Matrix rigidity and cardiac reprogramming
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ABSTRACT:
PROVIDER: PRJNA517614 | ENA |
REPOSITORIES: ENA
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Project description:Direct cardiac reprogramming from fibroblasts holds great potential for disease modeling, drug screening, and regeneration. However, cardiac reprogramming remains inefficient in vitro, and induced cardiomyocytes (iCMs) generated in vitro are less mature than those in vivo, suggesting undefined biophysical factors may inhibit cardiac reprogramming. Previous studies mainly used conventional polystyrene dishes, and thus the effect of matrix rigidity on cardiac reprogramming remains unclear. Here, we developed a Matrigel-based hydrogel culture system to determine the effect of matrix rigidity and mechanotransduction on cardiac reprogramming. We found that soft matrix rigidity comparable to myocardium greatly enhanced cardiac reprogramming in combination with Gata4, Hand2, Mef2c, and Tbx5. Mechanistically, soft matrix enhanced cardiac reprogramming via inhibition of Rho/ROCK, actomyosin, and YAP/TAZ pathway, and suppression of fibroblast program, which were activated on rigid substrate. Intriguingly, inhibition of YAP/TAZ further suppressed integrin-mediated signaling to create a positive feedback loop for robust reprogramming. Thus, mechanotransduction may represent a new target for cardiac reprogramming.
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Project description:Direct cardiac reprogramming to induce cardiomyocyte-like cells, e.g. by GMT (Gata4, Mef2c and Tbx5), is a promising route for regenerating damaged heart in vivo and disease modeling in vitro. Supplementation with additional factors and chemical agents can enhance efficiency but raises concerns regarding selectivity to cardiac fibroblasts and complicates delivery for in situ cardiac reprogramming. Here, we screened 2000 chemicals with known biological activities and found that a combination of 2C (SB431542 and Baricitinib) significantly enhances cardiac reprogramming by GMT. Without Gata4, MT (Mef2c and Tbx5) plus 2C could selectively reprogram cardiac fibroblasts with enhanced efficiency, kinetics and cardiomyocyte function. More importantly, 2C+MYOCD selectively reprograms human cardiac fibroblasts into cardiomyocyte-like cells. 2C enhances cardiac reprogramming by inhibiting Alk5, Tyk2 and downregulating Oas2, Oas3, Serpina3n and Tgfbi. 2C thus enables selective and robust cardiac reprogramming that can greatly facilitate disease modeling in vitro and advance clinical therapeutic heart regeneration in vivo.
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Project description:Robust Cardiac Reprogramming Systems with Selectivity to Cardiac Fibroblasts
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