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

Abstract

Summary Several studies have reported reprogramming of fibroblasts to induced cardiomyocytes; however, reprogramming to proliferative induced cardiac progenitor cells (iCPCs) remains to be accomplished. Here we report that a combination of eleven or five cardiac factors along with canonical Wnt and JAK/STAT signaling reprogrammed adult cardiac, lung and tail-tip fibroblasts into iCPCs. The iCPCs were cardiac mesoderm-restricted progenitors, which could be extensively expanded 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.

ATP-dependent chromatin remodeling during mammalian development

“…Indeed, BAF60C along with the cardiac transcription factors TBX5 and GATA4 function together to reprogram mouse mesoderm to beating cardiomyocytes (Takeuchi and Bruneau, 2009). BAF60C is also an essential factor that cooperates with other cardiac transcription factors to reprogram fibroblasts into cardiovascular precursors, further highlighting its importance in cardiac differentiation (Lalit et al, 2016). Expression of Baf60c (Smarcd3), along with Tbx5 and Gata4, is induced by the Nodal and BMP4 antagonist CER1, resulting in recruitment of BAF60C to an enhancer of Nkx2-5 during cardiomyocyte differentiation (Cai et al, 2013).…”

Functional characterization of human pluripotent stem cell-derived arterial endothelial cells

“…Finally, we tested the function of the human pluripotent stem cell-derived AECs in a mouse model of myocardial infarction (32,33). To induce myocardial infarction, the left coronary artery was permanently ligated.…”

Pediatric dilated cardiomyopathy hearts display a unique gene expression profile

“…Although hypertrophy was not observed in pediatric DCM myocytes, IPA predicted a decrease in contractility (Z score = -1.578, P = 0.002) and function of the cardiovascular system (Z score = -2.07, P = 0.00022) (Supplemental Figure 6, B and C) Pluripotent factors activate the fetal gene program (FGP) and induce expression of genes dysregulated in pediatric DCM. To test the hypothesis that the pattern of gene expression observed in pediatric DCM was consistent with pluripotent signals, NRVMs were treated with WNT activator and leukemia inhibitory factor (LIF), factors involved in maintenance of a proliferative/reprogrammed state in cardiac progenitor cells (13). In addition, cells were treated with FGF2, which induces cardiomyocyte differentiation (14).…”