title: Long-Term Outcome of Administration of c-kit(POS) Cardiac Progenitor Cells After Acute Myocardial Infarction: Transplanted Cells Do not Become Cardiomyocytes, but Structural and Functional Improvement and Proliferation of Endogenous Cells Persist for at Least One Year.
abstract: BACKGROUND
  Cardiac progenitor cells (CPCs) improve left ventricular remodeling and function after acute or chronic myocardial infarction. However, the long-term (>5 weeks) effects, potential tumorigenicity, and fate of transplanted CPCs are unknown.
  
  
  OBJECTIVE
  To assess the outcome of CPC therapy at 1 year.
  
  
  RESULTS
  Female rats underwent a 90-minute coronary occlusion; 4 hours after reperfusion, they received intracoronarily vehicle or 1 million male, syngeneic CPCs. One year later, CPC-treated rats exhibited smaller scars and more viable myocardium in the risk region, along with improved left ventricular remodeling and regional and global left ventricular function. No tumors were observed. Some transplanted (Y-chromosome(POS)) CPCs (or their progeny) persisted and continued to proliferate, but they failed to acquire a mature cardiomyocyte phenotype and were too few (4-8% of nuclei) to account for the benefits of CPC therapy. Surprisingly, CPC transplantation triggered a prolonged proliferative response of endogenous cells, resulting in increased formation of endothelial cells and Y-chromosome(NEG) CPCs for 12 months and increased formation, for at least 7 months, of small cells that expressed cardiomyocytic proteins (α-sarcomeric actin) but did not have a mature cardiomyocyte phenotype.
  
  
  CONCLUSIONS
  The beneficial effects of CPCs on left ventricular remodeling and dysfunction are sustained for at least 1 year and thus are likely to be permanent. Because transplanted CPCs do not differentiate into mature myocytes, their major mechanism of action must involve paracrine actions. These paracrine mechanisms could be very prolonged because some CPCs engraft, proliferate, and persist at 1 year. This is the first report that transplantation of any cell type in the heart induces a proliferative response that lasts at least 1 year. The results strongly support the safety and clinical utility of CPC therapy.
authors.affiliation: From the Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, KY.
authors.forename: Xian-Liang
authors.initials: XL
authors.lastname: Tang
authors.affiliation: From the Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, KY.
authors.forename: Qianhong
authors.initials: Q
authors.lastname: Li
authors.affiliation: From the Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, KY.
authors.forename: Gregg
authors.initials: G
authors.lastname: Rokosh
authors.affiliation: From the Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, KY.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Sanganalmath
authors.affiliation: From the Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, KY.
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.affiliation: From the Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, KY.
authors.forename: Qinghui
authors.initials: Q
authors.lastname: Ou
authors.affiliation: From the Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, KY.
authors.forename: Heather
authors.initials: H
authors.lastname: Stowers
authors.affiliation: From the Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, KY.
authors.forename: Greg
authors.initials: G
authors.lastname: Hunt
authors.affiliation: From the Division of Cardiovascular Medicine, Institute of Molecular Cardiology, University of Louisville, KY. rbolli@louisville.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
mesh_terms: D053687:Adult Stem Cells / Q000737:chemistry / Q000166:cytology / Q000637:transplantation*; D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation; D002455:Cell Division; D019070:Cell Lineage; D004261:DNA Replication; D005260:Female; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology; D017404:In Situ Hybridization, Fluorescence; D017493:Leukocyte Common Antigens / Q000032:analysis; D008297:Male; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D016037:Single-Blind Method; D013997:Time Factors; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000209:etiology
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D017493:Leukocyte Common Antigens; C516771:Ptprc protein, rat
keywords: myocardial infarction; stem cells; ventricular function; ventricular remodeling
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