Enhancing and stabilization of cord blood regulatory T-cell suppressive function by human mesenchymal stem cell (MSC)-derived exosomes

Abstract

FOXP3 + regulatory T cells (Tregs) are central to maintaining peripheral tolerance and immune homeostasis. They have the potential to be developed as a cellular therapy to treat various clinical ailments such as autoimmune disorders, inflammatory diseases and to improve transplantation outcomes. However, a major question remains whether Tregs can persist and exert their function effectively in a disease state, where a broad spectrum of inflammatory mediators could inactivate Tregs. In this study, we investigated the potential of mesenchymal stem cell (MSC)-derived exosomes to promote and sustain Tregs function. MSC-conditioned media (MSC-CM) cultured Tregs were more suppressive in both polyclonal and allogeneic responses and were resistant to inflammatory stimulation in vitro compared to the controls. A similar enhancement of Treg function was also observed by culturing Tregs with MSC-derived exosomes alone. The enhanced suppressive activity and stability of Treg cultured in MSC-CM was reduced when exosomes were depleted from MSC-CM. We identified that MSC-derived exosomes could upregulate the expression of LC3(II/I), phosphorylate Jak3 and Stat5 to promote Treg survival, and regulate FOXP3 expression in Tregs. Overall, our study demonstrates that MSC-derived exosomes are capable of enhancing Hucb-Tregs function and stability by activating autophagy and Stat5 signaling pathways. Our findings provide a strong rationale for utilizing MSC-derived exosomes as an effective strategy to enhance Treg function, and improve the overall Tregs-based cell therapy landscape.

Human umbilical cord blood mononuclear cells transplantation for perinatal brain injury

“…Under certain circumstances, MSCs can regulate the differentiation of monocytes, maturation of dendritic cells, and lymphocyte proliferation [62][63][64]. In addition, MSC derived exosomes could enhance and stabilize of UCB-derived Tregs suppressive function [65]. Transplantation of UCB-MNCs can promote the repair of HIBD and improve the motor ability and spatial memory in neonatal HIBD rats.…”

Extracellular Vesicle Depletion Protocols of Foetal Bovine Serum Influence Umbilical Cord Mesenchymal Stromal Cell Phenotype, Immunomodulation, and Particle Release

“…In fact, the delivery of MSC EV cargo allows them to recreate the abilities of their parental cells. This includes inhibiting leukocyte proliferation [5,6], biasing an antiinflammatory phenotype [7][8][9], and improving the prognosis of immune-based disorders, both in animal models [10][11][12] and the clinic [13,14].…”