Reproductive biomedicine online · 2024
Ovarian support cell in-vitro maturation results in healthy murine live births with no evidence of reprotoxicology in a multigenerational study.
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Marchante Maria, Barrachina Ferran, Mestres Enric, Acacio Monica, Potts Kathryn S, Piechota Sabrina, Paulsen Bruna, Noblett Alexander D, Figueroa Alexandra B, Costa-Borges Nuno, Kramme Christian C
Аннотация
RESEARCH QUESTION: Does application of human-stem-cell-derived ovarian support cells (OSC) for in-vitro maturation (IVM) have a safe reproductive toxicity profile?
DESIGN: In total, 70 stimulated B6/CBA female mice (6-8 weeks old) were used to collect immature oocytes (n = 2025) at the germinal vesicle stage. Oocytes were retrieved denuded (n = 930) or with cumulus cells [cumulus-oocyte complexes (COC), n = 1095], and were assigned at random to the traditional IVM group (traditional IVM medium) or the OSC IVM group (same IVM medium supplemented with human OSC). Metaphase II oocytes were inseminated by intracytoplasmic sperm injection and cultured to blastocyst stage. Vitrified blastocysts were transferred to pseudopregnant females, and F1 offspring were evaluated for various health and developmental metrics. Select F1 mice were outbred to produce the F2 generation, assessing live births, sex ratio, morphology, behaviour and health.
RESULTS: In mice, OSC IVM with COC exhibited a decreased maturation rate compared with traditional IVM with denuded oocytes (P = 0.0101). Subsequent embryo culture yielded similar cleavage rates between the four groups (P = 0.7547). However, there was a significant distinction in blastocyst formation, with OSC IVM with COC showing a higher blastocyst formation rate (56.1 ± 19.2%) than traditional IVM with denuded oocytes (38.0 ± 16.2; P = 0.0063) and traditional IVM with COC (41.5 ± 15.9; P = 0.0408). Live births, sex ratio, development and behaviour in the F1 and F2 generations revealed no adverse effects or significant differences, confirming the absence of long-term toxicity.
CONCLUSIONS: This study demonstrates the safety of OSC IVM, with no adverse effects on embryo development or offspring health and fertility across generations.
DESIGN: In total, 70 stimulated B6/CBA female mice (6-8 weeks old) were used to collect immature oocytes (n = 2025) at the germinal vesicle stage. Oocytes were retrieved denuded (n = 930) or with cumulus cells [cumulus-oocyte complexes (COC), n = 1095], and were assigned at random to the traditional IVM group (traditional IVM medium) or the OSC IVM group (same IVM medium supplemented with human OSC). Metaphase II oocytes were inseminated by intracytoplasmic sperm injection and cultured to blastocyst stage. Vitrified blastocysts were transferred to pseudopregnant females, and F1 offspring were evaluated for various health and developmental metrics. Select F1 mice were outbred to produce the F2 generation, assessing live births, sex ratio, morphology, behaviour and health.
RESULTS: In mice, OSC IVM with COC exhibited a decreased maturation rate compared with traditional IVM with denuded oocytes (P = 0.0101). Subsequent embryo culture yielded similar cleavage rates between the four groups (P = 0.7547). However, there was a significant distinction in blastocyst formation, with OSC IVM with COC showing a higher blastocyst formation rate (56.1 ± 19.2%) than traditional IVM with denuded oocytes (38.0 ± 16.2; P = 0.0063) and traditional IVM with COC (41.5 ± 15.9; P = 0.0408). Live births, sex ratio, development and behaviour in the F1 and F2 generations revealed no adverse effects or significant differences, confirming the absence of long-term toxicity.
CONCLUSIONS: This study demonstrates the safety of OSC IVM, with no adverse effects on embryo development or offspring health and fertility across generations.