Abstract
RationaleThe adult myocardium has been reported to harbor several classes of multipotent progenitor cells (CPCs) with tri-lineage differentiation potential. It is not clear whether c-kit+CPCs represent a uniform precursor population or a more complex mixture of cell types.ObjectiveTo characterize and understand vasculogenic heterogeneity within c-kit+presumptive cardiac progenitor cell populations.Methods and Resultsc-kit+, sca-1+ CPCs obtained from adult mouse left ventricle expressed stem cell-associated genes, including Oct-4 and Myc, and were self-renewing, pluripotent and clonogenic. Detailed single cell clonal analysis of 17 clones revealed that most (14/17) exhibited trilineage differentiation potential. However, striking morphological differences were observed among clones that were heritable and stable in long-term culture. 3 major groups were identified: round (7/17), flat or spindle-shaped (5/17) and stellate (5/17). Stellate morphology was predictive of vasculogenic differentiation in Matrigel. Genome-wide expression studies and bioinformatic analysis revealed clonally stable, heritable differences in stromal cell-derived factor-1 (SDF-1) expression that correlated strongly with stellate morphology and vasculogenic capacity. Endogenous SDF-1 production contributed directly to vasculogenic differentiation: both shRNA-mediated knockdown of SDF-1 and AMD3100, an antagonist of the SDF-1 receptor CXC chemokine Receptor-4 (CXCR4), reduced tube-forming capacity, while exogenous SDF-1 induced tube formation by 2 non-vasculogenic clones. CPCs producing SDF-1 were able to vascularize Matrigel dermal implants in vivo, while CPCs with low SDF-1 production were not.ConclusionsClonogenic c-kit+, sca-1+ CPCs are heterogeneous in morphology, gene expression patterns and differentiation potential. Clone-specific levels of SDF-1 expression both predict and promote development of a vasculogenic phenotype via a previously unreported autocrine mechanism.
Highlights
Heart failure is a lethal and disabling end result of a number of highly prevalent cardiovascular diseases, including hypertension and coronary atherosclerosis, and is estimated to affect 2.8% of the present US population[1]
Clonogenic c-kit+, sca-1+ classes of multipotent progenitor cells (CPCs) are heterogeneous in morphology, gene expression patterns and differentiation potential
We performed single cell cloning to study the properties of one type of cardiac progenitor cell: sca-1+, c-kit+CPCs derived from the left ventricles of adult mouse hearts. We show that these cells exhibit a surprising degree of clonally stable heterogeneity in morphology, gene expression and functional properties, and importantly, in the potential for vasculogenic differentiation
Summary
Heart failure is a lethal and disabling end result of a number of highly prevalent cardiovascular diseases, including hypertension and coronary atherosclerosis, and is estimated to affect 2.8% of the present US population[1]. Studies have revealed that many adult tissues, notably bone marrow, and skeletal muscle, synovium and adipose tissue, contain self-renewing, pluripotent cells capable of repairing injured myocardium and/or improving blood flow to the heart ([11,12, 13,14], reviewed in [15]) These insights have led to a rapid and intensive pursuit of regenerative strategies to increase the number of functional cardiac myocytes and blood vessels in the damaged and failing myocardium (reviewed in[16,17,18,19,20,21]). There is no agreement on the mechanism of action of stem cell therapy, nor on the optimal method, dose and timing of their delivery; the best source of reparative cells has yet to be established[31,32,33,34]
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