TY - JOUR
T1 - SDF-1-enhanced cardiogenesis requires CXCR4 induction in pluripotent stem cells
AU - Chiriac, Anca
AU - Terzic, Andre
AU - Park, Sungjo
AU - Ikeda, Yasuhiro
AU - Faustino, Randolph
AU - Nelson, Timothy J.
N1 - Funding Information:
Acknowledgments The authors thank James E. Tarara and the Mayo Clinic Flow Cytometry and Optical Morphology Resource Core for their expertise. This work was supported by National Institutes of Health (R01HL083439, T32HL007111, R56AI074363), Marriott Individualized Medicine Program, Marriott Heart Disease Research Program, and Mayo Clinic.
PY - 2010/12
Y1 - 2010/12
N2 - Transformation of pluripotent stem cells into cardiac tissue is the hallmark of cardiogenesis, yet procardiogenic signals remain partially understood. Preceding cardiogenic induction, a surge in CXCR4 chemokine receptor expression in the early stages of stem cell lineage specification coincides with the acquisition of pre-cardiac profiles. Accordingly, CXCR4 selection, in conjunction with mesoderm-specific VEGF type II receptor FLK-1 co-expression, segregates cardiogenic populations. To assess the functionality of the CXCR4 biomarker, targeted activation and disruption were here exploited in the context of embryonic stem cell-derived cardiogenesis. Implicated as a cardiogenic hub through unbiased bioinformatics analysis, induction of the CXCR4/SDF-1 receptor- ligand axis triggered enhanced beating activity in stem cell progeny. Gene expression knockdown of CXCR4 disrupted spontaneous embryoid body differentiation and blunted the expression of cardiogenic markers MEF2C, Nkx2.5, MLC2a, MLC2v, and cardiac-MHC. Exogenous SDF-1 treatment failed to rescue cardiogenic-deficient phenotype, demonstrating a requirement for CXCR4 expression in mediating SDF-1 effects. Thus, a pro-cardiogenic signaling role for the CXCR4/SDF1 axis is herein revealed within pluripotent stem cell progenitors, exposing a functional target to promote lineage-specific differentiation.
AB - Transformation of pluripotent stem cells into cardiac tissue is the hallmark of cardiogenesis, yet procardiogenic signals remain partially understood. Preceding cardiogenic induction, a surge in CXCR4 chemokine receptor expression in the early stages of stem cell lineage specification coincides with the acquisition of pre-cardiac profiles. Accordingly, CXCR4 selection, in conjunction with mesoderm-specific VEGF type II receptor FLK-1 co-expression, segregates cardiogenic populations. To assess the functionality of the CXCR4 biomarker, targeted activation and disruption were here exploited in the context of embryonic stem cell-derived cardiogenesis. Implicated as a cardiogenic hub through unbiased bioinformatics analysis, induction of the CXCR4/SDF-1 receptor- ligand axis triggered enhanced beating activity in stem cell progeny. Gene expression knockdown of CXCR4 disrupted spontaneous embryoid body differentiation and blunted the expression of cardiogenic markers MEF2C, Nkx2.5, MLC2a, MLC2v, and cardiac-MHC. Exogenous SDF-1 treatment failed to rescue cardiogenic-deficient phenotype, demonstrating a requirement for CXCR4 expression in mediating SDF-1 effects. Thus, a pro-cardiogenic signaling role for the CXCR4/SDF1 axis is herein revealed within pluripotent stem cell progenitors, exposing a functional target to promote lineage-specific differentiation.
KW - CXCR4
KW - Cardiogenesis
KW - Pluripotent stem cells
KW - SDF-1
UR - http://www.scopus.com/inward/record.url?scp=79952803897&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79952803897&partnerID=8YFLogxK
U2 - 10.1007/s12265-010-9219-1
DO - 10.1007/s12265-010-9219-1
M3 - Article
C2 - 20842469
AN - SCOPUS:79952803897
SN - 1937-5387
VL - 3
SP - 674
EP - 682
JO - Journal of cardiovascular translational research
JF - Journal of cardiovascular translational research
IS - 6
ER -