Implications of mesenchymal stem cells in regenerative medicine

Abstract Mesenchymal stem cells (MSCs) are a population of multipotent progenitors which reside in bone marrow, fat, and some other tissues and can be isolated from various adult and fetal tissues. Self-renewal potential and multipotency are MSC’s hallmarks. They have the capacity of proliferation and differentiation into a variety of cell lineages like osteoblasts, condrocytes, adipocytes, fibroblasts, cardiomyocytes. MSCs can be identified by expression of some surface molecules like CD73, CD90, CD105, and lack of hematopoietic specific markers including CD34, CD45, and HLA-DR. They are hopeful tools for regenerative medicine for repairing injured tissues. Many studies have focused on two significant features of MSC therapy: (I) systemically administered MSCs home to sites of ischemia or injury, and (II) MSCs can modulate T-cell-mediated immunological responses. MSCs express chemokine receptors and ligands involved in cells migration and homing process. MSCs induce immunomedulatory effects on the innate (dendritic cells, monocyte, natural killer cells, and neutrophils) and the adaptive immune system cells (T helper-1, cytotoxic T lymphocyte, and B lymphocyte) by secreting soluble factors like TGF-β, IL-10, IDO, PGE-2, sHLA-G5, or by cell–cell interaction. In this review, we discuss the main applications of mesenchymal stem in Regenerative Medicine and known mechanisms of homing and Immunomodulation of MSCs.

[1]  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.

[2]  O. Koç,et al.  Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells. , 2005, Experimental hematology.

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

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

[5]  Ariel Miller,et al.  Mesenchymal stem cells as an immunomodulatory therapeutic strategy for autoimmune diseases. , 2011, Autoimmunity reviews.

[6]  F. Dazzi,et al.  Mesenchymal stem cells for graft‐versus‐host disease: Close encounters with T cells , 2008, European journal of immunology.

[7]  D. Meldrum,et al.  The immunomodulatory properties of mesenchymal stem cells: implications for surgical disease. , 2011, The Journal of surgical research.

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

[9]  E. Gócza,et al.  Mesenchymal Stem Cells Cooperate with Bone Marrow Cells in Therapy of Diabetes , 2008, Stem cells.

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

[11]  S. Gerson,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. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  E. Guinan,et al.  Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation , 2003, Transplantation.

[13]  W. Wallace,et al.  Differential Effects of CD18, CD29, and CD49 Integrin Subunit Inhibition on Neutrophil Migration in Pulmonary Inflammation1 , 2001, The Journal of Immunology.

[14]  B. Baradaran,et al.  Immunomodulatory nature and site specific affinity of mesenchymal stem cells: a hope in cell therapy. , 2014, Advanced pharmaceutical bulletin.

[15]  Frank P Barry,et al.  Mesenchymal stem cells avoid allogeneic rejection , 2005, Journal of Inflammation.

[16]  M. Richard,et al.  Human Bone Marrow Mesenchymal Stem Cells Can Express Insulin and Key Transcription Factors of the Endocrine Pancreas Developmental Pathway upon Genetic and/or Microenvironmental Manipulation In Vitro , 2005, Stem cells.

[17]  Hulun Li,et al.  Administration of bone marrow stromal cells ameliorates experimental autoimmune myasthenia gravis by altering the balance of Th1/Th2/Th17/Treg cell subsets through the secretion of TGF-β , 2009, Journal of Neuroimmunology.

[18]  M. Pevsner-Fischer,et al.  Toll-like receptors and their ligands control mesenchymal stem cell functions. , 2007, Blood.

[19]  B. Thébaud,et al.  Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. , 2012, Stem cells and development.

[20]  Giselle Chamberlain,et al.  Concise Review: Mesenchymal Stem Cells: Their Phenotype, Differentiation Capacity, Immunological Features, and Potential for Homing , 2007, Stem cells.

[21]  M. Shi,et al.  Immunomodulatory properties and therapeutic application of mesenchymal stem cells , 2011, Clinical and experimental immunology.

[22]  M. Aurrand-Lions,et al.  Adhesion mechanisms regulating the migration of monocytes , 2004, Nature Reviews Immunology.

[23]  R. Alon,et al.  Immune cell migration in inflammation: present and future therapeutic targets , 2005, Nature Immunology.

[24]  W. Krivit,et al.  Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. , 1999, Current opinion in neurology.

[25]  N. Arsenijević,et al.  Interleukin-1 receptor antagonist (IL-1Ra) and IL-1Ra producing mesenchymal stem cells as modulators of diabetogenesis , 2010, Autoimmunity.

[26]  S. Perez,et al.  Interactions Between Human Mesenchymal Stem Cells and Natural Killer Cells , 2006, Stem cells.

[27]  J. Schwarzbauer,et al.  Fibronectin fragmentation promotes α4β1 integrin-mediated contraction of a fibrin-fibronectin provisional matrix , 2005 .

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

[29]  C Dumitrache,et al.  Mesenchymal stem cells: Stem cell therapy perspectives for type 1 diabetes. , 2009, Diabetes & metabolism.

[30]  M. Krampera,et al.  Mesenchymal stem cells for clinical application , 2010, Vox sanguinis.

[31]  Jae W. Lee,et al.  Potential application of mesenchymal stem cells in acute lung injury , 2009, Expert opinion on biological therapy.

[32]  E. Lam,et al.  Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. , 2005, Blood.

[33]  I. Morita,et al.  Regulation of bone morphogenetic protein‐2 expression by endogenous prostaglandin E2 in human mesenchymal stem cells , 2004, Journal of cellular physiology.

[34]  A. Esmaeilzadeh,et al.  Introducing the immunomodulatory effects of mesenchymal stem cells in an experimental model of Behcet's disease , 2012 .

[35]  Jiqi Yan,et al.  Mesenchymal stem cell-conditioned medium reduces liver injury and enhances regeneration in reduced-size rat liver transplantation. , 2013, The Journal of surgical research.

[36]  A. Caplan,et al.  Mesenchymal stem cells as trophic mediators , 2006, Journal of cellular biochemistry.

[37]  C. Jorgensen,et al.  Mesenchymal Stem Cells Inhibit Human Th17 Cell Differentiation and Function and Induce a T Regulatory Cell Phenotype , 2010, The Journal of Immunology.

[38]  F. Djouad,et al.  Mesenchymal Stem Cells Inhibit the Differentiation of Dendritic Cells Through an Interleukin‐6‐Dependent Mechanism , 2007, Stem cells.

[39]  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.

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

[41]  G. Pizzolo,et al.  Regenerative and immunomodulatory potential of mesenchymal stem cells. , 2006, Current opinion in pharmacology.

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

[43]  S. Akira,et al.  Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. , 2006, Immunity.

[44]  Jakub Tolar,et al.  Concise Review: Hitting the Right Spot with Mesenchymal Stromal Cells , 2010, Stem cells.

[45]  L. Moretta,et al.  Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. , 2008, Blood.

[46]  S. Haynesworth,et al.  Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation , 2004, Bone Marrow Transplantation.

[47]  Ulrich Göbel,et al.  bloodjournal.hematologylibrary.org at PENN STATE UNIVERSITY on February 20, 2013. For personal use , 2004 .

[48]  R. Alon,et al.  Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. , 1999, Science.

[49]  F. Benvenuto,et al.  Reciprocal Interactions Between Human Mesenchymal Stem Cells and γδ T Cells Or Invariant Natural Killer T Cells , 2009, Stem cells.

[50]  K. Atkinson,et al.  Mesenchymal stem cells: Immunobiology and therapeutic potential in kidney disease (Review Article) , 2007, Nephrology.

[51]  P. Rameshwar,et al.  Veto-Like Activity of Mesenchymal Stem Cells: Functional Discrimination Between Cellular Responses to Alloantigens and Recall Antigens1 , 2003, The Journal of Immunology.

[52]  B. Kalionis,et al.  Immunosuppressive Properties of Mesenchymal Stem Cells , 2011, Stem Cell Reviews and Reports.

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

[54]  A. Cometa,et al.  Inherited thrombocytopenias: from genes to therapy , 1994 .

[55]  Wei Zhang,et al.  Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. , 2004, Stem cells and development.

[56]  E. Ruoslahti.  Fibronectin in cell adhesion and invasion , 2004, Cancer and Metastasis Reviews.

[57]  O. Ringdén,et al.  Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells , 2003, Transplantation.

[58]  W. Koo,et al.  Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. , 2001, Blood.

[59]  R. Willemze,et al.  Mesenchymal Stem Cells Inhibit Generation and Function of Both CD34+-Derived and Monocyte-Derived Dendritic Cells1 , 2006, The Journal of Immunology.

[60]  A. Nicolaou,et al.  The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. , 2010, International immunopharmacology.

[61]  D. Munn,et al.  Prevention of allogeneic fetal rejection by tryptophan catabolism. , 1998, Science.

[62]  A I Caplan,et al.  Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. , 1995, Bone marrow transplantation.

[63]  O. Mandelboim,et al.  Inhibitory NK Receptor Recognition of HLA-G: Regulation by Contact Residues and by Cell Specific Expression at the Fetal-Maternal Interface , 2010, PloS one.

[64]  Ronald G. Tompkins,et al.  Mesenchymal Stem Cells: Mechanisms of Immunomodulation and Homing , 2010, Cell transplantation.

[65]  M. Stojkovic,et al.  Regenerative Medicine Concise Review: Mesenchymal Stem Cell Treatment of the Complications of Diabetes Mellitus , 2022 .

[66]  J. Glowacki,et al.  Age‐related decline in the osteogenic potential of human bone marrow cells cultured in three‐dimensional collagen sponges , 2001, Journal of cellular biochemistry.

[67]  L. Fouillard,et al.  Selected Stro‐1‐enriched bone marrow stromal cells display a major suppressive effect on lymphocyte proliferation , 2009, International journal of laboratory hematology.

[68]  N. Ishiguro,et al.  Transplantation of marrow-derived mesenchymal stem cells and platelet-rich plasma during distraction osteogenesis--a preliminary result of three cases. , 2004, Bone.

[69]  F. Montecucco,et al.  Human Mesenchymal Stem Cells Inhibit Neutrophil Apoptosis: A Model for Neutrophil Preservation in the Bone Marrow Niche , 2008, Stem cells.

[70]  T. Springer,et al.  Expression of Stromal-Derived Factor-1 Is Decreased by IL-1 and TNF and in Dermal Wound Healing1 , 2001, The Journal of Immunology.

[71]  R. Muschel,et al.  Mesenchymal Stem Cells Prevent the Rejection of Fully Allogenic Islet Grafts by the Immunosuppressive Activity of Matrix Metalloproteinase-2 and -9 , 2009, Diabetes.

[72]  Q. Han,et al.  Effects of allogeneic bone marrow-derived mesenchymal stem cells on T and B lymphocytes from BXSB mice. , 2005, DNA and cell biology.

[73]  R. Cancedda,et al.  Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway , 2005, European journal of immunology.

[74]  R. Bronson,et al.  Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[75]  Jason S. Mitchell,et al.  Contrasting Roles for Domain 4 of VCAM-1 in the Regulation of Cell Adhesion and Soluble VCAM-1 Binding to Integrin α4β11 , 2006, The Journal of Immunology.

[76]  Jung‐Sik Kim,et al.  Immunomodulation of Delayed-Type Hypersensitivity Responses by Mesenchymal Stem Cells Is Associated with Bystander T Cell Apoptosis in the Draining Lymph Node , 2010, The Journal of Immunology.

[77]  L. Cheng,et al.  Suppression of human peripheral blood lymphocyte proliferation by immortalized mesenchymal stem cells derived from bone marrow of Banna Minipig inbred-line. , 2004, Transplantation proceedings.

[78]  L. Moretta,et al.  Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. , 2006, Blood.

[79]  P. Holt,et al.  Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signaling pathway. , 1998, Journal of immunology.

[80]  Yufang Shi,et al.  The role of IL-6 in inhibition of lymphocyte apoptosis by mesenchymal stem cells. , 2007, Biochemical and biophysical research communications.

[81]  E. Ruoslahti,et al.  β1 Integrins Are Critically Involved in Neutrophil Locomotion in Extravascular Tissue In Vivo , 1998, The Journal of experimental medicine.

[82]  N. Rouas-Freiss,et al.  Human Leukocyte Antigen‐G5 Secretion by Human Mesenchymal Stem Cells Is Required to Suppress T Lymphocyte and Natural Killer Function and to Induce CD4+CD25highFOXP3+ Regulatory T Cells , 2008, Stem cells.

[83]  F. Djouad,et al.  Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. , 2003, Blood.

[84]  O. Ringdén,et al.  Mesenchymal Stem Cells Inhibit the Expression of CD25 (Interleukin‐2 Receptor) and CD38 on Phytohaemagglutinin‐Activated Lymphocytes , 2004, Scandinavian journal of immunology.

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

[86]  E. Horwitz,et al.  MSCs in hematopoietic cell transplantation. , 2011, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[87]  O. Ringdén,et al.  TRANSPLANTATION IN RELATION TO THE TREATMENT OF INHERITED DISEASE , 1984, Transplantation.

[88]  R. Steinman,et al.  Dendritic cells and the control of immunity , 1998, Nature.

[89]  F. Djouad,et al.  Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications , 2010, Stem Cell Research & Therapy.

[90]  A. Nauta,et al.  Immunomodulatory properties of mesenchymal stromal cells. , 2007, Blood.

[91]  Sergio Romagnani,et al.  Role for Interferon‐γ in the Immunomodulatory Activity of Human Bone Marrow Mesenchymal Stem Cells , 2006 .

[92]  Sergio Romagnani,et al.  Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. , 2006, Stem cells.

[93]  R. Sackstein.  The lymphocyte homing receptors: gatekeepers of the multistep paradigm , 2005, Current opinion in hematology.

[94]  Jason S. Mitchell,et al.  Contrasting roles for domain 4 of VCAM-1 in the regulation of cell adhesion and soluble VCAM-1 binding to integrin alpha4beta1. , 2006, Journal of immunology.

[95]  Mohamed H. Sayegh,et al.  Immunomodulation by Mesenchymal Stem Cells , 2008, Diabetes.

[96]  D. Sillence,et al.  Clinical variability in osteogenesis imperfecta-variable expressivity or genetic heterogeneity. , 1979, Birth defects original article series.

[97]  Y. Bertrand,et al.  Human mesenchymal stem cells suppress induction of cytotoxic response to alloantigens. , 2004, Biorheology.

[98]  B. Seliger,et al.  The immunomodulatory capacity of mesenchymal stem cells. , 2012, Trends in molecular medicine.

[99]  Kazuya Sato,et al.  Mesenchymal stromal cells for graft-versus-host disease : basic aspects and clinical outcomes. , 2010, Journal of clinical and experimental hematopathology : JCEH.

[100]  Antonio Uccelli,et al.  Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis , 2007, Annals of neurology.

[101]  P. Hematti,et al.  Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. , 2009, Experimental hematology.

[102]  L. Moretta,et al.  MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. , 2009, Blood.

[103]  Ira Mellman,et al.  Dendritic Cells Specialized and Regulated Antigen Processing Machines , 2001, Cell.

[104]  K. Gyo,et al.  Experimental vestibular neuritis induced by herpes simplex virus. , 1993, Acta oto-laryngologica. Supplementum.

[105]  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.

[106]  J. Ryan,et al.  Interferon‐γ does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells , 2007 .

[107]  Yuan Yang,et al.  The immunomodulatory activity of human umbilical cord blood‐derived mesenchymal stem cells in vitro , 2009, Immunology.

[108]  O. Ringdén,et al.  Immunomodulation by mesenchymal stem cells and clinical experience , 2007, Journal of internal medicine.

[109]  M. Soleimani,et al.  Isolation and ex vivo expansion of human umbilical cord blood-derived CD34+ stem cells and their cotransplantation with or without mesenchymal stem cells , 2009, Hematology.