Autologous transplantation of thecal stem cells restores ovarian function in nonhuman primates

Abstract

Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity under the age of 40. Theca cells (TCs) play a vital role during folliculogenesis and TCs dysfunction participate in the pathogenesis of POI. Therefore, transplantation of thecal stem cells (TSCs), which are capable of self-renewal and differentiation into mature TCs, may provide a new strategy for treating POI. To investigate the feasibility, safety, and efficacy of TSCs transplantation in clinically relevant non-human primate (NHP) models, we isolate TSCs from cynomolgus monkeys, and these cells are confirmed to expand continuously and show potential to differentiate into mature TCs. In addition, engraftment of autologous TSCs into POI monkeys significantly improves hormone levels, rescues the follicle development, promotes the quality of oocytes and boosts oocyte maturation/fertilization rate. Taken together, these results for the first time suggest that autologous TSCs can ameliorate POI symptoms in primate models and shed new light on developing stem cell therapy for POI.

Temporal and spatial dynamics mapping reveals follicle development regulated by different stromal cell populations

“…The putative undifferentiated progenitor theca cells do not express LH receptors (LHRs) or steroidogenic enzymes and are therefore not LH responsive, showing that initiation of theca cell differentiation is gonadotropin independent 24 . Recently, studies have also shown that autologous transplantation of thecal stem cells restores ovarian function in nonhuman primates 25 . The thecal stem cells used were total ovarian stromal cells, not a single-cell population.…”

Characterization of ovarian progenitor cells for their potential to generate steroidogenic theca cells in vitro

“…Ovary somatic progenitor cells have been studied over the years for their abilities to generate functional theca steroidogenic cells. Putative theca stem cells have been reported from various species based on their abilities to give rise to steroidogenic theca-like cells in vitro ( Honda et al 2007 , Lee et al 2013 , Adib & Valojerdi 2017 , Dalman et al 2018 , Asiabi et al 2020 , Chen et al 2021 ). However, except for the few studies that used the theca layer to isolate cells, the true identities and locations of these cells in other studies are difficult to determine since the studies cultured cells without pre-purification.…”

“…Isolation and culture of theca progenitor cells was done in different species before ( Honda et al 2007 , Lee et al 2013 , Adib & Valojerdi 2017 , Dalman et al 2018 , Asiabi et al 2020 , Chen et al 2021 ). Cells cultured by these studies were not pre-purified, so the in vivo identity of the cells was not always clear.…”

“…Since theca cells are not found in the early follicles and are only observed once a follicle developed with two or more layers of granulosa cells, it suggests that theca cells have to be recruited or newly developed from progenitors during folliculogenesis even in the adult. Isolation and culture of potential steroidogenic theca progenitor cells was carried out for various species, including mouse ( Honda et al 2007 ), porcine ( Lee et al 2013 ), sheep ( Adib & Valojerdi 2017 ), monkey ( Chen et al 2021 ), and human ( Dalman et al 2018 , Asiabi et al 2020 ). These studies consistently demonstrated that mammalian ovaries of adults contain theca cell progenitors.…”

Current state of stem cell research in non-human primates: an overview

“…Theca stem cells (TSCs) isolated from cynomolgus monkeys and transplanted into monkeys with premature ovarian insufficiency (POI) showed that it can significantly improve hormone levels, rescue follicle development, improve oocyte quality, and increase the oocyte maturation/fertilization rate. It was first shown that autologous TSCs can improve the symptoms of POI in primates, and provide new hope for the development of stem cell therapy for POI [ 93 ].…”