The ovary has two main roles, as the female reproductive organ and a hormone secretion system. The ovaries function cyclically; in humans, their function declines with age from the mid-30s, and their menopause-disrupting endocrine function starts mid-50s as well (1). In fact, ovarian function declines early relative to that of other organs in the body and is also implicated in forecasting ovarian menopause (2). The mechanism underlying reduction in ovarian function with aging is a major question in reproductive medicine and has been investigated for several decades. In addition to the loss of ovarian reproductive function, menopause is an unavoidable part of aging and involves the deterioration of general health, such as by increasing the risks of cardiovascular disease, osteoporosis, vasomotor symptoms, depression, and cognitive impairment (3). Reproductive aging and menopause are increasingly significant health issues because more women plan to delay childbearing, and their life expectancy has increased (4). However, although many approaches have been applied to maintain the ovarian reservoir and to extend reproductive potential, effective clinically applicable protocols have not been identified.
A recent study focused on preventing pathological changes in ovarian cells by mTOR inhibition, which postponed follicular activation and development and then extended the follicle reserve and endocrine function of the ovaries (1). Additionally, ovarian fibrosis in stromal interstitial tissues surrounding follicles is the key causal factor of obesity-induced ovarian dysfunction and the process is similar to that of reproductive aging (5). Indeed, a reduction in adverse factors, inducing a high level of inflammation, reactive oxygen species (ROS), DNA damage, and apoptosis, could improve follicle quality and ovarian lifespan (6–9).
Furthermore, several studies have focused on the biomolecular interactions taking place in human bone marrow during aging. In addition to remodeling of the mesenchymal stromal cell population in bone marrow (10), changes in macrophages and macrophage-like immature cells (myeloid-derived suppressor cells, MDSCs) also occur during aging in healthy or tumor-bearing hosts (11). MDSC consist of two large groups of cells: granulocytic MDSCs (G-MDSCs), which are phenotypically and morphologically similar to neutrophils, and monocytic MDSCs (M-MDSCs), which are similar to monocytes (12). These cells suppress innate and adaptive immunity and promote aging-related fibrosis and have been found in many other abnormal conditions, such as autoimmunity, infection, diabetes and cardiac aging (13, 14). Several studies have reported that increased MDSC numbers contribute to the development of these disorders, and the transplantation of mesenchymal progenitor cells (MPCs) obtained from various sources has beneficial effects on blocking or delaying the progression of diseases through suppression of inflammation and immune attack (15–17).
MPCs derived from adult and fetal tissues have been proposed as a new therapeutic cell source for the clinical treatment of various diseases (18). In fact, MPCs secrete multiple cytokines and growth factors, that can regulate immune reactions, apoptosis, cell survival and cell proliferation (19). However, the application of these tissue-specific MPCs still have some drawbacks; for example, the harvesting of MPCs demands invasive surgical procedures that may cause severe side effects and the manufacturing protocol for MPCs is difficult to standardize because of donor heterogeneity. Furthermore, MPCs have limited cell growth capacity in culture; therefore, it is difficult to obtain sufficient quantities for clinical use (20–22).
Recently, human embryonic stem cell-derived MPCs (hESC-MPCs) have been suggested as an alternative source to MPCs owing to their high proliferative capacity and ease of standardization. Our previous studies and many others have demonstrated that MPCs can restore function in models of premature ovarian insufficiency (23–25) and various other diseases (26–28). However, in a middle-aged female model undergoing natural aging, it was not determined whether hESC-MPCs have a beneficial effect on the long-term maintenance of reproductive fecundity and the ovarian reservoir or how their transplantation regulates ovarian function. In the present study, we found that multiple introductions of hESC-MPCs may contribute to preserving ovarian function in perimenopausal female mice by suppressing apoptosis and fibrosis and may maintain oocyte competence and delay reproductive senescence.