Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors

Abstract

SUMMARY The reprogramming of fibroblasts to induced pluripotent stem (iPS) cells raises the possibility that a somatic cell could be reprogrammed to an alternative differentiated fate without first becoming a stem/progenitor cell. A large pool of fibroblasts exists in the post-natal heart, yet no single “master regulator” of direct cardiac reprogramming has been identified. Here, we report that a combination of three developmental transcription factors (i.e., Gata4, Mef2c and Tbx5) rapidly and efficiently reprogrammed post-natal cardiac or dermal fibroblasts directly into differentiated cardiomyocyte-like cells. Induced cardiomyocytes expressed cardiac-specific markers, had a global gene expression profile similar to cardiomyocytes, and contracted spontaneously. Fibroblasts transplanted into mouse hearts one day after transduction of the three factors also differentiated into cardiomyocyte-like cells. These findings demonstrate that functional cardiomyocytes can be directly reprogrammed from differentiated somatic cells by defined factors. Reprogramming of endogenous or explanted fibroblasts might provide a source of cardiomyocytes for regenerative approaches.

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

“…Together with Baf60 and Gata4, Tbx5 induces the formation of ectopic cardiomyocytes in mouse embryonic mesoderm (Takeuchi and Bruneau, 2009) and, as shown recently, the transduction of Tbx5, Mef2c, and Gata4 into cardiac fibroblasts leads to the stimulation of cardiomyocyte formation (Ieda et al, 2010), indicating the importance of Tbx5 for cardiogenesis. Until now, there were no data available analyzing Tbx5 function with respect to the novel concept of two separate cardiac lineages derived from a common precursor cell population.…”

Looking proximally and distally: 100 years of limb regeneration and beyond

“…The characterization of blastema cell surface antigen and micro-RNAs will also be important. Might it be possible to directly reprogram dermal fibroblasts in situ to limb cell types other than cartilage, for example muscle, as has been reported for the reprogramming of mammalian neonatal cardiac fibroblasts into functional cardiomyocytes (Ieda et al, 2010)? This would be valuable as a therapy to reconstitute individual limb tissues damaged by injury.…”

Different requirements for GATA factors in cardiogenesis are mediated by non‐canonical Wnt signaling

“…Takeuchi and Bruneau (2009) show that GATA4 acts together with Tbx5 and Baf60c to direct ectopic differentiation of mouse mesoderm into beating cardiomyocytes. And more recently Ieda et al (2010) have reported that GATA4 is among a combination of three developmental transcription factors (i.e., with Mef2c and Tbx5) that rapidly and efficiently reprogramme post-natal cardiac or dermal fibroblasts directly into differentiated cardiomyocyte-like cells.…”

“…Recent studies in mouse have confirmed the importance of this factor and show that GATA4 is among three factors (GATA4, Tbx5, and Baf60c) that together are sufficient for transdifferentiation of non-cardiogenic mesoderm into beating cardiomyocytes (Takeuchi and Bruneau, 2009). In addition, GATA4 together with Mef2c and Tbx5 is able to reprogram postnatal cardiac or dermal fibroblasts directly into differentiated cardiomyocytes-like-cells (Ieda et al, 2010).…”