Cava-Cami Berta, Galvao Antonio, Van Ranst Heidi, Stocker William A, Harrison Craig A, Smitz Johan, De Vos Michel, Kelsey Gavin, Anckaert Ellen
Follicle Biology Laboratory, Research Group Genetics, Reproduction and Development, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Institute of Animal Reproduction and Food Research, Polish Academy of Science, Olsztyn, Poland.
Mol Hum Reprod. 2025 Jan 17;31(1). doi: 10.1093/molehr/gaaf001.
Biphasic IVM can be offered as a patient-friendly alternative to conventional ovarian stimulation in IVF patients predicted to be hyper-responsive to ovarian stimulation. However, cumulative live birth rates after IVM per cycle are lower than after conventional ovarian stimulation for IVF. In different animal species, supplementation of IVM media with oocyte-secreted factors (OSFs) improves oocyte developmental competence through the expression of pro-ovulatory genes in cumulus cells. Whether the addition of OSFs in human biphasic IVM culture impacts the transcriptome of oocytes and cumulus cells retrieved from small antral follicles in minimally stimulated non-hCG-triggered IVM cycles remains to be elucidated. To answer this, human cumulus-oocyte complexes (COCs) that were fully surrounded by cumulus cells or partially denuded at the time of retrieval were cultured in a biphasic IVM system either without or with the addition of pro-cumulin, a GDF9:BMP15 heterodimer. Oocytes and their accompanying cumulus cells were collected separately, and single-cell RNA-seq libraries were generated. The transcriptomic profile of cumulus cells revealed that pro-cumulin upregulated the expression of genes involved in cumulus cell expansion and proliferation while downregulating steroidogenesis, luteinization, and apoptosis pathways. Moreover, pro-cumulin modulated the immature oocyte transcriptome during the pre-maturation step, including regulating translation, apoptosis, and mitochondria remodeling pathways in the growing germinal vesicle oocytes. The addition of pro-cumulin also restored the transcriptomic profile of matured metaphase II oocytes that were partially denuded at collection. These results suggest that cumulus cell and oocyte transcriptome regulation by pro-cumulin may increase the number of developmentally competent oocytes after biphasic IVM treatment. Future studies should assess the effects of pro-cumulin addition in human biphasic IVM at the proteomic level and the embryological outcomes, particularly its potential to enhance outcomes of oocytes that are partially denuded at COC collection.
对于预计对卵巢刺激反应过度的体外受精（IVF）患者，双相未成熟卵母细胞体外成熟培养（IVM）可作为一种对患者友好的传统卵巢刺激替代方案。然而，IVM每个周期后的累积活产率低于IVF的传统卵巢刺激。在不同动物物种中，向IVM培养基中添加卵母细胞分泌因子（OSFs）可通过卵丘细胞中促排卵基因的表达提高卵母细胞发育能力。在最小刺激且未使用人绒毛膜促性腺激素（hCG）触发的IVM周期中，向人双相IVM培养中添加OSFs是否会影响从小窦卵泡中获取的卵母细胞和卵丘细胞的转录组仍有待阐明。为了回答这个问题，将在获取时被卵丘细胞完全包围或部分剥脱的人卵丘-卵母细胞复合体（COCs）在双相IVM系统中培养，该系统不添加或添加原积蛋白（一种生长分化因子9：骨形态发生蛋白15异二聚体）。分别收集卵母细胞及其伴随的卵丘细胞，并生成单细胞RNA测序文库。卵丘细胞的转录组分析表明，原积蛋白上调参与卵丘细胞扩展和增殖的基因表达，同时下调类固醇生成、黄体化和凋亡途径。此外，原积蛋白在成熟前阶段调节未成熟卵母细胞转录组，包括调节生长中的生发泡卵母细胞中的翻译、凋亡和线粒体重塑途径。添加原积蛋白还恢复了采集时部分剥脱的成熟中期II卵母细胞的转录组谱。这些结果表明，原积蛋白对卵丘细胞和卵母细胞转录组的调节可能会增加双相IVM治疗后发育能力良好的卵母细胞数量。未来的研究应在蛋白质组水平评估添加原积蛋白对人双相IVM的影响以及胚胎学结局，特别是其增强COC采集时部分剥脱的卵母细胞结局的潜力。
