Cardiac progenitors induced from human induced pluripotent stem cells with cardiogenic small molecule effectively regenerate infarcted hearts and attenuate fibrosis

Wanling Xuan, Yan Wang, Yao Liang Tang, Ailia Ali, Hong Hu, Mark Maienschein-Cline, Muhammad Ashraf

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Cardiac progenitor cells (CPCs) being multipotent offer a promising source for cardiac repair due to their ability to proliferate and multiply into cardiac lineage cells. Here, we explored a novel strategy for human CPCs generation from human induced pluripotent stem cells (hiPSCs) using a cardiogenic small molecule, isoxazole (ISX-9) and their ability to grow in the scar tissue for functional improvement in the infarcted myocardium. CPCs were induced from hiPSCs with ISX-9. CPCs were characterized by immunocytochemistry and RT-PCR. The CPC survival and differentiation in the infarcted hearts were determined by in vivo transplantation in immunodeficient mice following left anterior descending artery ligation and their effects were determined on fibrosis and functional improvement. ISX-9 simultaneously induced expression of cardiac transcription factors, NK2 homeobox 5, islet-1, GATA binding protein 4, myocyte enhancer factor-2 in hiPSCs within 3 days of treatment and successfully differentiated into three cardiac lineages in vitro. Messenger RNA and microRNA-sequencing results showed that ISX-9 targeted multiple cardiac differentiation, proliferation signaling pathways and upregulated myogenesis and cardiac hypertrophy related-microRNA. ISX-9 activated multiple pathways including transforming growth factor b induced epithelial-mesenchymal transition signaling, canonical, and non-canonical Wnt signaling at different stages of cardiac differentiation. CPCs transplantation promoted myoangiogenesis, attenuated fibrosis, and led to functional improvement in treated mice.

Original languageEnglish (US)
Pages (from-to)627-639
Number of pages13
JournalShock
Volume50
Issue number6
DOIs
StatePublished - Jan 1 2018

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Keywords

  • Cardiac progenitor cell
  • Isoxazole
  • Myocardial infarction
  • Regeneration
  • Stem cell

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

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