Immunoregulation of follicular renewal, selection, POF, and menopause in vivo, vs. neo-oogenesis in vitro, POF and ovarian infertility treatment, and a clinical trial

Abstract

The immune system plays an important role in the regulation of tissue homeostasis ("tissue immune physiology"). Function of distinct tissues during adulthood, including the ovary, requires (1) Renewal from stem cells, (2) Preservation of tissue-specific cells in a proper differentiated state, which differs among distinct tissues, and (3) Regulation of tissue quantity. Such morphostasis can be executed by the tissue control system, consisting of immune system-related components, vascular pericytes, and autonomic innervation. Morphostasis is established epigenetically, during morphogenetic (developmental) immune adaptation, i.e., during the critical developmental period. Subsequently, the tissues are maintained in a state of differentiation reached during the adaptation by a “stop effect” of resident and self renewing monocyte-derived cells. The later normal tissue is programmed to emerge (e.g., late emergence of ovarian granulosa cells), the earlier its function ceases. Alteration of certain tissue differentiation during the critical developmental period causes persistent alteration of that tissue function, including premature ovarian failure (POF) and primary amenorrhea. In fetal and adult human ovaries the ovarian surface epithelium cells called ovarian stem cells (OSC) are bipotent stem cells for the formation of ovarian germ and granulosa cells. Recently termed oogonial stem cells are, in reality, not stem but already germ cells which have the ability to divide. Immune system-related cells and molecules accompany asymmetric division of OSC resulting in the emergence of secondary germ cells, symmetric division, and migration of secondary germ cells, formation of new granulosa cells and fetal and adult primordial follicles (follicular renewal), and selection and growth of primary/preantral, and dominant follicles. The number of selected follicles during each ovarian cycle is determined by autonomic innervation. Morphostasis is altered with advancing age, due to degenerative changes of the immune system. This causes cessation of oocyte and follicular renewal at 38 +/-2 years of age due to the lack of formation of new granulosa cells. Oocytes in primordial follicles persisting after the end of the prime reproductive period accumulate genetic alterations resulting in an exponentially growing incidence of fetal trisomies and other genetic abnormalities with advanced maternal age. The secondary germ cells also develop in the OSC cultures derived from POF and aging ovaries. In vitro conditions are free of immune mechanisms, which prevent neo-oogenesis in vivo. Such germ cells are capable of differentiating in vitro into functional oocytes. This may provide fresh oocytes and genetically related children to women lacking the ability to produce their own follicular oocytes. Further study of "immune physiology" may help us to better understand ovarian physiology and pathology, including ovarian infertility caused by POF or by a lack of ovarian follicles with functional oocytes in aging ovaries. The observations indicating...

Plasticity of granulosa cells: on the crossroad of stemness and transdifferentiation potential

“…We speculate that this hypothesis can be upgraded with the factor of location in the granulosa layers. Moreover, the question whether granulosa stem cells originate from the first line of flattened GCs in the primordial follicle or from the granulosa nests in ovarian surface epithelium [7] still remains opened.…”

Ovarian Stem Cell Nests in Reproduction and Ovarian Aging

“…In addition, researchers also found that with increasing age, the immune system inevitably degraded. First, the thymus function declines followed by a decline in ovarian function [27]. These results demonstrate that there is a close relationship between the immune system and the ovarian function.…”

“…The conclusions are based on the following phenomenon of ovarian [27-29]: the immune relevant cells in the ovary rete tunnels, are necessary for the formation of ovary by OGSCs. Human embryonic ovary is determined by the evolution of the ovarian stem cells in the genital ridge peritoneal mesothelium, formed from the rete ovary in the mesonephric duct.…”

Post-natal oogenesis: a concept for controversy that intensified during the last decade

“…The OSE was supposed to be a source of germ cells, and new primordial follicles were developed by the accumulation of oocytes with nests of primitive granulosa cells in the ovarian cortex (Bukovsky et al, 1995). In 2005, a study of the possibility of neooogenesis and granulosa cell generation was done on cultures derived from the surface epithelium of adult human ovaries (Bukovsky et al, 2005).…”