Can Molecular Attributes of Mammalian Granulosa Cells and Ovarian Putative Stem Cells Predestine Them to Be a Promising Tool for Tissue Engineering and Regenerative Medicine?

Granulosa cells (GCs) and ovarian putative stem cells (oPSCs) represent distinct but complementary populations within the mammalian ovary. While GCs have long been considered terminally differentiated and hormonally specialized, emerging evidence indicates that they retain epigenetic plasticity and, under defined conditions, can be reprogrammed into cells exhibiting pluripotent-like features. In contrast, oPSCs, including oogonial stem cells (OSCs) and very small embryonic-like stem cells (VSELs), are naturally multipotent and capable of spontaneous or inducible differentiation into neural, endothelial, and other somatic lineages. Both cell types express stemness-related markers, such as OCT4, SOX2, and c-KIT, and demonstrate potential for self-renewal and lineage conversion. Recent advances in chemical modulation of epigenetic reprogramming, particularly with agents from the family of non-specific DNA methyltransferase (DNMT) inhibitors, such as 5-azacytidine (5-azaC), highlight the feasibility of generating functional, lineage-specific derivatives of GCs or oPSCs without genetic manipulation. Not without significance is also the fact that extended/high-dose 5-azaC-mediated modulation can induce cell senescence or apoptotic/necrotic death. Therefore, dosing must be carefully titrated, which strongly supports a dose- and/or time-dependent mechanism for 5-azaC-based epigenetic modification in treated cells. This study aims to summarize the molecular and functional properties of mammalian GCs and oPSCs, emphasizing their applicability in regenerative medicine and reproductive bioengineering, with a focus on safe, patient-specific cell-based therapies.