Lineage Reprogramming of Fibroblasts into Proliferative Induced Cardiac Progenitor Cells by Defined Factors

Pratik A. Lalit, Max R. Salick, Daryl O. Nelson, Jayne M. Squirrell, Christina M. Shafer, Neel G. Patel, Imaan Saeed, Eric G. Schmuck, Yogananda S. Markandeya, Rachel Wong, Martin R. Lea, Kevin W. Eliceiri, Timothy A. Hacker, Wendy C. Crone, Michael Kyba, Daniel J. Garry, Ron Stewart, James A. Thomson, Karen M. Downs, Gary E. LyonsTimothy J. Kamp

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

Summary Several studies have reported reprogramming of fibroblasts into induced cardiomyocytes; however, reprogramming into proliferative induced cardiac progenitor cells (iCPCs) remains to be accomplished. Here we report that a combination of 11 or 5 cardiac factors along with canonical Wnt and JAK/STAT signaling reprogrammed adult mouse cardiac, lung, and tail tip fibroblasts into iCPCs. The iCPCs were cardiac mesoderm-restricted progenitors that could be expanded extensively while maintaining multipotency to differentiate into cardiomyocytes, smooth muscle cells, and endothelial cells in vitro. Moreover, iCPCs injected into the cardiac crescent of mouse embryos differentiated into cardiomyocytes. iCPCs transplanted into the post-myocardial infarction mouse heart improved survival and differentiated into cardiomyocytes, smooth muscle cells, and endothelial cells. Lineage reprogramming of adult somatic cells into iCPCs provides a scalable cell source for drug discovery, disease modeling, and cardiac regenerative therapy. Lalit et al. report that a combination of cardiac factors and signaling molecules reprogram adult mouse fibroblasts into expandable induced cardiac progenitor cells (iCPCs). iCPCs are multipotent and can differentiate into cardiomyocytes, smooth muscle, and endothelial cells. Moreover, iCPCs generate myocardium when injected into the embryonic and adult post-MI mouse heart.

Original languageEnglish (US)
Pages (from-to)354-367
Number of pages14
JournalCell Stem Cell
Volume18
Issue number3
DOIs
StatePublished - Mar 3 2016

Bibliographical note

Funding Information:
We would like to thank the UWCCC Experimental Pathology Core (especially Joe Hardin) for help with immunohistochemistry experiments. M.R.S. and W.C.C. would also like to thank the Graduate School at the University of Wisconsin-Madison. The research was supported by NIH Grants U01HL099773 (to T.J.K. and J.A.T.), R01 HL129798 (to T.J.K. and G.E.L.), RO1 HD42706 and RO1 HD079481 (to K.M.D), S10RR025644 (to T.J.K.), and AHA pre-doctoral fellowship 12PRE9520035 (to P.A.L.).

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