Project Summary/Abstract
Critical maturation steps of mammalian heart development take place during the first few weeks after birth.
During this time, cardiomyocytes undergo critical changes in cell structure, metabolism and gene expression, all
which are essential for the proper function of the heart. CM are in contact with different cell types including
fibroblasts, which have been identified as key central regulators of ventricular maturation and remodeling during
both development and injury. However, the pathways utilized by fibroblasts and cardiomyocytes cells to
communicate during postnatal heart development remain unknown. Recently RNA sequencing identified Growth
differentiation factor 10 (GDF10), also known as Bmp3b, as an upregulated ligand in postnatal cardiac fibroblasts
compared to mature quiescent fibroblasts which suggest, GDF10 plays a role in the crosstalk between
cardiomyocyte and fibroblasts during neonatal development. Interestingly, in skeletal muscle, GDF10 is essential
for maintaining myofiber mass maintenance and adult Gdf10 null mice develop left ventricle hypertrophy.
Further, single-cell sequencing of fat cells found GDF10 to directly modulate PPAR-gamma nuclear abundance
and transcriptional activity, which is known to be important for cardiac energy shift in cardiomyocyte, suggesting
that GDF10 might be important for mitochondrial maturation during heart development. However, the exact role
of GDF10 in the proper maturation of the heart remains to be defined. Our preliminary studies indicate that in
vitro treatment with GDF10 induces size increase and a switch towards mature myosin isoform expression in
neonatal cardiomyocyte which suggests that GDF10 action during cardiac development might be important for
proper maturation. Further, gene expression profiling of neonatal cardiomyocyte and fibroblasts revealed
fibroblast expressed GDF10 to strongly correlate with Activin receptor expression on cardiomyocytes, which
have been implicated in GDF family signaling in cardiomyocytes. Finally, our preliminary studies show that gdf10
null hearts at postnatal day 7 have myocardial growth defects similar to hypoplastic left heart syndrome. The
central hypothesis of this proposal is that cardiac fibroblast secreted GDF10, signaling through activin
receptors, is essential for cardiomyocyte hypertrophy and mitochondrial maturation during
development. Aim 1 will determine if GDF10, through Smad 1/5/8 signaling induces cardiomyocytes
hypertrophy and mitochondrial maturation. In parallel, bulk RNA-sequencing of GDF10, activin receptor inhibitor
ACE031 and GDF10+ACE031 treated cardiomyocyte cells will give us an in-depth understanding of direct
GDF10 targets that induce CM maturation. In Aim 2, we will determine whether GDF10 signaling is required for
CM hypertrophy and metabolic maturation in vivo by extensively examining gdf10 null hearts and measuring
changes in cardiomyocyte cell size and sarcomeric assembly. Additionally, we will evaluate fetal and adult
metabolic and contractile protein gene expression of Gdf10 null mice compared to controls. Our long-term goal
is to determine GDF10 as a key crosstalk ligand between fibroblasts and cardiomyocytes in the mammalian
postnatal cardiac development and if the loss of this communication impairs maturation of cardiomyocytes by
decreasing cardiomyocyte hypertrophy.