Uscategui Calderon Maria, Spaeth Maria L, Granitto Marissa, Gonzalez Brittany A, Weirauch Matthew T, Kottyan Leah C, Yutzey Katherine E
Molecular and Developmental Biology Graduate Program, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA; The Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
The Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
J Mol Cell Cardiol. 2025 Apr;201:16-31. doi: 10.1016/j.yjmcc.2025.01.010. Epub 2025 Feb 3.
Cardiomyocytes and cardiac fibroblasts undergo coordinated maturation after birth, and cardiac fibroblasts are required for postnatal cardiomyocyte maturation in mice. Here, we investigate the role of cardiac fibroblast-expressed Growth Differentiation Factor 10 (GDF10) in postnatal heart development. In neonatal mice, Gdf10 is expressed specifically in cardiac fibroblasts, with its highest expression coincident with the onset of cardiomyocyte cell cycle arrest and transition to hypertrophic growth. In neonatal rat ventricular myocyte (NRVM) cultures, GDF10 treatment promotes cardiomyocyte maturation indicated by increased binucleation, downregulation of cell cycle progression genes, and upregulation of cell cycle inhibitor genes. GDF10 treatment leads to an increase in cardiomyocyte cell size, together with increased expression of mature sarcomeric protein isoforms and decreased expression of fetal cardiac genes. RNAsequencing of GDF10-treated NRVM shows an increase in the expression of genes related to myocardial maturation, including upregulation of sodium and potassium channel genes. In vivo, loss of Gdf10 leads to a delay in myocardial maturation indicated by decreased cardiomyocyte cell size and binucleation, as well as increased mitotic activity, at postnatal (P) day 7. Further, induction of mature sarcomeric protein isoform gene expression is delayed, and expression of cell cycle progression genes is prolonged. However, by P10, indicators of cardiomyocyte maturation and mitotic activity are normalized in Gdf10-null hearts relative to controls. Together, these results implicate GDF10 as a novel crosstalk mediator between cardiomyocytes and cardiac fibroblasts, which is required for appropriate timing of cardiomyocyte maturation steps including binucleation, hypertrophy, mature sarcomeric isoform gene expression, and cell cycle arrest in the postnatal period.
出生后，心肌细胞和心脏成纤维细胞会经历协调的成熟过程，并且小鼠出生后心肌细胞的成熟需要心脏成纤维细胞。在此，我们研究心脏成纤维细胞表达的生长分化因子10（GDF10）在出生后心脏发育中的作用。在新生小鼠中，Gdf10特异性地在心脏成纤维细胞中表达，其最高表达与心肌细胞细胞周期停滞以及向肥大生长转变的开始相一致。在新生大鼠心室肌细胞（NRVM）培养物中，GDF10处理可促进心肌细胞成熟，表现为双核化增加、细胞周期进展基因下调以及细胞周期抑制基因上调。GDF10处理导致心肌细胞大小增加，同时成熟肌节蛋白亚型的表达增加，胎儿心脏基因的表达减少。对经GDF10处理的NRVM进行RNA测序显示，与心肌成熟相关的基因表达增加，包括钠和钾通道基因的上调。在体内，Gdf10缺失导致出生后（P）第7天心肌成熟延迟，表现为心肌细胞大小和双核化减少，以及有丝分裂活性增加。此外，成熟肌节蛋白亚型基因表达的诱导延迟，细胞周期进展基因的表达延长。然而，到P10时，相对于对照组，Gdf10基因敲除心脏中心肌细胞成熟和有丝分裂活性的指标恢复正常。总之，这些结果表明GDF10是心肌细胞和心脏成纤维细胞之间一种新的信号传导介质，是出生后心肌细胞成熟步骤（包括双核化、肥大、成熟肌节亚型基因表达和细胞周期停滞）适时发生所必需的。
