Article

Journal of Cardiovascular Translational Research

, Volume 3, Issue 6, pp 674-682

SDF-1-Enhanced Cardiogenesis Requires CXCR4 Induction in Pluripotent Stem Cells

  • Anca ChiriacAffiliated withMarriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medical Genetics, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic
  • , Andre TerzicAffiliated withMarriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medical Genetics, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic
  • , Sungjo ParkAffiliated withMarriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medical Genetics, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic
  • , Yasuhiro IkedaAffiliated withDepartment of Molecular Medicine, Mayo Clinic
  • , Randolph FaustinoAffiliated withMarriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medical Genetics, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic
  • , Timothy J. NelsonAffiliated withMarriott Heart Disease Research Program, Division of General Internal Medicine and Transplant Center, Department of Medicine, Mayo Clinic Email author 

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Abstract

Transformation of pluripotent stem cells into cardiac tissue is the hallmark of cardiogenesis, yet pro-cardiogenic 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.

Keywords

Cardiogenesis Pluripotent stem cells SDF-1 CXCR4