Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails

Abstract

The direct conversion, or transdifferentiation, of non-cardiac cells into cardiomyocytes by forced expression of transcription factors and microRNAs provides promising approaches for cardiac regeneration. However, genetic manipulations raise safety concerns and are thus not desirable in most clinical applications. The discovery of full chemically induced pluripotent stem cells suggest the possibility of replacing transcription factors with chemical cocktails. Here, we report the generation of automatically beating cardiomyocyte-like cells from mouse fibroblasts using only chemical cocktails. These chemical-induced cardiomyocyte-like cells (CiCMs) express cardiomyocyte-specific markers, exhibit sarcomeric organization, and possess typical cardiac calcium flux and electrophysiological features. Genetic lineage tracing confirms the fibroblast origin of these CiCMs. Further studies show the generation of CiCMs passes through a cardiac progenitor stage instead of a pluripotent stage. Bypassing the use of viral-derived factors, this proof of concept study lays a foundation for in vivo cardiac transdifferentiation with pharmacological agents and possibly safer treatment of heart failure.

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].…”

Transcriptional control of cardiac fibroblast plasticity

“…Other early cardiac transcription factors, such as Nkx2.5 , Mesp1 , and myocardin are less critical, or even inhibit reprogramming whereas Hand2 can increase the percentage of cells transformed into atrial, ventricular, and pacemaker CMCs [182–184]. Similar reports have used small molecules in combination with the pluripotency factor OCT4 to produce CMC-like cells from fibroblasts [185, 186]. Importantly, cellular reprogramming strategies have proven efficacious in blunting cardiac dysfunction and remodeling in rodent models of MI [182, 187, 188].…”

Direct Cardiac Cellular Reprogramming for Cardiac Regeneration

“…Subsequent studies have utilized chemical cocktails without any transcription factors to induce reprogramming in both murine and human fibroblasts through epigenetic modulation [35, 42]. Such chemically induced cardiomyocyte-like cells (CiCMs) may be a harbinger of future inventive approaches in cardiac reprogramming.…”