Mesenchymal stem cells use integrin beta1 not CXC chemokine receptor 4 for myocardial migration and engraftment.

Recent evidence has demonstrated the importance of bone marrow-derived mesenchymal stem cells (BM-MSCs) in the repair of damaged myocardium. The molecular mechanisms of engraftment and migration of BM-MSCs in the ischemic myocardium are unknown. In this study, we developed a functional genomics approach toward the identification of mediators of engraftment and migration of BM-MSCs within the ischemic myocardium. Our strategy involves microarray profiling (>22,000 probes) of ischemic hearts, complemented by reverse transcription-polymerase chain reaction and fluorescence-activated cell sorting of corresponding adhesion molecule and cytokine receptors in BM-MSCs to focus on the coexpressed pairs only. Our data revealed nine complementary adhesion molecules and cytokine receptors, including integrin beta1, integrin alpha4, and CXC chemokine receptor 4 (CXCR4). To examine their functional contributions, we first blocked selectively these receptors by preincubation of BM-MSCs with specific neutralizing antibodies, and then we administered these cells intramyocardially. A significant reduction in the total number of BM-MSC in the infarcted myocardium was observed after integrin beta1 blockade but not integrin alpha4 or CXCR4 blockade. The latter observation is distinctively different from that reported for hematopoietic stem cells (HSCs). Thus, our data show that BM-MSCs use a different pathway from HSCs for intramyocardial trafficking and engraftment.

[1]  G. Edelman,et al.  Site-restricted expression of cytotactin during development of the chicken embryo , 1986, The Journal of cell biology.

[2]  R. Ganju,et al.  The α-Chemokine, Stromal Cell-derived Factor-1α, Binds to the Transmembrane G-protein-coupled CXCR-4 Receptor and Activates Multiple Signal Transduction Pathways* , 1998, The Journal of Biological Chemistry.

[3]  B. Fleischmann,et al.  Bone marrow–derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation , 2004, Nature Medicine.

[4]  M. Hiroe,et al.  Tenascin-C Modulates Adhesion of Cardiomyocytes to Extracellular Matrix during Tissue Remodeling after Myocardial Infarction , 2001, Laboratory Investigation.

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

[6]  B. Gersh.  Stem Cell Mobilization Induced by Subcutaneous Granulocyte-Colony Stimulating Factor to Improve Cardiac Regeneration After Acute ST-Elevation Myocardial Infarction: Result of the Double-Blind, Randomized, Placebo-Controlled Stem Cells in Myocardial Infarction (STEMMI) Trial , 2007 .

[7]  J. Morgan,et al.  Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats. , 2002, Journal of applied physiology.

[8]  Hung-Fat Tse,et al.  Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation , 2003, The Lancet.

[9]  Geoffrey C Gurtner,et al.  Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1 , 2004, Nature Medicine.

[10]  Ling-jia Wang,et al.  Engraftment assessment in human and mouse liver tissue after sex‐mismatched liver cell transplantation by real‐time quantitative PCR for Y chromosome sequences , 2002, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[11]  G. Schulze-Tanzil,et al.  Increase of fibronectin and osteopontin in porcine hearts following ischemia and reperfusion , 2005, Journal of Molecular Medicine.

[12]  James T. Willerson,et al.  Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure , 2003, Circulation.

[13]  Sean P. Palecek,et al.  Integrin-ligand binding properties govern cell migration speed through cell-substratum adhesiveness , 1997, Nature.

[14]  M. Pittenger,et al.  Mesenchymal stem cells and their potential as cardiac therapeutics. , 2004, Circulation research.

[15]  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.

[16]  L. Lindbom,et al.  Integrin-dependent neutrophil migration in extravascular tissue. , 2002, Seminars in immunology.

[17]  Z. Ding,et al.  Role of &agr;4 Integrin and VCAM-1 in CD18-Independent Neutrophil Migration Across Mouse Cardiac Endothelium , 2002, Circulation research.

[18]  F. Chu,et al.  Fibroblasts are in a position to provide directional information to migrating neutrophils during pneumonia in rabbit lungs. , 1996, Microvascular research.

[19]  Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) , 2002 .

[20]  Melinda Larsen,et al.  Cell and fibronectin dynamics during branching morphogenesis , 2006, Journal of Cell Science.

[21]  L. Silengo,et al.  Expression and functional analysis of a cytoplasmic domain variant of the beta 1 integrin subunit , 1993, The Journal of cell biology.

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

[23]  D. Lauffenburger,et al.  Cell Migration: A Physically Integrated Molecular Process , 1996, Cell.

[24]  H. Johnsen,et al.  Stem Cell Mobilization Induced by Subcutaneous Granulocyte-Colony Stimulating Factor to Improve Cardiac Regeneration After Acute ST-Elevation Myocardial Infarction: Result of the Double-Blind, Randomized, Placebo-Controlled Stem Cells in Myocardial Infarction (STEMMI) Trial , 2006, Circulation.

[25]  N. Gattermann,et al.  Intrakoronare, humane autologe Stammzelltransplantation zur Myokardregeneration nach Herzinfarkt , 2001 .

[26]  J. Murphy-Ullrich.  The de-adhesive activity of matricellular proteins: is intermediate cell adhesion an adaptive state? , 2001, The Journal of clinical investigation.

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

[28]  James J. Campbell,et al.  Sustained Activation of Cell Adhesion Is a Differentially Regulated Process in B Lymphopoiesis , 2003, The Journal of experimental medicine.

[29]  A. Kurtz,et al.  Cyclic AMP stimulates renin gene transcription in juxtaglomerular cells , 2002, Pflügers Archiv.

[30]  A. Issekutz,et al.  The β1 integrin, very late activation antigen‐4 on human neutrophils can contribute to neutrophil migration through connective tissue fibroblast barriers , 1997, Immunology.

[31]  Y. Yoon,et al.  Functional disruption of α4 integrin mobilizes bone marrow–derived endothelial progenitors and augments ischemic neovascularization , 2006, The Journal of experimental medicine.

[32]  Joshua M Hare,et al.  Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[33]  A. Zeiher,et al.  Infarct Remodeling After Intracoronary Progenitor Cell Treatment in Patients With Acute Myocardial Infarction (TOPCARE-AMI): Mechanistic Insights From Serial Contrast-Enhanced Magnetic Resonance Imaging , 2003, Circulation.

[34]  D J Prockop,et al.  Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Irving L. Weissman,et al.  Hematopoietic Stem Cells Are Uniquely Selective in Their Migratory Response to Chemokines , 2002, The Journal of experimental medicine.

[36]  J. Ingwall,et al.  Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts , 2003, Nature Medicine.

[37]  Eric J Topol,et al.  Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy , 2003, The Lancet.

[38]  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.

[39]  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.

[40]  P. Anversa,et al.  Myocyte renewal and ventricular remodelling , 2002, Nature.

[41]  S. Homma,et al.  Neovascularization of ischemic myocardium by human bone-marrow–derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function , 2001, Nature Medicine.

[42]  P. Brecher,et al.  Rapid expression of fibronectin in the rabbit heart after myocardial infarction with and without reperfusion. , 1992, The Journal of clinical investigation.

[43]  Bernd Westphal,et al.  Autologous bone-marrow stem-cell transplantation for myocardial regeneration , 2003, The Lancet.

[44]  M. Entman,et al.  Of mice and dogs: species-specific differences in the inflammatory response following myocardial infarction. , 2004, The American journal of pathology.

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

[46]  I. Weissman,et al.  Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium , 2004, Nature.

[47]  M. Hiroe,et al.  Tenascin-C regulates recruitment of myofibroblasts during tissue repair after myocardial injury. , 2005, The American journal of pathology.

[48]  N. Sharpe,et al.  Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. , 2000, Circulation.

[49]  P. Wernet,et al.  [Intracoronary, human autologous stem cell transplantation for myocardial regeneration following myocardial infarction]. , 2001, Deutsche medizinische Wochenschrift.

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

[51]  M. Harmsen,et al.  Increased inflammatory response and neovascularization in reperfused vs. non-reperfused murine myocardial infarction. , 2006, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.