Oocyte and cumulus cell cooperativity and metabolic plasticity under the direction of oocyte paracrine factors

ABSTRACT Mammalian oocytes develop and mature in a mutually dependent relationship with surrounding cumulus cells. The oocyte actively regulates cumulus cell differentiation and function by secreting soluble paracrine oocyte-secreted factors (OSFs). We characterized the molecular mechanisms by which two model OSFs, cumulin and BMP15, regulate oocyte maturation and cumulus-oocyte cooperativity. Exposure to these OSFs during maturation altered the proteomic and multispectral autofluorescence profiles of both the oocyte and cumulus cells. In oocytes, cumulin significantly upregulated proteins involved in nuclear function. In cumulus cells, both OSFs elicited marked upregulation of a variety of metabolic processes (mostly anabolic), including lipid, nucleotide, and carbohydrate metabolism, while mitochondrial metabolic processes were downregulated. The mitochondrial changes were validated by functional assays confirming altered mitochondrial morphology, respiration, and content, whilst maintaining ATP homeostasis. Collectively, these data demonstrate that OSFs remodel cumulus cell metabolism during oocyte maturation in preparation for ensuing fertilization and embryonic development. HIGHLIGHTS During oocyte maturation, oocyte-secreted factors promote cell cooperativity between the oocyte and cumulus cells by altering the molecular composition of both cell types. Oocyte-secreted factors downregulate protein catabolic processes, and upregulate DNA binding, translation, and ribosome assembly in oocytes. Oocyte-secreted factors alter mitochondrial number, morphology, and function in cumulus cells. Oocyte-secreted factors further enhance metabolic plasticity in cumulus cells by upregulating anabolic pathways for macromolecules and small molecule organics. The oocyte, via oocyte-secreted factors, instructs cumulus cells to increase metabolic workload on its behalf, thereby subduing oocyte metabolism.