Oocyte secreted factors regulate insulin growth factor 2 (IGF2) expression in human primary cumulus granulosa cells

pressed genes in KO CCs compared to WT in 3and 6-month-old mice, respectively. Among them, 163 genes were common differentially expressed at both age groups. Pathway analysis revealed apoptosis and phagosomelysosome pathways to be uniquely affected at 3and 6-month-old KO CCs, respectively. IF microscopy for apoptotic and cell proliferation markers in ovarian sections and COCs confirmed RNAseq findings with increased immunoreactivity for TUNEL and decreased expression of Ki67 and PCNA (p<0.05). Electron microscopy revealed significant impairment of mitochondrial dynamics in Clpp-deficient cumulus cells with lower aspect ratio (length/width; 1.92 0.04 vs. 1.64 0.04, p<0.0001). qRT-PCR showed a significant decrease in expression of genes involved in mitochondrial dynamics, Mfn1, Mfn2 and Opa1 (p<0.05). CONCLUSIONS: Impaired mitochondrial stress response in cumulus cells with targeted deletion of Clpp is associated with significant changes in CC transcriptome and mitochondrial dynamics that culminate in increased apoptotic cell death and accelerated follicular depletion. The relevance of these parameters in women undergoing IVF and whether they can be exploited to improve treatment outcomes remain to be investigated.