Stem cell interaction with somatic niche may hold the key to fertility restoration in cancer patients

Deepa Bhartiya, Kalpana Sriraman, Seema Parte, Deepa Bhartiya, Kalpana Sriraman, Seema Parte

Abstract

The spontaneous return of fertility after bone marrow transplantation or heterotopic grafting of cryopreserved ovarian cortical tissue has surprised many, and a possible link with stem cells has been proposed. We have reviewed the available literature on ovarian stem cells in adult mammalian ovaries and presented a model that proposes that the ovary harbors two distinct populations of stem cells, namely, pluripotent, quiescent, very small embryonic-like stem cells (VSELs), and slightly larger "progenitor" ovarian germ stem cells (OGSCs). Besides compromising the somatic niche, oncotherapy destroys OGSCs since, like tumor cells, they are actively dividing; however VSELs persist since they are relatively quiescent. BMT or transplanted ovarian cortical tissue may help rejuvenate the ovarian niche, which possibly supports differentiation of persisting VSELs resulting in neo-oogenesis and follicular development responsible for successful pregnancies. Postnatal oogenesis in mammalian ovary from VSELs may be exploited for fertility restoration in cancer survivors including those who were earlier deprived of gametes and/or gonadal tissue cryopreservation options.

Figures

Figure 1
Figure 1
VSELs and OGSCs in adult mammalian ovary. (a) Immunolocalization of OCT-4, a stem cell marker on mouse ovarian cell smear using polyclonal antibody raised against C-terminal domain of OCT-4 (magnification 20x). Two distinct populations of stem cells were observed nuclear OCT-4 positive VSELs (arrow) and cytoplasmic OCT-4 positive OGSCs (asterisk). Inset is representative of the two stem cell populations by confocal microscopy using propidium iodide (PI) as a counterstain (magnification 63x with 5x optical zoom). VSEL has yellow stained nuclei as a result of co-localization of FITC labeled OCT-4 and PI whereas OGSC has distinct PI-stained red nuclei and cytoplasmic OCT-4. (b) Relative expression of Oct-4 and Oct-4A (transcript specific for pluripotent state) mRNA levels in normal mouse ovary by Q-PCR analysis. The levels of Oct-4A transcript in comparison to total Oct-4 were significantly lower suggesting that the VSELs positive for Oct-4A are less abundant compared to OGSCs. (c) H & E staining of human perimenopausal ovary surface epithelium smear showing the presence of RBCs, very small VSELs (arrow), and slightly bigger OGSCs (asterisk; present either as isolated cells or as clusters termed “germ cell nests” in developing ovary) (magnification 40x). Note the high nucleo-cytoplasmic ratio in stem cells with intense nuclear Hematoxylin staining.
Figure 2
Figure 2
Proposed model for postnatal oogenesis in adult mammalian ovary. Pluripotent stem cells with nuclear OCT-4 (VSELs) being located in the ovary surface epithelium (OSE). These cells undergo asymmetric cell division and give rise to cells with cytoplasmic OCT-4 (OGSCs, which intensely stain with Haematoxylin). The OGSCs undergo further proliferation, meiosis, and differentiation to assemble into primordial follicles in the OSE. The granulosa cells are formed by the epithelial cells that undergo epithelial mesenchymal transition [30]. As the follicles grow and further mature, they shift into the ovarian medulla. Confocal images represent VSEL and OGSC isolated by scraping the surface epithelium of perimenopausal human ovary [30].

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