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ERBB2 and YAP1 Combine to Drive Adult Cardiac Regeneration

Review of "ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration" from Nature Cell Biology by Stuart P. Atkinson

Following acute myocardial infarction, the adult mammalian heart's inability to replace lost cardiomyocytes combined with scarring at the injured area [1] leads to a permanent loss of contractile force and heart failure. Interestingly, studies have established that the neonatal mammalian heart does display some level of cardiac regeneration shortly after birth [2], suggesting the potential for this mechanism to become activated in later life given the correct stimuli.

Researchers led by Eldad Tzahor (Weizmann Institute of Science, Rehovot, Israel) previously established a role for the tyrosine kinase receptor ERBB2 in NRG1 (Neuregulin 1)-induced cardiomyocyte proliferation during mouse embryonic and neonatal stages and demonstrated how ERBB2 expression induced a regenerative response following myocardial infarction [3]. The team now returns with a Nature Cell Biology article [4], in which Aharonov et al. reveal the essential nature of crosstalk between ERBB2–NRG1 signaling and the Hippo-YAP1 (Yes-associated protein 1) mechanotransduction pathway [5] during heart regeneration in the adult mouse. Are we one step closer to inducing cardiac regeneration in the infarcted human heart?

The authors induced cardiac regeneration in scarred adult mouse hearts via the transient and cardiomyocyte-specific expression of ERBB2 [3]. This induced cytoskeletal remodeling (including alterations to microfilaments, intermediate filaments, and microtubules) to shift cardiomyocytes from contractile force propagation to a nuclear-directed force, junction dissolution, and extracellular matrix turnover suggestive of an epithelial-mesenchymal transition. Importantly, ERBB2 overexpression also prompted cardiomyocyte proliferation and migration and scar replacement with new cardiomyocytes.

Given the altered mechanical state of cardiomyocytes during ERBB2-driven cardiac regeneration, the authors hypothesized a potential role for the Hippo-YAP1 mechanotransduction pathway, and subsequent analyses established enriched YAP nuclear accumulation, elevated YAP levels, ERK-dependent mitogenic phosphorylation and activation of YAP1, strong YAP transcriptional activation, and the interaction of YAP1 with nuclear-envelope and cytoskeletal components in ERBB2-expressing cardiomyocytes. The importance of YAP1 to cardiac regeneration was underscored by both the lack of ERBB2-mediated regeneration in the absence of YAP1 and the lack of ERBB2-expressing cardiomyocyte proliferation in the presence of YAP1 phospho-mutants.

Overall, the authors provide evidence for the crucial role of an ERBB2/YAP signaling cascade in cardiac regeneration in adult mice - can we take advantage of this information to induce cardiac regeneration in the infarcted human heart? Stay tuned to the Stem Cells Portal to find out!

References

  1. Tzahor E and Poss KD, Cardiac regeneration strategies: Staying young at heart. Science 2017;356:1035.
  2. Porrello ER, Mahmoud AI, Simpson E, et al., Transient regenerative potential of the neonatal mouse heart. Science 2011;331:1078-1080.
  3. D’Uva G, Aharonov A, Lauriola M, et al., ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nature Cell Biology 2015;17:627-638.
  4. Aharonov A, Shakked A, Umansky KB, et al., ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration. Nature Cell Biology 2020;22:1346-1356.
  5. Panciera T, Azzolin L, Cordenonsi M, et al., Mechanobiology of YAP and TAZ in physiology and disease. Nature Reviews Molecular Cell Biology 2017;18:758-770.