National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture and Rural Affairs; College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China.
Biol Reprod. 2021 May 7;104(5):1114-1125. doi: 10.1093/biolre/ioab009.
Conventional heterologous mitochondrial replacement therapy is clinically complicated by "tri-parental" ethical concerns and limited source of healthy donor oocytes or zygotes. Autologous mitochondrial transfer is a promising alternative in rescuing poor oocyte quality and impaired embryo developmental potential associated with mitochondrial disorders, including aging. However, the efficacy and safety of mitochondrial transfer from somatic cells remains largely controversial, and unsatisfying outcomes may be due to distinct mitochondrial state in somatic cells from that in oocytes. Here, we propose a potential strategy for improving in vitro fertilization (IVF) outcomes of aging female patients via mitochondrial transfer from induced pluripotent stem (iPS) cells. Using naturally aging mice and well-established cell lines as models, we found iPS cells and oocytes share similar mitochondrial morphology and functions, whereas the mitochondrial state in differentiated somatic cells is substantially different. By microinjection of isolated mitochondria into fertilized oocytes following IVF, our results indicate that mitochondrial transfer from iPS, but not MEF cells, can rescue the impaired developmental potential of embryos from aging female mice and obtain an enhanced implantation rate following embryo transfer. The beneficial effect may be explained by the fact that mitochondrial transfer from iPS cells not only compensates for aging-associated loss of mtDNA, but also rescues mitochondrial metabolism of subsequent preimplantation embryos. Using mitochondria from iPS cells as the donor, our study not only proposes a promising strategy for improving IVF outcomes of aging females, but also highlights the importance of synchronous mitochondrial state in supporting embryo developmental potential.
传统的异源线粒体替代疗法在临床上受到“三亲”伦理问题的困扰，并且健康的供体卵母细胞或胚胎来源有限。自体线粒体转移是一种有前途的替代方法，可以挽救与线粒体疾病相关的卵母细胞质量差和胚胎发育潜能受损的问题，包括衰老。然而，来自体细胞的线粒体转移的疗效和安全性在很大程度上仍存在争议，并且不满意的结果可能是由于体细胞中的线粒体状态与卵母细胞中的线粒体状态不同。在这里，我们提出了一种通过从诱导多能干细胞（iPS）细胞中转移线粒体来改善老年女性患者体外受精（IVF）结局的潜在策略。使用自然衰老的小鼠和成熟的细胞系作为模型，我们发现 iPS 细胞和卵母细胞具有相似的线粒体形态和功能，而分化的体细胞中的线粒体状态则大不相同。通过在 IVF 后将分离的线粒体微注射到受精卵中，我们的结果表明，线粒体可以从 iPS 细胞而不是 MEF 细胞中转移，从而挽救衰老雌性小鼠胚胎发育潜能受损，并在胚胎移植后提高着床率。这种有益的效果可以通过以下事实来解释：从 iPS 细胞中转移线粒体不仅可以补偿与衰老相关的 mtDNA 丢失，而且可以挽救随后的胚胎前植入期的线粒体代谢。使用 iPS 细胞的线粒体作为供体，我们的研究不仅提出了一种改善老年女性 IVF 结局的有前途的策略，而且还强调了同步线粒体状态对支持胚胎发育潜能的重要性。
