Reprogramming of fibroblasts into expandable cardiovascular progenitor cells via small molecules in xeno-free conditions

Cardiovascular progenitor cells that self-renew in chemically defined and xeno-free conditions and that preserve their cardiovascular differentiation capacity in vitro and in vivo can be derived from fibroblasts via a cocktail of six small molecules. A major hurdle in cardiac cell therapy is the lack of a bona fide autologous stem-cell type that can be expanded long-term and has authentic cardiovascular differentiation potential. Here we report that a proliferative cell population with robust cardiovascular differentiation potential can be generated from mouse or human fibroblasts via a combination of six small molecules. These chemically induced cardiovascular progenitor cells (ciCPCs) self-renew long-term in fully chemically defined and xeno-free conditions, with faithful preservation of the CPC phenotype and of cardiovascular differentiation capacity in vitro and in vivo. Transplantation of ciCPCs into infarcted mouse hearts improved animal survival and cardiac function up to 13 weeks post-infarction. Mechanistically, activated fibroblasts revert to a plastic state permissive to cardiogenic signals, enabling their reprogramming into ciCPCs. Expanded autologous cardiovascular cells may find uses in drug discovery, disease modelling and cardiac cell therapy.

Automated summary

A combination of small molecules can generate a cell population with cardiovascular differentiation potential from fibroblasts. These chemically induced cardiovascular progenitor cells (ciCPCs) can self-renew and preserve their differentiation capacity in chemically defined and xeno-free conditions. Transplantation of ciCPCs into infarcted mouse hearts improves cardiac function. Expanded autologous cardiovascular cells have important applications in drug discovery, disease modeling, and cardiac cell therapy.