| Project Detail |
Reactivating endogenous heart regeneration
In mammals, the heart has a brief regenerative window shortly after birth, but adult human cardiomyocytes have a very low turnover rate, limiting heart regeneration. This limitation often leads to heart failure in diseases involving cardiomyocyte loss, such as acute ischaemia. Funded by the European Research Council, the REACTIVA project aims to reactivate an endogenous heart-regeneration mechanism. This approach is based on the fact that most adult cardiomyocytes cannot divide due to polyploidy, which relates to high contractility needs. Researchers identified a molecular signature of adult diploid cardiomyocytes, whose proliferation is controlled by a repressor transcription factor. Inhibiting this factor could promote adult heart regeneration.
The mammalian heart is a non-regenerative organ due to the extremely limited ability of fully differentiated cardiomyocytes (CMs) to proliferate. While neonatal hearts still contain mostly diploid CMs and regenerate efficiently, physiological postnatal CM polyploidization/hypertrophy ensures the contractile capacity of the adult myocardium but represents a roadblock to cardiac regeneration. Due to this limitation, diseases that provoke CM loss, like acute ischemia, frequently lead to heart failure. REACTIVA will establish a new strategy for heart regeneration based on the reactivation of a dormant endogenous mechanism, thereby achieving unprecedented advances in the field of cardiac regenerative biology. In mice, the proportion of adult diploid CMs (ADCs) correlates with regenerative ability, however, efforts to identify a molecular signature for ADCs have been unsuccessful, which has precluded exploring their roles in heart regeneration. Using an improved methodology for single-CM RNAseq, my group has identified a molecular signature of ADCs related to the fetal program and controlled by a single repressor transcription factor. This factor is specifically expressed in the polyploid CM population (PCM) and its inhibition in the postnatal mouse heart robustly increases ADC abundance and proliferative activity. Based on these findings, we propose that ADCs underlie a vestigial endogenous mechanism for adult mammalian heart renewal and that their stimulation will promote heart regeneration. REACTIVA will exploit our new findings on ADCs to 1) Fully characterize the ADC regulatory network, identifying factors to modulate it, 2) Identify and trace ADCs in the adult heart, defining their niches and contribution to renew and expand the CM population during heart homeostasis, aging and disease, 3) Use the generated knowledge to induce ADC activation with the goal of promoting adult mammalian heart regeneration. |
