From Mesenchymal Stromal Cells to Extracellular Vesicles: Scalable Strategies for Ovarian Stroma Regeneration.

Ovarian aging is characterized by the reduction of the follicular pool and a progressive loss in oocyte quality. Although these changes have initially been attributed to oocyte alterations, increasing evidence indicates that stromal deterioration plays a central role in this process. Stromal remodeling involves complex interactions among structural, molecular, and cell communication disruptions. This review discusses the main ovarian stroma shifts related to aging, emphasizing ECM remodeling, biomechanical changes, and cell signaling dysfunction. In light of the multifactorial nature of ovarian aging, no single therapeutic strategy is likely to fully address stromal dysfunction. In this context, Mesenchymal Stromal Cells (MSCs) and their secreted Extracellular Vesicles (EVs) have emerged as promising approaches, given their ability to deliver a diverse and functionally complementary set of bioactive molecules that collectively modulate inflammation, support extracellular matrix remodeling, and restore cell communication. Notably, EVs retain key paracrine effects of MSCs while offering advantages in safety and manufacturability, supporting the transition from cell-based to cell-free therapies. Accordingly, this review also examines this therapeutic shift, highlighting the role of MSCs and EVs in stromal regeneration. By integrating ovarian biology with biotechnological bioprocesses, we discuss key translational challenges-including scalability, quality control, and regulatory considerations-that are critical for the development of effective stroma-targeted interventions aimed at preserving or restoring ovarian function.