Abstract
Parthenogenetic embryos, created by activation and diploidization of oocytes, arrest at mid-gestation for defective paternal imprints, which impair placental development. Also, viable offspring has not been obtained without genetic manipulation from parthenogenetic embryonic stem cells (pESCs) derived from parthenogenetic embryos, presumably attributable to their aberrant imprinting. We show that an unlimited number of oocytes can be derived from pESCs and produce healthy offspring. Moreover, normal expression of imprinted genes is found in the germ cells and the mice. pESCs exhibited imprinting consistent with exclusively maternal lineage, and higher X-chromosome activation compared to female ESCs derived from the same mouse genetic background. pESCs differentiated into primordial germ cell-like cells (PGCLCs) and formed oocytes following in vivo transplantation into kidney capsule that produced fertile pups and reconstituted ovarian endocrine function. The transcriptome and methylation of imprinted and X-linked genes in pESC-PGCLCs closely resembled those of in vivo produced PGCs, consistent with efficient reprogramming of methylation and genomic imprinting. These results demonstrate that amplification of germ cells through parthenogenesis faithfully maintains maternal imprinting, offering a promising route for deriving functional oocytes and having potential in rebuilding ovarian endocrine function.
Highlights
In most mammalian species, follicular reserve is determined at birth, and progressively declines with age
Normal expression of imprinted genes is found in the germ cells and the mice. parthenogenetic embryonic stem cells (pESCs) exhibited imprinting consistent with exclusively maternal lineage, and higher X-chromosome activation compared to female embryonic stem cell (ESC) derived from the same mouse genetic background. pESCs differentiated into primordial germ cell-like cells (PGCLCs) and formed oocytes following in vivo transplantation into kidney capsule that produced fertile pups and reconstituted ovarian endocrine function
Various pESC lines obtained from MII oocytes demonstrated germline competence (Fig. 1G). pESC lines generated from different mouse strains exhibited variability in the efficiency of cell line derivation from blastocysts, from 22% to 57%
Summary
Follicular reserve is determined at birth, and progressively declines with age. Parthenogenetic embryos, formed from activation and diploidization of oocytes, do not contain a paternal genome, such that parthenotes arrest at mid-gestation from defects in genomic imprinting and placental malfunction (Barton et al 1984; Surani et al 1984; Barlow and Bartolomei 2014). Despite their developmental incompetence, parthenogenetic embryonic stem cells (pESCs) can be generated from parthenogenetic embryos, and allay ethical concerns associated with destruction of viable embryos (Sousa and Wilmut 2007). Parthenogenetic embryonic stem cells (pESCs) can be generated from parthenogenetic embryos, and allay ethical concerns associated with destruction of viable embryos (Sousa and Wilmut 2007). pESCs are produced from oocytes by chemical activation e.g., with strontium (Sr2+)
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