Hippo Pathway Effector Tead1 Induces Cardiac Fibroblast to Cardiomyocyte Reprogramming

Area of Science:

• Cardiovascular Research
• Stem Cell Biology
• Regenerative Medicine

Background:

• In situ cell transdifferentiation offers a promising route for myocardial tissue regeneration by converting fibroblasts into induced cardiomyocytes.
• Current transdifferentiation methods exhibit low efficiency, particularly in human cells.
• The Hippo pathway's role in regulating cell proliferation and differentiation presents a potential target for enhancing cardiomyocyte generation.

Purpose of the Study:

• To investigate the efficacy of Hippo pathway intermediates, specifically Yap (yes-associated protein), Taz (transcriptional activator binding domain), and Tead1 (TEA domain transcription factor 1), in enhancing induced cardiomyocyte generation.
• To determine if Tead1 can improve the efficiency and maturity of cardiomyocyte reprogramming compared to established factors.

Main Methods:

• Screening of Hippo effectors Yap, Taz, and Tead1 in combination with cardio-differentiating factors Gata4, Mef2C, and Tbx5 (GMT).
• Assessing reprogramming efficacy by measuring cardiac troponin T (cTnT) expression and sarcomere organization in mouse, rat, and human fibroblasts.
• Investigating the epigenetic mechanisms by analyzing histone modifications (H3K4me3) at target gene promoters.

Main Results:

• Tead1 (Td) significantly increased cTnT expression by nearly 3-fold in mouse and rat fibroblasts compared to GMT alone.
• Replacing Tbx5 with Tead1 (GMTd) in the factor cocktail resulted in the most substantial enhancement of cTnT expression (17% vs. 5.4%) and improved sarcomere organization in rat fibroblasts.
• GMTd treatment led to observable cell contractility (beating) in 6% of treated cells by 4 weeks, a phenomenon not observed with GMT alone.
• Human cardiac fibroblasts also showed significantly increased cTnT expression with GMTd compared to GMT (7.5% vs. 3.0%).
• GMTd administration upregulated H3K4me3 marks at the promoters of cardiac differentiation and mitochondrial biogenesis genes.

Conclusions:

• The Hippo pathway intermediate Tead1 is a critical regulator that substantially boosts the efficiency of cardiac reprogramming.
• Tead1 enhances the generation of mature induced cardiomyocytes with improved functionality, including contractility.
• These findings highlight Tead1 as a key component for advancing human cardiodifferentiation strategies and potential therapeutic applications in cardiac repair.