Ovarian-Cell-Like Cells from Skin Stem Cells Restored Estradiol Production and Estrus Cycling in Ovariectomized Mice

Abstract

Reduction of estradiol production and high serum concentrations of follicular stimulating hormone (FSH) are endocrine disorders associated with premature ovarian failure. Here, we report that transplantation of ovarianlike cells differentiated from stem cells restored endogenous serum estradiol levels. Stem cells were isolated from postnatal mouse skin and differentiated into ovarian-cell-like cells that are consistent with female germ, and ovarian follicle somatic cells. The ovarian-cell-like cells were transplanted into ovariectomized mice (Cell Trans), whereas control mice were subjected to bilateral ovariectomies without cell transplantation (OVX). Using vaginal cytology analysis, it was revealed that in 13 out of 19 Cell Trans mice, estrus cycles were restored around 8 weeks after cell transplantation and were maintained until 16 weeks post-transplantation, whereas in the OVX group, all mice were arrested at metestrus/diestrus of the estrus cycle. The uterine weight in the Cell Trans group was similar to sham operation mice (Sham OP), while severe uterine atrophy and a decreased uterine weight were observed in the OVX group. Histologically, ectopic follicle-like structures and blood vessels were found within and around the transplants. At 12-14 weeks after cell transplantation, mean serum estradiol level in Cell Trans mice (178.0 -35 pg/mL) was comparable to that of the Sham OP group (188.9 -29 pg/mL), whereas it was lower in the OVX group (59.0 -4 pg/mL). Serum FSH concentration increased in the OVX group (1.62 -0.32 ng/mL) compared with the Sham OP group (0.39 -0.34 ng/mL). Cell Trans mice had a similar FSH level (0.94 -0.23 ng/mL; P < 0.05) to Sham OP mice. Our results suggest that ovarian somatic cells differentiated from stem cells are functional in vivo. In addition to providing insights into the function of ovarian somatic cells derived from stem cells, our study may offer potential therapeutic means for patients with hypo-estradiol levels like those encountered in premature ovarian failure.

In vitro differentiation of germ cells from stem cells: a comparison between primordial germ cells and in vitro derived primordial germ cell-like cells

“… 52 , 76 , 80 , 82 , 83 , 84 , 85 Particularly surprising is the formation of aggregates resembling cumulus-oocyte complexes from either female or male foetal porcine or newborn mouse SDSCs. 75 , 86 , 87 , 88 , 89 , 90 In all cases, however, the OLCs showed morphological and molecular abnormalities and were not proved to be functional. Our interpretation is that under certain in vitro conditions, some types of stem cells can acquire morphological and molecular features of oocytes independently from meiosis and proper follicle assembly.…”

Differentiation of early germ cells from human skin-derived stem cells without exogenous gene integration

“…Our previous investigations demonstrated that SDSCs from fetal porcine and newborn mouse can differentiate into early GCLCs that express the same markers as in vivo counterparts 10 11 12 . These early germ cells can further differentiate into OLCs that can restore estrus cycling in ovariectomized mice 21 . All these data indicate that SDSCs may be used as autologous stem cell types for medical applications.…”

“…One suggestion is to try human follicular fluid. If successful, the transplantation of these autologous OLCs may be used as a therapeutic method for restoring estradiol production in menopausal women as indicated by previous study on mouse model 21 .…”

The crucial role of Activin A on the formation of primordial germ cell-like cells from skin-derived stem cells in vitro

“…21 Particularly, it has Keywords: activin A, differentiation, primordial germ cells, skin-derived stem cells, smad3 been reported that SDSCs isolated from fetal porcine or newborn mouse skin can be differentiated into germ cells or granulosa cells. 10,17,[22][23][24] Due to its easy access and the differentiation proficiency, SDSCs are thought to be an ideal source for PGC-like cells (PGCLCs) induction in vitro.…”