Abstract
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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aged
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Animals
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Antigens, CD34 / analysis
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Antigens, Differentiation / analysis
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Antigens, Ly / analysis
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Blood Cells / cytology*
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Bone Marrow Cells / chemistry
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Bone Marrow Cells / cytology*
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Bone Marrow Cells / drug effects
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Cell Lineage
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Chemokine CXCL12
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Chemokines, CXC / biosynthesis
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Chemokines, CXC / genetics
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Chemokines, CXC / physiology
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Chemotaxis / drug effects
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Heart / physiology*
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Hepatocyte Growth Factor / biosynthesis
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Hepatocyte Growth Factor / genetics
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Hepatocyte Growth Factor / physiology
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Humans
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Interleukin-6
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Leukemia Inhibitory Factor
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Leukemia Inhibitory Factor Receptor alpha Subunit
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Leukocyte Common Antigens / analysis
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Membrane Proteins / analysis
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Mice
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Mice, Inbred BALB C
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Middle Aged
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Myocardial Infarction / pathology*
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Myocardium / chemistry
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Myocardium / cytology*
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Organ Specificity
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Proteins / genetics
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Proteins / physiology
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Proto-Oncogene Proteins c-met / antagonists & inhibitors
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Proto-Oncogene Proteins c-met / physiology
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RNA, Messenger / biosynthesis
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Receptors, CXCR4 / analysis
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Receptors, CXCR4 / antagonists & inhibitors
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Receptors, CXCR4 / physiology
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Receptors, Cytokine / antagonists & inhibitors
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Receptors, Cytokine / physiology
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Receptors, OSM-LIF
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Regeneration / physiology*
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Stem Cells / chemistry
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Stem Cells / cytology*
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Stem Cells / drug effects
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Tissue Extracts / pharmacology
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Vascular Endothelial Growth Factor A / biosynthesis
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Vascular Endothelial Growth Factor A / genetics
Substances
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Antigens, CD34
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Antigens, Differentiation
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Antigens, Ly
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CXCL12 protein, human
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Chemokine CXCL12
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Chemokines, CXC
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Cxcl12 protein, mouse
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Interleukin-6
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LIF protein, human
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LIFR protein, human
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Leukemia Inhibitory Factor
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Leukemia Inhibitory Factor Receptor alpha Subunit
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Lif protein, mouse
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Lifr protein, mouse
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Ly6a protein, mouse
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Membrane Proteins
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Proteins
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RNA, Messenger
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Receptors, CXCR4
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Receptors, Cytokine
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Receptors, OSM-LIF
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Tissue Extracts
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Vascular Endothelial Growth Factor A
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Hepatocyte Growth Factor
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Proto-Oncogene Proteins c-met
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Leukocyte Common Antigens