mechanisms underlying the migration of these cells remain unclear. Chemokine receptors and their ligands and adhesion molecules play an important role in tissue‐specific homing of leukocytes and have also been implicated in trafficking of hematopoietic precursors into and through tissue. Several studies have reported the functional expression of various chemokine receptors and adhesion molecules on human MSCs. Harnessing the migratory potential of MSCs by modulating their chemokine‐chemokine receptor interactions may be a powerful way to increase their ability to correct inherited disorders of mesenchymal tissues or facilitate tissue repair in vivo. The current review describes what is known about MSCs and their capacity to home to tissues together with the associated molecular mechanisms involving chemokine receptors and adhesion molecules.

[1]  B. Palsson,et al.  Human Adult Stem Cells , 2009 .

[2]  N. Gallay,et al.  The In Vitro Migration Capacity of Human Bone Marrow Mesenchymal Stem Cells: Comparison of Chemokine and Growth Factor Chemotactic Activities , 2007, Stem cells.

[3]  M. Endres,et al.  Towards in situ tissue repair: Human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2 , 2007, Journal of cellular biochemistry.

[4]  P. Tiberghien,et al.  Human and rodent bone marrow mesenchymal stem cells that express primitive stem cell markers can be directly enriched by using the CD49a molecule , 2007, Cell and Tissue Research.

[5]  E. Seifried,et al.  Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells. , 2006, Blood.

[6]  K. Houkin,et al.  Intravenous administration of glial cell line‐derived neurotrophic factor gene‐modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat , 2006, Journal of neuroscience research.

[7]  R. Schwinger,et al.  Mesenchymal stem cells transmigrate over the endothelial barrier. , 2006, European journal of cell biology.

[8]  Massimo Franchini,et al.  Mesenchymal stem cells for bone, cartilage, tendon and skeletal muscle repair. , 2006, Bone.

[9]  V. Eder,et al.  Multipotential Mesenchymal Stem Cells Are Mobilized into Peripheral Blood by Hypoxia , 2006, Stem Cells.

[10]  Steve S. Lee,et al.  Intravenous mesenchymal stem cell therapy early after reperfused acute myocardial infarction improves left ventricular function and alters electrophysiologic properties. , 2006, International journal of cardiology.

[11]  A. Lucia,et al.  Mobilisation of mesenchymal cells into blood in response to skeletal muscle injury , 2006, British Journal of Sports Medicine.

[12]  Wei Zheng,et al.  Effects of Myocardial Transplantation of Marrow Mesenchymal Stem Cells Transfected with Vascular Endothelial Growth Factor for the Improvement of Heart Function and Angiogenesis after Myocardial Infarction , 2006, Cardiology.

[13]  Robert L Wilensky,et al.  A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. , 2006, European heart journal.

[14]  J. Klein-Nulend,et al.  Osteogenesis versus chondrogenesis by BMP-2 and BMP-7 in adipose stem cells. , 2006, Biochemical and biophysical research communications.

[15]  I. Ghiran,et al.  Human Bone Marrow Stromal Cells Express a Distinct Set of Biologically Functional Chemokine Receptors , 2006, Stem cells.

[16]  N. Gorin,et al.  Local Irradiation Not Only Induces Homing of Human Mesenchymal Stem Cells at Exposed Sites but Promotes Their Widespread Engraftment to Multiple Organs: A Study of Their Quantitative Distribution After Irradiation Damage , 2006, Stem cells.

[17]  S. Bossi,et al.  Bloodstream cells phenotypically identical to human mesenchymal bone marrow stem cells circulate in large amounts under the influence of acute large skin damage: new evidence for their use in regenerative medicine. , 2006, Transplantation proceedings.

[18]  G. D. De Keulenaer,et al.  Mesenchymal stem cell adhesion to cardiac microvascular endothelium: activators and mechanisms. , 2006, American journal of physiology. Heart and circulatory physiology.

[19]  R. Pochampally,et al.  A subset of human rapidly self-renewing marrow stromal cells preferentially engraft in mice. , 2006, Blood.

[20]  R. Ransohoff,et al.  The many roles of chemokines and chemokine receptors in inflammation. , 2006, The New England journal of medicine.

[21]  M. Frid,et al.  Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. , 2006, The American journal of pathology.

[22]  D. Toomre,et al.  Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains , 2006, Nature Cell Biology.

[23]  J. Bulte,et al.  MR evaluation of the glomerular homing of magnetically labeled mesenchymal stem cells in a rat model of nephropathy. , 2006, Radiology.

[24]  F. Benvenuto,et al.  Human mesenchymal stem cells modulate B-cell functions. , 2006, Blood.

[25]  Yan-min Zhang,et al.  Migration of intravenously grafted mesenchymal stem cells to injured heart in rats. , 2005, Sheng li xue bao : [Acta physiologica Sinica].

[26]  G. Mancardi,et al.  Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. , 2005, Blood.

[27]  E. Bonifacio,et al.  Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. , 2005, Blood.

[28]  M. Liebergall,et al.  Murine spinal fusion induced by engineered mesenchymal stem cells that conditionally express bone morphogenetic protein-2. , 2005, Journal of neurosurgery. Spine.

[29]  P. Nelson,et al.  Human adult CD34- progenitor cells functionally express the chemokine receptors CCR1, CCR4, CCR7, CXCR5, and CCR10 but not CXCR4. , 2005, Stem cells and development.

[30]  K. Ohta,et al.  Vascular Endothelial Growth Factor–Expressing Mesenchymal Stem Cell Transplantation for the Treatment of Acute Myocardial Infarction , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[31]  Yi Zhang,et al.  Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. , 2005, Blood.

[32]  T. Lapidot,et al.  Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. , 2005, Blood.

[33]  F. Djouad,et al.  Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis. , 2005, Arthritis and rheumatism.

[34]  Lisa M. Ebert,et al.  Chemokine-mediated control of T cell traffic in lymphoid and peripheral tissues. , 2005, Molecular immunology.

[35]  Andrea Bacigalupo,et al.  Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[36]  O. Ringdén,et al.  Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[37]  D. Mevorach,et al.  Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. , 2005, Blood.

[38]  M. Pittenger,et al.  Human mesenchymal stem cells modulate allogeneic immune cell responses. , 2005, Blood.

[39]  B. Yue,et al.  Ectopic bone formation of human bone morphogenetic protein-2 gene transfected goat bone marrow-derived mesenchymal stem cells in nude mice. , 2005, Chinese journal of traumatology = Zhonghua chuang shang za zhi.

[40]  H. Okano,et al.  Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. , 2004, Blood.

[41]  H. Ohgushi,et al.  Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis. , 2004, American journal of physiology. Heart and circulatory physiology.

[42]  Yan Huang,et al.  Stromal Cell–Derived Factor-1α Plays a Critical Role in Stem Cell Recruitment to the Heart After Myocardial Infarction but Is Not Sufficient to Induce Homing in the Absence of Injury , 2004, Circulation.

[43]  I. Bellantuono,et al.  A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. , 2004, Blood.

[44]  Heather Kalish,et al.  Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI. , 2004, Blood.

[45]  Moustapha Hassan,et al.  Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells , 2004, The Lancet.

[46]  A. Flake,et al.  Mesenchymal stem cells: paradoxes of passaging. , 2004, Experimental hematology.

[47]  B. Larson,et al.  Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. , 2004, Blood.

[48]  J. Wergedal,et al.  Local ex vivo gene therapy with bone marrow stromal cells expressing human BMP4 promotes endosteal bone formation in mice , 2004, The journal of gene medicine.

[49]  G. Sukhikh,et al.  Mesenchymal Stem Cells , 2002, Bulletin of Experimental Biology and Medicine.

[50]  O. Ringdén,et al.  Immunologic properties of human fetal mesenchymal stem cells. , 2004, American journal of obstetrics and gynecology.

[51]  O. Ringdén,et al.  HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. , 2003, Experimental hematology.

[52]  Robert A. Kloner,et al.  Systemic Delivery of Bone Marrow–Derived Mesenchymal Stem Cells to the Infarcted Myocardium: Feasibility, Cell Migration, and Body Distribution , 2003, Circulation.

[53]  G. Kopen,et al.  Characterization of mesenchymal stem cells isolated from murine bone marrow by negative selection , 2003, Journal of cellular biochemistry.

[54]  F. Claas,et al.  Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. , 2003, Blood.

[55]  J. Hata,et al.  In vivo cardiovasculogenesis by direct injection of isolated adult mesenchymal stem cells. , 2003, Experimental cell research.

[56]  Naftali Kaminski,et al.  Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[57]  Elizabeth Simpson,et al.  Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. , 2003, Blood.

[58]  V. Starnes,et al.  Migration of mesenchymal stem cells to heart allografts during chronic rejection , 2003, Transplantation.

[59]  J. Isner,et al.  Stromal Cell–Derived Factor-1 Effects on Ex Vivo Expanded Endothelial Progenitor Cell Recruitment for Ischemic Neovascularization , 2003, Circulation.

[60]  J. Lévesque,et al.  Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. , 2003, The Journal of clinical investigation.

[61]  G. Reilly,et al.  BMP Responsiveness in Human Mesenchymal Stem Cells , 2003, Connective tissue research.

[62]  O. Ringdén,et al.  Mesenchymal Stem Cells Inhibit and Stimulate Mixed Lymphocyte Cultures and Mitogenic Responses Independently of the Major Histocompatibility Complex , 2003, Scandinavian journal of immunology.

[63]  R. Willemze,et al.  Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. , 2003, Haematologica.

[64]  Paul Emery,et al.  Isolation and characterization of bone marrow multipotential mesenchymal progenitor cells. , 2002, Arthritis and rheumatism.

[65]  Min Zhu,et al.  Human adipose tissue is a source of multipotent stem cells. , 2002, Molecular biology of the cell.

[66]  D. Meyer,et al.  Guidance of Primordial Germ Cell Migration by the Chemokine SDF-1 , 2002, Cell.

[67]  M. Andreeff,et al.  Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. , 2002, Cancer research.

[68]  R. Taichman,et al.  G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4 , 2002, Nature Immunology.

[69]  L. Muul,et al.  Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[70]  R. Alon,et al.  Endothelial Chemokines Destabilize L-selectin-mediated Lymphocyte Rolling without Inducing Selectin Shedding* 210 , 2002, The Journal of Biological Chemistry.

[71]  C. Carlo-Stella,et al.  Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. , 2002, Blood.

[72]  A. Manira,et al.  Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[73]  M. Aurrand-Lions,et al.  The last molecular fortress in leukocyte trans-endothelial migration , 2002, Nature Immunology.

[74]  Kevin McIntosh,et al.  Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. , 2002, Experimental hematology.

[75]  D. Benayahu,et al.  Identification of cultured progenitor cells from human marrow stroma , 2002, Journal of cellular biochemistry.

[76]  I. Petit G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4 , 2002, Nature Immunology.

[77]  C. Verfaillie,et al.  Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. , 2001, Blood.

[78]  M. Chopp,et al.  Treatment of Traumatic Brain Injury in Adult Rats with Intravenous Administration of Human Bone Marrow Stromal Cells , 2001, Neurosurgery.

[79]  N. Fisk,et al.  Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. , 2001, Blood.

[80]  J Kohyama,et al.  Brain from bone: efficient "meta-differentiation" of marrow stroma-derived mature osteoblasts to neurons with Noggin or a demethylating agent. , 2001, Differentiation; research in biological diversity.

[81]  Federica Limana,et al.  Mobilized bone marrow cells repair the infarcted heart, improving function and survival , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[82]  M. Baggiolini Chemokines in pathology and medicine , 2001, Journal of internal medicine.

[83]  M. Entman,et al.  Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. , 2001, The Journal of clinical investigation.

[84]  A. Caplan,et al.  The Dynamic in vivo Distribution of Bone Marrow-Derived Mesenchymal Stem Cells after Infusion , 2001, Cells Tissues Organs.

[85]  David M. Bodine,et al.  Bone marrow cells regenerate infarcted myocardium , 2001, Nature.

[86]  M. Chopp,et al.  Therapeutic Benefit of Intravenous Administration of Bone Marrow Stromal Cells After Cerebral Ischemia in Rats , 2001, Stroke.

[87]  S. Gronthos,et al.  Integrin-mediated interactions between human bone marrow stromal precursor cells and the extracellular matrix. , 2001, Bone.

[88]  T. A. Hewett,et al.  Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. , 2001, Experimental hematology.

[89]  Alan W. Flake,et al.  Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep , 2000, Nature Medicine.

[90]  N. Zvaifler,et al.  Mesenchymal cells expressing bone morphogenetic protein receptors are present in the rheumatoid arthritis joint. , 2000, Arthritis and rheumatism.

[91]  Jill Moss,et al.  Mesenchymal precursor cells in the blood of normal individuals , 2000, Arthritis Research & Therapy.

[92]  I. Black,et al.  Adult rat and human bone marrow stromal cells differentiate into neurons , 2000, Journal of neuroscience research.

[93]  Kathleen M. Smith,et al.  Identification of a Novel Chemokine (CCL28), which Binds CCR10 (GPR2)* , 2000, The Journal of Biological Chemistry.

[94]  Weiqi Wang,et al.  Cutting Edge: The Orphan Chemokine Receptor G Protein-Coupled Receptor-2 (GPR-2, CCR10) Binds the Skin-Associated Chemokine CCL27 (CTACK/ALP/ILC)1 , 2000, The Journal of Immunology.

[95]  D J Prockop,et al.  Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[96]  J. Gutiérrez-Ramos,et al.  Eotaxin: from an eosinophilic chemokine to a major regulator of allergic reactions. , 1999, Immunology today.

[97]  James J. Campbell,et al.  Human G Protein–Coupled Receptor Gpr-9-6/Cc Chemokine Receptor 9 Is Selectively Expressed on Intestinal Homing T Lymphocytes, Mucosal Lymphocytes, and Thymocytes and Is Required for Thymus-Expressed Chemokine–Mediated Chemotaxis , 1999, The Journal of experimental medicine.

[98]  P. Conget,et al.  Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells , 1999, Journal of cellular physiology.

[99]  D J Prockop,et al.  Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[100]  James J. Campbell,et al.  The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells , 1999, Nature.

[101]  B. Frenkel,et al.  Osteoblast-specific gene expression after transplantation of marrow cells: implications for skeletal gene therapy. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[102]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[103]  Darwin J. Prockop,et al.  Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta , 1999, Nature Medicine.

[104]  Jakob S. Jensen,et al.  Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. , 1999, The Journal of clinical investigation.

[105]  F. Sánchez‐Madrid,et al.  Leukocyte polarization in cell migration and immune interactions , 1999, The EMBO journal.

[106]  A. Mantovani,et al.  Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. , 1998, Journal of immunology.

[107]  M. Baggiolini Chemokines and leukocyte traffic , 1998, Nature.

[108]  Joseph Zaia,et al.  Mesenchymal Stem Cell Surface Antigen SB‐10 Corresponds to Activated Leukocyte Cell Adhesion Molecule and Is Involved in Osteogenic Differentiation , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[109]  C. Mackay,et al.  The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. , 1998, The Journal of clinical investigation.

[110]  A M Mackay,et al.  Chondrogenic differentiation of cultured human mesenchymal stem cells from marrow. , 1998, Tissue engineering.

[111]  C. Mackay,et al.  Functional expression of the eotaxin receptor CCR3 in T lymphocytes co-localizing with eosinophils , 1997, Current Biology.

[112]  M. Auer,et al.  Transcytosis and Surface Presentation of IL-8 by Venular Endothelial Cells , 1997, Cell.

[113]  A I Caplan,et al.  Stimulatory Effects of Basic Fibroblast Growth Factor and Bone Morphogenetic Protein‐2 on Osteogenic Differentiation of Rat Bone Marrow‐Derived Mesenchymal Stem Cells , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[114]  D. Prockop Marrow Stromal Cells as Stem Cells for Nonhematopoietic Tissues , 1997, Science.

[115]  Wei Wang,et al.  A new class of membrane-bound chemokine with a CX3C motif , 1997, Nature.

[116]  A. Caplan,et al.  Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5‐azacytidine , 1995, Muscle & nerve.

[117]  D. Largaespada,et al.  Lymphotactin: a cytokine that represents a new class of chemokine. , 1994, Science.

[118]  V. Koteliansky,et al.  Stromal cells from human long-term marrow cultures are mesenchymal cells that differentiate following a vascular smooth muscle differentiation pathway. , 1993, Blood.

[119]  A. Caplan,et al.  Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies. , 1992, Bone.

[120]  S. Bruder,et al.  In vitro differentiation of bone and hypertrophic cartilage from periosteal-derived cells. , 1991, Experimental cell research.

[121]  D. Gazit,et al.  Kinetics and differentiation of marrow stromal cells in diffusion chambers in vivo. , 1986, Journal of cell science.

[122]  C. R. Howlett,et al.  Formation of bone and cartilage by marrow stromal cells in diffusion chambers in vivo. , 1980, Clinical orthopaedics and related research.

[123]  H. Broxmeyer,et al.  Characterization of human bone marrow fibroblast colony-forming cells (CFU-F) and their progeny. , 1980, Blood.

[124]  N. Kulagina,et al.  Fibroblast precursors in normal and irradiated mouse hematopoietic organs. , 1976, Experimental hematology.