Immunomodulatory and regenerative effects of human umbilical cord MSC-EVs in Cutaneous Leishmaniasis

Extracellular vesicles (EVs) derived from human umbilical cord Mesenchymal Stem Cells (hUCMSC-EVs) are emerging as promising immunomodulatory agents in inflammatory disorders. However, their potential for infectious diseases remains poorly explored.

We investigated the effects of hUCMSC-EVs in experimental Cutaneous Leishmaniasis (CL) caused by Leishmania braziliensis using both in vitro and in vivo approaches. EVs were isolated and characterized according to MISEV guidelines. Their immunomodulatory properties were evaluated in murine macrophages, and their therapeutic efficacy was tested in a preclinical model of CL.

Treatment with hUCMSC-EV modulated the phenotype of L. braziliensis-infected bone marrow-derived macrophages toward a mixed M1/M2 profile, enhancing TNF-α and IL-10 secretion and reducing intracellular parasite load. Protemic analysis of the EV content was correlated with response to wounding and wound healing biological processes, which were confirmed in scratch and cell migration assays. In vivo, intravenous administration of hUCMSC-EV to infected mice reduced lesion thickness and collagen deposition at the infection site.

Our findings demonstrate that stimulation with hUCMSC-EVs enhanced Leishmania killing, inducing the upregulation of immune mediators. hUCMSC-EVs also promoted wound closure and keratinocyte migration. In vivo, intravenous injection of hUCMSC-EVs impaired lesion development, supporting their potential as an adjunctive therapy for CL. This study lays the groundwork for further investigation into MSC-EVs in host-directed therapies for infectious diseases.