The revolutionizing somatic cell reprogramming/transdifferentiation technologies provide a new path for cell replacement therapies and drug screening. The original method for reprogramming involves the delivery of exogenous transcription factors, leading to the safety concerns about the possible genome integration.

Small-molecule compounds-mediated reprogramming has several unique advantages, such as structural versatility and being easy to control in a time- and concentration-dependent way. More importantly, small molecules have been used as drugs to treat human diseases for thousands of years. Several types of cells, including induced pluripotent stem cells, neural progenitor cells, neurons, endodermal progenitors and cardiomyocytes, have been generated from various types of somatic cells with chemical cocktails. However, it remains unclear whether these chemicals could induce in vivo reprogramming.

Recently, in a paper published in Cell Research, Prof. XIE Xin’s group from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences, reported the chemical-induced cardiac reprogramming in vivo, providing a starting point for further optimization on inducing cardiac regeneration.

Prof. XIE’s group has focused on chemical-induced somatic cell reprogramming and transdifferentiation studies for a few years. In 2015, they reported that a chemical cocktail containing BrdU can generate iPSCs without any genetic factors. In the same year, they reported the generation of spontaneously beating cardiomyocyte-like cells from mouse fibroblasts by using only 3-7 small molecule compounds.

These chemical-induced cardiomyocyte-like cells (CiCMs) express cardiomyocyte-specific markers, exhibit sarcomeric organization, and possess typical cardiac calcium flux and electrophysiological features.

Recently, based on the hypothesis that the microenvironment in the heart might facilitate the induction and survival of CiCMs, Prof. XIE’s group gave mice a chemical cocktail CRFVPTM (C, CHIR99021; R, RepSox; F, Forskolin; V, VPA; P, Parnate; T, TTNPB; M, Rolipram) that has been proven to induce CiCM generation in vitro. With lineage tracing methods, this cocktail was found to induce the generation of CiCMs from cardiac fibroblasts.

The reprogramming could be observed after only 1-week treatment of the cocktail. After 6-weeks treatment, the emerging CiCMs were very similar to the neighboring cardiomyocytes in terms of size, shape, and expression of cardiac markers. More interestingly, this chemical cocktail could also reduce the fibrosis and promote functional recovery of mice after myocardial infarction.

Although the efficiency of the in vivo chemical-induced cardiac reprogramming is still low, this study is a proof of concept that chemical cocktails could be used to induce somatic cell reprogramming in vivo and the chemical combination provides a starting point for further optimization to induce cardiac regeneration.

This work is conceived and supervised by Prof. XIE Xin at SIMM. She is the deputy director of the National Center for Drug Screening of SIMM and an adjunct professor of Tongji University. Prof. XIE’s group mainly focuses on GPCR-based drug discovery and chemical biology of stem cells. Ms. Chenwen Huang, a Ph.D. candidate from Tongji University, is the first author.

This work was supported by the Chinese Academy of Sciences, the Ministry of Science and Technology of China, and the National Natural Science Foundation of China.

Original article link: http://www.nature.com/articles/s41422-018-0036-4

Figure: A. Schemes of drug treatment to induce in vivo cardiac reprogramming in Fsp1-cre: R26RtdTomato mice. B. Eight-week old Fsp1-cre: R26RtdTomato mice were given CRFVPTM or vehicle once a week for 6 weeks, long and rod shaped cardiomyocytes could be observed to emerge from tdTomato+ cardiac fibroblasts. （Image courtesy of Cell Research）

Contact person: Prof. XIE Xin (Email: xxie@simm.ac.cn)

(Credit: XIE Xin; Editor: PAN Peihua)