Cardiovascular research · 2026
Reintroducing FABP5 in adulthood activates cell cycle in cardiomyocytes.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Salama Abou Bakr M, Ou Qinghui, Dwenger Marc, Wells Collin K, Gebreil Ahmad, Miller Jessica, Abou Farraj Kamal, Nong Yibing, Wahid Reham M, Abdelhafez Hania, Arai Momo, Dastagir Muzammil, Khan Mohammad Salman, Mathew Pretty R, Hamouda Mohamed, Baraka Nourhan M, Elhelaly Waleed M, Rhamfield Jordan, Kulkarni Om, Huelsmann Joern, Taha Sara, Liu Rebecca, Bench Sarah, Kang Sung Wook, Rodriguez Victoria, Kraushaar Daniel, Lee Hyun-Sung, Eberlin Livia S, Hill Bradford G, Rosengart Todd K, Abouleisa Riham R E, Mohamed Tamer M A
Аннотация
BACKGROUND AND AIMS: Adult cardiomyocytes (CMs) have minimal proliferative capacity, limiting the heart's ability to regenerate after injury. While neonatal CMs can proliferate, the signaling pathways governing this process are poorly understood. This study aims to identify and reintroduce the neonatal-specific CM proliferation sensitizing signal to restore cell-cycle in adult CMs.
METHODS AND RESULTS: We identified CD36 as a marker for the neonatal spontaneously proliferating CMs. Bulk and Single cell RNAseq, and spatial transcriptomics analyses of the P1 WT, CD36KO and CD36CKO hearts revealed that a CD36/FABP5/PPARδ signaling axis was uniquely expressed in spontaneously proliferating CMs. Using unbiased metabolomics and spatial metabolomics, we discovered that CD36KO and CD36cKO hearts had a 50% reduction in retinoic acid (RA) levels, implicating CD36 in regulating RA intracellular levels. Moreover, the pro-proliferative effect of RA treatment was lost in CD36KO or FABP5 knockdown CMs. To confirm the causality of this proposed mechanism, in vivo, crossing CD36KO with CM-specific PPARδ overexpression (PPARδCTG) only in CMs rescued the proliferation deficiency phenotype in CD36KO in the P1 hearts. Finally, reintroduction of FABP5, the rate limiting step of this signaling pathway, in adult hearts, using an inducible CM-specific FABP5 knock-in mouse (FABP5KI) was sufficient to drive CM cell cycle entry and led to significantly improved cardiac function following myocardial infarction in adult mice.
CONCLUSION: RA/CD36/FABP5/PPARδ signaling pathway is essential for spontaneous neonatal CM proliferation. Re-activating this pathway in adult hearts through FABP5 overexpression is sufficient to induce functional recovery after ischemic injury, identifying FABP5 as a potential therapeutic target for cardiac regeneration.
METHODS AND RESULTS: We identified CD36 as a marker for the neonatal spontaneously proliferating CMs. Bulk and Single cell RNAseq, and spatial transcriptomics analyses of the P1 WT, CD36KO and CD36CKO hearts revealed that a CD36/FABP5/PPARδ signaling axis was uniquely expressed in spontaneously proliferating CMs. Using unbiased metabolomics and spatial metabolomics, we discovered that CD36KO and CD36cKO hearts had a 50% reduction in retinoic acid (RA) levels, implicating CD36 in regulating RA intracellular levels. Moreover, the pro-proliferative effect of RA treatment was lost in CD36KO or FABP5 knockdown CMs. To confirm the causality of this proposed mechanism, in vivo, crossing CD36KO with CM-specific PPARδ overexpression (PPARδCTG) only in CMs rescued the proliferation deficiency phenotype in CD36KO in the P1 hearts. Finally, reintroduction of FABP5, the rate limiting step of this signaling pathway, in adult hearts, using an inducible CM-specific FABP5 knock-in mouse (FABP5KI) was sufficient to drive CM cell cycle entry and led to significantly improved cardiac function following myocardial infarction in adult mice.
CONCLUSION: RA/CD36/FABP5/PPARδ signaling pathway is essential for spontaneous neonatal CM proliferation. Re-activating this pathway in adult hearts through FABP5 overexpression is sufficient to induce functional recovery after ischemic injury, identifying FABP5 as a potential therapeutic target for cardiac regeneration.