Hippo Pathway Effector Tead1 Induces Cardiac Fibroblast to Cardiomyocyte Reprogramming

Abstract

Background The conversion of fibroblasts into induced cardiomyocytes may regenerate myocardial tissue from cardiac scar through in situ cell transdifferentiation. The efficiency transdifferentiation is low, especially for human cells. We explored the leveraging of Hippo pathway intermediates to enhance induced cardiomyocyte generation. Methods and Results We screened Hippo effectors Yap (yes‐associated protein), Taz (transcriptional activator binding domain), and Tead1 (TEA domain transcription factor 1; Td) for their reprogramming efficacy with cardio‐differentiating factors Gata4, Mef2C, and Tbx5 (GMT). Td induced nearly 3‐fold increased expression of cardiomyocyte marker cTnT (cardiac troponin T) by mouse embryonic and adult rat fibroblasts versus GMT administration alone ( P <0.0001), while Yap and Taz failed to enhance cTnT expression. Serial substitution demonstrated that Td replacement of TBX5 induced the greatest cTnT expression enhancement and sarcomere organization in rat fibroblasts treated with all GMT substitutions (GMTd versus GMT: 17±1.2% versus 5.4±0.3%, P <0.0001). Cell contractility (beating) was seen in 6% of GMTd‐treated cells by 4 weeks after treatment, whereas no beating GMT‐treated cells were observed. Human cardiac fibroblasts likewise demonstrated increased cTnT expression with GMTd versus GMT treatment (7.5±0.3% versus 3.0±0.3%, P <0.01). Mechanistically, GMTd administration increased expression of the trimethylated lysine 4 of histone 3 (H3K4me3) mark at the promoter regions of cardio‐differentiation genes and mitochondrial biogenesis regulator genes in rat and human fibroblast, compared with GMT. Conclusions These data suggest that the Hippo pathway intermediate Tead1 is an important regulator of cardiac reprogramming that increases the efficiency of maturate induced cardiomyocytes generation and may be a vital component of human cardiodifferentiation strategies.

Mapping the cardiac vascular niche in heart failure

“…4f ), which is an important cofactor downstream of the hippo pathway 37 . Several studies investigated the role of hippo pathway activity in cardiac disease 38 – 40 , with one recent study specifically showing its importance for pro-fibrotic fibroblasts activation 41 . We next correlated TF activity with the ECM score to identify TFs that might regulate ECM expression (Fig.…”

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“…Lysine is also often involved in histone modification and therefore affects the epigenome. According to reports, the acetylation of histone lysine is associated with myocardial remodeling ( Peng et al, 2021 ; Han et al, 2022 ), and the lysine methylation of histone promotes the reprogramming of myocardial cells by fibroblasts ( Singh et al, 2021 ). Meanwhile, histone lysine-specific demethylase one induced renal fibrosis ( Dong et al, 2022 ; Zhang et al, 2022 ).…”

p63 silencing induces epigenetic modulation to enhance human cardiac fibroblast to cardiomyocyte-like differentiation

“…For cell contractility co-culture studies, cardiomyocytes were isolated from 0 to 3 day old rat pups under protocol AN-6223, as previously described 28 – 30 . Human cardiac fibroblasts were treated with GFP-labeled reprogramming factors (GMT, shp63+ H/M, p63-TID+ H/M) and one week after treatment as described above, cells were harvested and re-plated onto neonatal rat cardiomyocytes at a ratio of 1:10 and cultured in DMEM/M-199/10% FBS medium 31 .…”

“…Ca 2+ transients were expressed as the 340/380‐nm ratios of the resulting 510‐nm emissions. Data were analyzed using Felix software (Photon Technology International) 8 , 9 , 28 – 30 .…”