Neural Crest–Derived Stem Cells Migrate and Differentiate Into Cardiomyocytes After Myocardial Infarction

Objective—We recently demonstrated that primitive neural crest–derived (NC) cells migrate from the cardiac neural crest during embryonic development and remain in the heart as dormant stem cells, with the capacity to differentiate into various cell types, including cardiomyocytes. Here, we examined the migration and differentiation potential of these cells on myocardial infarction (MI). Methods and Results—We obtained double-transgenic mice by crossing protein-0 promoter-Cre mice with Floxed–enhanced green fluorescent protein mice, in which the NC cells express enhanced green fluorescent protein. In the neonatal heart, NC stem cells (NCSCs) were localized predominantly in the outflow tract, but they were also distributed in a gradient from base to apex throughout the ventricular myocardium. Time-lapse video analysis revealed that the NCSCs were migratory. Some NCSCs persisted in the adult heart. On MI, NCSCs accumulated at the ischemic border zone area (BZA), which expresses monocyte chemoattractant protein-1 (MCP-1). Ex vivo cell migration assays demonstrated that MCP-1 induced NCSC migration and that this chemotactic effect was significantly depressed by an anti-MCP-1 antibody. Small NC cardiomyocytes first appeared in the BZA 2 weeks post-MI and gradually increased in number thereafter. Conclusion—These results suggested that NCSCs migrate into the BZA via MCP-1/CCR2 signaling and contribute to the provision of cardiomyocytes for cardiac regeneration after MI.

[1]  P. Kolattukudy,et al.  Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications. , 2009, Clinical science.

[2]  H. Okano,et al.  Ontogeny and multipotency of neural crest-derived stem cells in mouse bone marrow, dorsal root ganglia, and whisker pad. , 2008, Cell stem cell.

[3]  T. Shimazaki,et al.  [Mammalian neural stem cells]. , 2008, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[4]  Mei Zhang,et al.  Dominant-negative mutation of monocyte chemoattractant protein-1 prevents vulnerable plaques from rupture in rabbits independent of serum lipid levels , 2008, Journal of cellular and molecular medicine.

[5]  S. Yuasa,et al.  Bone Marrow–Derived Cells Are Involved in the Pathogenesis of Cardiac Hypertrophy in Response to Pressure Overload , 2007, Circulation.

[6]  W. Rostène,et al.  Chemokines and chemokine receptors in the brain: implication in neuroendocrine regulation. , 2007, Journal of molecular endocrinology.

[7]  H. Okano,et al.  Isolation of Multipotent Neural Crest‐Derived Stem Cells from the Adult Mouse Cornea , 2006, Stem cells.

[8]  H. Okano,et al.  Subventricular Zone-Derived Neuroblasts Migrate and Differentiate into Mature Neurons in the Post-Stroke Adult Striatum , 2006, The Journal of Neuroscience.

[9]  Hideyuki Okano,et al.  New Neurons Follow the Flow of Cerebrospinal Fluid in the Adult Brain , 2006, Science.

[10]  T. Shimazaki,et al.  Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart , 2005, The Journal of cell biology.

[11]  B. Rollins,et al.  CCL2/Monocyte Chemoattractant Protein-1 Regulates Inflammatory Responses Critical to Healing Myocardial Infarcts , 2005, Circulation research.

[12]  U. Suter,et al.  Neural crest stem cell maintenance by combinatorial Wnt and BMP signaling , 2005, The Journal of cell biology.

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

[14]  David R. Kaplan,et al.  A dermal niche for multipotent adult skin-derived precursor cells , 2004, Nature Cell Biology.

[15]  Yunqing Shi,et al.  Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. , 2003, Developmental cell.

[16]  Michael D. Schneider,et al.  Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Bronner‐Fraser,et al.  Neural crest specification: migrating into genomics , 2003, Nature Reviews Neuroscience.

[18]  D. Torella,et al.  Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration , 2003, Cell.

[19]  T. Pietri,et al.  The human tissue plasminogen activator-Cre mouse: a new tool for targeting specifically neural crest cells and their derivatives in vivo. , 2003, Developmental biology.

[20]  A. Graham,et al.  The neural crest , 2003, Current Biology.

[21]  M. Rudnicki,et al.  The post‐natal heart contains a myocardial stem cell population , 2002, FEBS letters.

[22]  O. Lindvall,et al.  Neuronal replacement from endogenous precursors in the adult brain after stroke , 2002, Nature Medicine.

[23]  A. Takeshita,et al.  Importance of Monocyte Chemoattractant Protein-1 Pathway in Neointimal Hyperplasia After Periarterial Injury in Mice and Monkeys , 2002, Circulation research.

[24]  F. Welt,et al.  Targeting CCR2 or CD18 Inhibits Experimental In-Stent Restenosis in Primates: Inhibitory Potential Depends on Type of Injury and Leukocytes Targeted , 2002, Circulation research.

[25]  A. Sadikot,et al.  Isolation of multipotent adult stem cells from the dermis of mammalian skin , 2001, Nature Cell Biology.

[26]  J. Miyazaki,et al.  A novel reporter mouse strain that expresses enhanced green fluorescent protein upon Cre‐mediated recombination , 2000, FEBS letters.

[27]  H. Okano,et al.  Musashi1: An Evolutionally Conserved Marker for CNS Progenitor Cells Including Neural Stem Cells , 2000, Developmental Neuroscience.

[28]  B. Hall,et al.  The neural crest as a fourth germ layer and vertebrates as quadroblastic not triploblastic , 2000, Evolution & development.

[29]  K. Abe,et al.  A novel transgenic technique that allows specific marking of the neural crest cell lineage in mice. , 1999, Developmental biology.

[30]  B. Rollins,et al.  Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein E-deficient mice. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[31]  B. Rollins,et al.  MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. , 1999, The Journal of clinical investigation.

[32]  B. Rollins,et al.  Monocyte chemoattractant protein-1. , 1999, Chemical immunology.

[33]  A. McMahon,et al.  Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase , 1998, Current Biology.

[34]  I. Charo,et al.  Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis , 1998, Nature.

[35]  P. Libby,et al.  Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. , 1998, Molecular cell.

[36]  R. Crystal,et al.  Efficient and Selective Adenovirus‐Mediated Gene Transfer Into Vascular Neointima , 1993, Circulation.

[37]  E. Frank,et al.  P0 is an early marker of the schwann cell lineage in chickens , 1991, Neuron.

[38]  G. Lemke,et al.  Isolation and analysis of the gene encoding peripheral myelin protein zero , 1988, Neuron.