Mesenchymal stem cells preserve neuronal architecture by reprogramming miRNA-mRNA regulatory networks in experimental cerebral malaria.

Cerebral malaria (CM) is associated with disruption of the blood-brain barrier (BBB), neurovascular injury, and high mortality. Although mesenchymal stem cells (MSCs) have demonstrated therapeutic efficacy in experimental cerebral malaria (ECM), the molecular mechanisms underlying these effects remain insufficiently defined. In this study, we investigated how MSC treatment modulates host miRNA networks during ECM using a Plasmodium berghei ANKA infection in C57BL/6 mice. MSC treatment significantly reduced clinical severity, improved survival, and preserved BBB integrity, as indicated by decreased Evans blue extravasation and reduced microvascular sequestration within brain. RNA sequencing identified 64 differentially expressed miRNAs associated with MSC treatment. Pathway enrichment using DIANA-miRPath v4.0 identified 23 miRNAs associated to CM-relevant pathways. Eleven miRNAs with highest pathway interactions were subsequently validated by RT-qPCR, confirming consistent down-regulation of eight miRNAs following MSC treatment. miRNA-mRNA network construction revealed several hub genes, including Rora, Nfia, Nfib, Slc1a2, Tcf4, Pura, and Atxn1, linked to neurological phenotypes relevant to CM pathology. Collectively, these findings suggest that MSCs mitigate ECM pathology by reprogramming miRNA-mRNA regulatory networks governing cerebral and neuronal stability. The identified miRNA-mRNA hubs represent promising candidates for future biomarker studies and may provide a foundation for the development of adjunctive therapeutic strategies against cerebral malaria.