Exploring the potential of in vitro extracellular vesicle generation in reproductive biology

Abstract

The interest in the growing field of extracellular vesicle (EV) research highlights their significance in intercellular signalling and the selective transfer of biological information between donor and recipient cells. EV studies have provided valuable insights into intercellular communication mechanisms, signal identification and their involvement in disease states, offering potential avenues for manipulating pathological conditions, detecting biomarkers and developing drug-delivery systems. While our understanding of EV functions in reproductive tissues has significantly progressed, exploring their potential as biomarkers for infertility, therapeutic interventions and enhancements in assisted reproductive technologies remains to be investigated. This knowledge gap stems partly from the difficulties associated with large-scale EV production relevant to clinical applications. Most existing studies on EV production rely on conventional 2D cell culture systems, characterized by suboptimal EV yields and a failure to replicate in vivo conditions. This results in the generation of EVs that differ from their in vivo counterparts. Hence, this review firstly delves into the importance of EVs in reproduction to then expand on current techniques for in vitro EV production, specifically examining diverse methods of culture and the potential of bioengineering technologies to establish innovative systems for enhanced EV production.

Keywords: bioengineering; improved EV yield; in vitro EV production.

FIGURE 1

Roles of EVs in different female reproductive tissues. EVs differ in their molecular content and role in biological processes based on cell of origin and its environment. Hence, EVs produced in different reproductive tissues also have different roles influencing important reproductive events. In the ovary (a), follicular EVs are involved in supporting the progression of folliculogenesis, oocyte maturation and in several signalling pathways that reinforces oocyte competence. In the oviduct (b), EVs from oviductal cells, oocytes, sperm and embryos are present, driving key reproductive events such as oocyte maturation, sperm capacitation and early embryo development. Endometrial Evs (c) and their interaction with embryonic EVs are crucial for endometrial receptivity, trophoblast adhesion and angiogenesis. Figure was made using Biorender, adapted from Kurian and Modi (2019) and Qamar et al. (2020).

FIGURE 2

Bioengineering platforms for improved EV production. The figure illustrates diverse bioengineering approaches employed in the in vitro production of extracellular vesicles (EVs), showcasing the continuum between throughput and physiological relevance. Each technology is strategically positioned on this spectrum to highlight its characteristics in terms of scalability and mimicry of natural physiological conditions. Figure was made using Biorender.