Abstract
Ovarian aging occurs earlier than somatic aging. We tested the hypothesis that ovarian functions could be artificially reconstructed by transplantation of primordial germ cells (PGCs). We compared various methods for transplantation of PGCs aggregated with gonadal somatic cells and showed that reconstituted ovaries exhibited folliculogenesis after transplantation of PGCs-aggregates into either kidney capsule or ovarian bursa. Neo-oogenesis occurred early after transplantation, as evidenced by the presence of prophase I meiocytes displaying homologous pairing. Moreover, endocrine function was recovered in ovariectomized recipients, including elevated levels of AMH and estradiol. Interestingly, folliculogenesis in the reconstituted ovaries failed to sustain past four weeks. Regardless of transplantation method, follicles diminished after 45 days, accompanied by increased apoptosis, and were undetectable after two months. Meanwhile, no replicative PGCs or prophase I meiocytes could be found. Together, transplantation of PGCs can effectively reconstitute ovarian functions but for limited time. These data suggest that PGCs do not undergo self-renewal but rapidly enter meiosis following transplantation. Global activation of primordial follicles in artificial ovaries can result in further rapid loss of germ cells. Methods for maintaining self-renewal and expansion in vivo of PGCs and controlling follicle activation will be essential for continuing maintenance of the functional reconstructed ovaries.
Highlights
Ovarian aging precedes somatic aging in most mammalian species
Efficiency to form oocytes or follicles was low following intra-ovarian injection of dissociated primordial germ cells (PGCs) with gonadal somatic cells labeled with AIE dots or derived from green fluorescent protein (GFP) fetuses (Supplementary Fig. S1A–D), consistent with previous studies showing low efficiency in folliculogenesis following transplantation via intro-ovarian injection of E12.5 PGCs with fetal ovarian cells labeled with GFP into adult ovaries[25]
We confirm that transplantation of PGCs/Germline Stem Cells (GSCs) aggregated with gonadal somatic cells effectively restores folliculogenesis and endocrine function, and transplantation to either kidney capsule or ovarian bursa results in similar effectiveness in recipient mice with or without ovaries
Summary
Ovarian aging precedes somatic aging in most mammalian species. Ovarian aging increases risk of genetic diseases in offspring and contributes to menopause-associated diseases[1], including cardiovascular mortality and stroke[2, 3], osteoporosis-related bone fractures[4], and colorectal cancer[5]. Functional oocytes can be developed in the recipients following transplantation or grafting of fetal gonads or PGCs aggregated with fetal somatic pre-granulosa cells into kidney capsule, ovarian bursa or intra-ovarian injection[22,23,24,25,26,27,28]. It remains to be determined how long the grafts or transplants continue to generate oocytes and folliculogenesis, and whether transplanted PGCs initiate self-renewal and neo-oogenesis. We undertook series of experiments to investigate for longer-term the function of reconstituted ovaries created by various methods
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