HIF-1α and Pro-Inflammatory Signaling Improves the Immunomodulatory Activity of MSC-Derived Extracellular Vesicles.

Marta Gómez-Ferrer,Maria Carmen Baquero,Pilar Sepúlveda,Christian M Sánchez-López,Akaitz Dorronsoro,Rafael Sánchez-Sánchez,Estela Villanueva-Badenas

doi:10.3390/ijms22073416

Abstract

Despite the strong evidence for the immunomodulatory activity of mesenchymal stromal cells (MSCs), clinical trials have so far failed to clearly show benefit, likely reflecting methodological shortcomings and lack of standardization. MSC-mediated tissue repair is commonly believed to occur in a paracrine manner, and it has been stated that extracellular vesicles (EVs) secreted by MSCs (EVMSC) are able to recapitulate the immunosuppressive properties of parental cells. As a next step, clinical trials to corroborate preclinical studies should be performed. However, effective dose in large mammals, including humans, is quite high and EVs industrial production is hindered by the proliferative senescence that affects MSCs during massive cell expansion. We generated a genetically modified MSC cell line overexpressing hypoxia-inducible factor 1-alpha and telomerase to increase the therapeutic potency of EVMSC and facilitate their large-scale production. We also developed a cytokine-based preconditioning culture medium to prime the immunomodulatory response of secreted EVs (EVMSC-T-HIFc). We tested the efficacy of this system in vitro and in a delayed-type hypersensitivity mouse model. MSC-T with an HIF-1α-GFP lentiviral vector (MSC-T-HIF) can be effectively expanded to obtain large amounts of EVs without major changes in cell phenotype and EVs composition. EVMSC-T-HIFc suppressed the proliferation of activated T-cells more effectively than did EVs from unmodified MSC in vitro, and significantly blunted the ear-swelling response in vivo by inhibiting cell infiltration and improving tissue integrity. We have developed a long-lived EV source that secretes high quantities of immunosuppressive EVs, facilitating a more standard and cost-effective therapeutic product.

Highlights

IntroductionMesenchymal stromal cells (MSCs) are multipotent progenitor cells that have the ability to differentiate into chondrocyte, osteoblast and adipocyte lineages [1]
Mesenchymal stromal cells (MSCs) have recently emerged as potential therapeutic agents to treat multiple diseases based both on their tissue regeneration and their immunosuppression capacity, and numerous preclinical studies have demonstrated that MSCs can ameliorate tissue damage after ischemic events and modulate acute and chronic inflammatory reactions [2]
The reparative capacity of MSCs is generally linked to their paracrine effects on target tissue/cells, and in particular the production of soluble factors, which are involved in the healing process

Summary

Introduction

Mesenchymal stromal cells (MSCs) are multipotent progenitor cells that have the ability to differentiate into chondrocyte, osteoblast and adipocyte lineages [1]. MSCs have recently emerged as potential therapeutic agents to treat multiple diseases based both on their tissue regeneration and their immunosuppression capacity, and numerous preclinical studies have demonstrated that MSCs can ameliorate tissue damage after ischemic events and modulate acute and chronic inflammatory reactions [2]. The reparative capacity of MSCs is generally linked to their paracrine effects on target tissue/cells, and in particular the production of soluble factors, which are involved in the healing process. MSCs are able to inhibit the proliferation of activated

Methods

Discussion

Conclusion