Oocyte Generation in Adult Mammalian Ovaries by Putative Germ Cells in Bone Marrow and Peripheral Blood

Abstract

It has been suggested that germline stem cells maintain oogenesis in postnatal mouse ovaries. Here we show that adult mouse ovaries rapidly generate hundreds of oocytes, despite a small premeiotic germ cell pool. In considering the possibility of an extragonadal source of germ cells, we show expression of germline markers in bone marrow (BM). Further, BM transplantation restores oocyte production in wild-type mice sterilized by chemotherapy, as well as in ataxia telangiectasia-mutated gene-deficient mice, which are otherwise incapable of making oocytes. Donor-derived oocytes are also observed in female mice following peripheral blood transplantation. Although the fertilizability and developmental competency of the BM and peripheral blood-derived oocytes remain to be established, their morphology, enclosure within follicles, and expression of germ-cell- and oocyte-specific markers collectively support that these cells are bona fide oocytes. These results identify BM as a potential source of germ cells that could sustain oocyte production in adulthood.

Bone marrow‐derived very small embryonic‐like stem cells: Their developmental origin and biological significance

“…Recently, BM was also, somewhat unexpectedly, identified as a source of Oct-4 ϩ oocyte-like (Johnson et al, 2005) and spermatogonia-like cells . This observation supports to some extent the concept that, during embryonic development, some of the stem cells from the germ lineage (Fig.…”

“…Stem cells that express early embryonic stem cell markers, including Oct-4, Nanog, and SSEA-1, had been identified in BM in several potential multipotent/PSC isolated from the BM or CB such as VSELs (Kucia et al, 2006b, MSC (Colter et al, 2001;Pochampally et al, 2004), MAPC (Jiang et al, 2002), MIAMI (DЈIp-polito et al, 2004), USSC (Kogler et al, 2004), and precursors of oocytes/ spermatogonia and precursors of shuttling between BM and heart cardiomyocytes (Johnson et al, 2005;Nayernia et al, 2006;Pallante et al, 2007). It is very likely that several investigators using different isolation strategies described the same populations of stem cells but gave them different names according to circumstance.…”

Personal reflections on Stan Korsmeyer and his continuing impact on our work to delineate the role of Bax in female reproduction

“…First, it is important to re-emphasize the wealth of data already available identifying Bax as a key proapoptotic constituent of the female germ cell death program under diverse conditions. 7,[13][14][15] With this in mind, along with recent data reporting that oocyte production in adult females, like sperm production in adult males, is sustained by germline stem cells, 17,18 we have begun to examine whether the 'nomenopause' ovarian phenotype of Bax-deficient female mice is due not only to a reduced incidence of oocyte death, as reported earlier, 14 but also to failed apoptotic deletion of germline stem cells in aging females. Whereas extensive experimentation is needed, and currently underway, to test the validity of this theory, as yet unpublished work using a different proapoptotic gene mutant mouse line has revealed a marked expansion of the oocyte-containing follicle pool in adult females that, unlike the Bax-deficient mouse, cannot be explained even in part by a reduced incidence of oocyte death.…”

“…14 Recently, however, our studies of oocyte death inadvertently led us to question the validity of the dogma of a fixed pool of oocytes at birth, 17 work that has since been followed by another study identifying a putative germline stem cell pool responsible for sustaining oocyte production in adult female mammals. 18 Although still controversial, these recent lines of investigation nonetheless open new ways of thinking about the mechanisms responsible for ovarian failure with age, and thus perhaps new ways to prevent it should such an outcome be clinically desirable in women.…”

“…This outcome has been considered as well, particularly in light of very recent preliminary data showing that transplantation of cell fractions containing putative female germline stem/progenitor cells into very old female mice does not result in the formation of new oocytes and follicles, 20 despite the fact that similar transplantation protocols restore oocyte and follicle production in young adult female mice conditioned beforehand with chemotherapeutic drugs. 18 Such findings argue that age-related gonadal failure in females is not due simply to erosion of the germline stem/ progenitor cell pool but also involves changes in the ovarian microenvironment that impair the ability of premeiotic germ cells to fulfill their differentiation program and form oocytes. This possibility actually aligns well with recent studies from male mice, in which germline stem cells remaining in testis of aged male mice that no longer produce sperm can initiate spermatogenesis if transferred into the testes of young adult male mice.…”