The ability to reprogram fibroblasts into cardiomyocytes has many therapeutic implications. Half of the cells in the heart are fibroblasts, so the ability to call upon this reservoir of cells already in the organ to become beating heart cells has tremendous promise for cardiac regeneration. Introducing the defined factors, or factors that mimic their effect, directly into the heart to create new heart muscle would avoid the need to inject stem cells into the heart and all the obstacles that go along with such cell-based therapies. In this study Deepak Srivastava and colleagues endeavoured to reprogram committed fibroblasts to cardiomyocytes and started with a pool of 14 candidate cardiomyocyte-inducing factors. Cardiomyocyte induction of mouse neonatal cardiac fibroblasts was observed 1 week after retroviral transduction in 1.7% of the cells. After fine-tuning the cocktail to combine crucial cardiac-inducing factors and exclude inhibitory or ineffective factors, a best set was identified, consisting of the transcription factors Gata4, Mef2c, and Tbx5. Use of this trio of factors increased the efficiency of direct cardiomyocyte induction to a remarkable 20%. Although induced cardiomyocytes (iCMs) displayed expression of cardiac proteins within a week, their further maturation occurred in the weeks thereafter: sarcomeric organization and contractility increased and electrical properties “matured.” As expected for true reprogramming, epigenetic resetting of a selected group of genes to that of a cardiomyocyte state was evident. Furthermore, by using inducible lentiviral expression, the authors showed that iCMs were stable for at least 1 week after the three factors were switched off. Most interestingly, in comparison to reprogramming of somatic cells to induced pluripotent stem cells (iPSCs), lineage reprogramming (both for cardiomyocytes as well as neuronal cells) appears to be rapid and relatively much more efficient. Srivastava and colleagues propose that the difference in efficiencies may be explained by the fact that the cells are directly converted to cardiomyocytes without reverting to precardiac developmental stages such as mesoderm or cardiac progenitor cells. Direct reprogramming has not yet been done in human cells and the hope is still to find small molecules, rather than genetic factors, that can be used to direct the cell-fate switch. There will be obvious important clinical implications if generic and robust iCM production protocols can be developed and applied for adult human cells. Although many hurdles remain to be overcome in order to establish effective cell-based therapies patient-derived iCMs may be used in the future for treatment of heart disease and would offer advantages over iPSC-derived cardiomyocytes.

Références : Masaki Iedasend, Ji-Dong Fu, Paul Delgado-Olguin, Vasanth Vedantham, Yohei Hayashi, Benoit G. Bruneau, Deepak Srivastavasend. Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors. Cell, 142(3): 375-386, 6 August 2010