Conversion of human fibroblasts into functional cardiomyocytes by small molecules

Abstract

Reprogramming somatic fibroblasts into alternative lineages would provide a promising source of cells for regenerative therapy. However, transdifferentiating human cells into specific homogeneous, functional cell types is challenging. Here we show that cardiomyocyte-like cells can be generated by treating human fibroblasts with a combination of nine compounds that we term 9C. The chemically induced cardiomyocyte-like cells uniformly contracted and resembled human cardiomyocytes in their transcriptome, epigenetic, and electrophysiological properties. 9C treatment of human fibroblasts resulted in a more open-chromatin conformation at key heart developmental genes, enabling their promoters and enhancers to bind effectors of major cardiogenic signals. When transplanted into infarcted mouse hearts, 9C-treated fibroblasts were efficiently converted to chemically induced cardiomyocyte-like cells. This pharmacological approach to lineage-specific reprogramming may have many important therapeutic implications after further optimization to generate mature cardiac cells.

A molecular roadmap for induced multi-lineage trans-differentiation of fibroblasts by chemical combinations

“…Enlightened by the idea, chemical cocktails that initiate neuronal trans-differentiation have been reported [22][23][24][25]. Similar approaches have been used to generate functional cardiac myocytes from both mouse and human fibroblasts [26][27]. Very recently, endodermal progenitors have also been obtained using the chemical reprogramming method [28].…”

FGF signaling enforces cardiac chamber identity in the developing ventricle

“…Efforts towards the in vitro differentiation of homogeneous populations of mature cardiomyocytes are moving increasingly towards protocols that employ cocktails of small molecules to manipulate signaling pathways and modify chromatin (e.g. Cao et al, 2016). As these protocols are further refined, it will be crucial to control not only the pathways that direct chamber-specific lineage decisions but also the and nkx2.7 (C,D) expression in dorsal views at 26.5 hpf, following heat shock at 18 hpf.…”

The Proangiogenic Potential of Mesenchymal Stem Cells and Their Therapeutic Applications

“…On the other hand, addition of an extra transcription factor Hand2 has also resulted in enhanced reprogramming efficiency [103]. In addition, combinations of small molecules such as SB431542, CHIR99021, 6-bromoindirubin-3′-oxime (BIO), and lithium chloride (LiCl) to replace transcription factors have also been reported to induce cardiac reprogramming [104]. Of note, CHIR99021 is a GSK3 inhibitor, which can up-regulate canonical Wnt signaling increased cardiac reprogramming efficiency.…”