Key result
Enforced expression of TCF21 in cardiac fibroblasts significantly reduced cardiac fibrosis and hypertrophy in response to 1 week of Ang II/phenylephrine infusion in adult mice.
Why the study?
TCF21 is downregulated in adult tissue-resident fibroblasts after injury, leading to the hypothesis that it regulates fibroblast differentiation in the adult mammalian heart to affect fibrosis.
Sustained TCF21 expression in adult cardiac fibroblasts prevents myofibroblast formation and reduces cardiac fibrosis and hypertrophy following injury in mouse models.
Sustained TCF21 expression reduces acute fibrosis and hypertrophy after injury in mice; leaves open whether targeting its downregulation offers clinical benefit.
BACKGROUND: TCF21 (transcription factor 21) is a bHLH (basic helix-loop-helix) protein required for the developmental specification of cardiac fibroblasts (CFs) from epicardial progenitor cells that surround the embryonic heart. In the adult heart, TCF21 is expressed in tissue-resident fibroblasts and is downregulated in response to injury or stimuli leading to myofibroblast differentiation. These findings led to the hypothesis that TCF21 regulates fibroblast differentiation in the adult mammalian heart to affect fibrosis. METHODS: Tamoxifen-inducible Cre genetic mouse models were used to permit either Tcf21 gene deletion or its enforced expression in adult CFs. Histological and echocardiographic analyses were used, as well as transcriptomic analysis to determine the consequences of TCF21 gain-of-function and loss-of-function in vivo. Genomic Tcf21 occupancy was identified by chromatin immunoprecipitation and sequencing in CFs. Myocardial infarction and AngII (angiotensin II)/phenylephrine served as models of cardiac fibrosis. RESULTS: Acute and long-term deletion of Tcf21 in CFs of the adult mouse heart does not alter fibroblast numbers, myofibroblast differentiation, or fibrosis. Fibroblast-specific Tcf21 gene–deleted mice demonstrate no significant alterations in cardiac function or scar formation in response to cardiac injury compared with control mice. In contrast, enforced expression of TCF21 in CFs inhibits myofibroblast differentiation and significantly reduces cardiac fibrosis and hypertrophy in response to 1 week of Ang II/phenylephrine infusion. Mechanistically, sustained TCF21 expression prevents the induction of genes associated with fibrosis and ECM (extracellular matrix) organization. CONCLUSIONS: TCF21 expression is not required to maintain the cell state of CFs in the adult heart. However, preventing the normal downregulation of TCF21 expression with injury reduces myofibroblast formation, cardiac fibrosis, and the acute cardiac hypertrophic response following 1 week of Ang II/phenylephrine stimulation.
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Johansen et al. (2024) studied Cardiac fibrosis. Tcf21 gene deletion or enforced expression vs. Control mice was evaluated on Myofibroblast differentiation, cardiac fibrosis, and hypertrophy. Enforced expression of TCF21 in cardiac fibroblasts significantly reduced cardiac fibrosis and hypertrophy in response to 1 week of Ang II/phenylephrine infusion in adult mice.
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