Human-induced pluripotent stem cell-derived ovarian support cell co-culture improves oocyte maturation in vitro after abbreviated gonadotropin stimulation

• DOI: 10.1093/humrep/dead205
• Publication Date: 2023-10-10T14:12:19Z
• Authors: Sabrina Piechota; Maria Marchante; Alexa Giovannini; Bruna Paulsen; Kathryn S Potts; Graham Rockwell; Caroline Aschenbe...; Alexander D Noblett; Alexandra B Figueroa; Marta Sanchez; Ferran Barrachina; Klaus Wiemer; Luis Guzman; Pedro Belchin; Merrick Pierson S...; Patrick R J Fortuna; Pranam Chatterjee; Nam D Tran; Dawn A Kelk; Marcy Forti; Shelby Marcinyshyn; Trozalla Smith; David H McCulloh; Marta-Julia Ferna...; Baruch Abittan; Silvia Ortiz; Joshua U Klein; Peter Klatsky; Daniel Ordonez-Perez; Christian C Kramme
• Keywords: In vitro maturation; Antral follicle; Ovarian hyperstimulation syndrome; Gonadotropin

Abstract STUDY QUESTION Can in vitro maturation (IVM) and developmental competence of human oocytes be improved by co-culture with ovarian support cells (OSCs) derived from human-induced pluripotent stem (hiPSCs)? SUMMARY ANSWER OSC-IVM significantly improves the rates metaphase II (MII) formation euploid Day 5 or 6 blastocyst formation, when compared to a commercially available IVM system. WHAT IS KNOWN ALREADY has historically shown highly variable performance maturing generating strong capacity, while limited studies have positive benefit primary granulosa cell for IVM. We recently reported development OSCs generated hiPSCs that recapitulate dynamic function vitro. DESIGN, SIZE, DURATION The study was designed as basic science study, using randomized sibling oocyte specimen allocation. Using pilot data, prospective sample size 20 donors at least 65 per condition were used subsequent experiments. A total 67 recruited undergo abbreviated gonadotropin stimulation without hCG triggers retrieved cumulus–oocyte complexes (COCs) allocated between control conditions (fetal-like OSC (FOSC)-IVM media-only IVM) three independent experimental design formats. duration 1 April 2022 July 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS Oocyte ages 19 37 years retrieval after informed consent, assessment anti-Mullerian hormone, antral follicle count, age, BMI pathology inclusion exclusion criteria. In experiment 1, 27 recruited, 2, 23 3, 17 3 sperm recruited. culture composed 100 000 suspension hCG, recombinant FSH, androstenedione, doxycycline supplementation. controls lacked contained either same supplementation, FSH only (a commercial control), FOSCs supplementation (Media control). Experiment OSC-IVM, FOSC-IVM, Media control, experiments 2 control. Primary endpoints first two MII (i.e. maturation) rate morphological quality assessment. third experiment, fertilization embryo assessed genetic testing aneuploidy epigenetic blastocysts. MAIN RESULTS AND THE ROLE OF CHANCE observed statistically significant improvement (∼1.5×) outcomes underwent Media-IVM FOSC-IVM 1. More specifically, group yielded 68% ± 6.83% SEM versus 46% 8.51% (P = 0.02592, unpaired t-test). 51% 9.23% which did not differ media 0.77 Additionally, ∼1.6× higher average 6.74% 43% 7.90% 0.0349, paired t-test) 2. differ. demonstrated COC (25% 7.47% vs 11% 3.82%, P 0.0349 logistic regression). Also OSC-treated blastocysts similar global germline differentially methylated region profiles conventional stimulation. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION While findings this are compelling, cohort remains powered on preliminary studies, research nature limits generalizability trials. use hCG-triggered cycles results heterogenous cohort, potential differences underlying state pre-IVM may limit bias findings. Further is needed clarify characterize precise mechanism action also establish whether these embryos capable implantation further development, key indication their clinical utility. WIDER IMPLICATIONS FINDINGS Together, demonstrate novel approach broad applicability modern ART practice. line produced those literature, outcome supports previous found benefits outcomes. system shows promise flexible can complement range styles patient populations. Particularly patients who cannot prefer stimulation, present viable path obtaining developmentally competent, mature oocytes. FUNDING/COMPETING INTEREST(s) A.D.N., A.B.F., A.G., B.P., C.A., C.C.K., F.B., G.R., K.S.P., K.W., M.M., P.C., S.P., M.-J.F.-G. shareholders for-profit biotechnology company Gameto Inc. P.R.J.F. declares paid consultancy P.C. Scientific Advisory Board D.H.M. received consulting services Granata Bio, Sanford Fertility Reproductive Medicine, Gameto, Buffalo IVF, travel Upper Egypt Assisted Reproduction Society. A.D.N. listed patent covering IVM: U.S. Provisional Patent Application No. 63/492,210. C.C.K. K.W. patents 17/846,725, U.S 17/846,845, International No.: PCT/US2023/026012. M.P.S., additionally transcription factor-directed production granulosa-like cells: PCT/US2023/065140, 63/326,640, 63/444,108. remaining authors no conflicts interest declare.