TY - JOUR
T1 - Heterogeneity in SDF-1 expression defines the vasculogenic potential of adult cardiac progenitor cells
AU - Rodrigues, Claudia O.
AU - Shehadeh, Lina A.
AU - Hoosien, Michael
AU - Otero, Valerie
AU - Chopra, Ines
AU - Tsinoremas, Nicholas F.
AU - Bishopric, Nanette H.
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2011/8/24
Y1 - 2011/8/24
N2 - Rationale: The 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. Objective: To characterize and understand vasculogenic heterogeneity within c-kit+presumptive cardiac progenitor cell populations. Methods and Results: c-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. Conclusions: Clonogenic 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.
AB - Rationale: The 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. Objective: To characterize and understand vasculogenic heterogeneity within c-kit+presumptive cardiac progenitor cell populations. Methods and Results: c-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. Conclusions: Clonogenic 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.
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U2 - 10.1371/journal.pone.0024013
DO - 10.1371/journal.pone.0024013
M3 - Article
C2 - 21887363
AN - SCOPUS:80052011666
VL - 6
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 8
M1 - e24013
ER -