Circulation Research. 2004;95:1191-1199
Published online before print November 18, 2004, doi: 10.1161/01.RES.0000150856.47324.5b
Published online before print November 18, 2004, doi: 10.1161/01.RES.0000150856.47324.5b
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© 2004 American Heart Association, Inc.
Cellular Biology |
Cells Expressing Early Cardiac Markers Reside in the Bone Marrow and Are Mobilized Into the Peripheral Blood After Myocardial Infarction
From the Stem Cell Biology Program (M.K., M.W., J.R., M.Z.R.), the Institute of Molecular Cardiology (B.D., G.H., Y.G., R.B.), and the Institute of Cellular Therapeutics (F.R., S.T.I.), University of Louisville, Louisville, Ken; and the European Stem Cell Therapeutic Excellence Center (M.M.), Cracow, Poland.
Correspondence to Mariusz Z. Ratajczak, MD, PhD, Stem Cell Biology Program, University of Louisville, 580 S Preston St, Baxter II, Rm 119E, Louisville, KY 40202; E-mail mzrata01{at}gwise.louisville.edu; or to Roberto Bolli, MD, Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292. E-mail rbolli{at}louisville.edu
The concept that bone marrow (BM)–derived cells participate in cardiac regeneration remains highly controversial and the identity of the specific cell type(s) involved remains unknown. In this study, we report that the postnatal BM contains a mobile pool of cells that express early cardiac lineage markers (Nkx2.5/Csx, GATA-4, and MEF2C). These cells are present in significant amounts in BM harvested from young mice but their abundance decreases with age; in addition, the responsiveness of these cells to gradients of motomorphogens SDF-1, HGF, and LIF changes with age. FACS analysis, combined with analysis of early cardiac markers at the mRNA and protein levels, revealed that cells expressing these markers reside in the nonadherent, nonhematopoietic CXCR4+/Sca-1+/lin–/CD45– mononuclear cell (MNC) fraction in mice and in the CXCR4+/CD34+/AC133+/CD45– BMMNC fraction in humans. These cells are mobilized into the peripheral blood after myocardial infarction and chemoattracted to the infarcted myocardium in an SDF-1-CXCR4–, HGF-c-Met–, and LIF-LIF-R–dependent manner. To our knowledge, this is the first demonstration that the postnatal BM harbors a nonhematopoietic population of cells that express markers for cardiac differentiation. We propose that these potential cardiac progenitors may account for the myocardial regenerative effects of BM. The present findings provide a novel paradigm that could reconcile current controversies and a rationale for investigating the use of BM-derived cardiac progenitors for myocardial regeneration.
Key Words: stem cells • bone marrow • myocardial infarction • myocardial regeneration • CXCR4-SDF-1 axis
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