Mesenchymal stem cell-derived extracellular vesicles conditionally ameliorate bone marrow failure symptoms in an immune-mediated aplastic anemia mouse model

Acquired forms of Aplastic anemia (AA) are characterized by T cell-mediated immune disease resulting in bone marrow (BM) failure and marrow hypoplasia. In these cases, it is a major challenge to modulate autoreactive T cell activity and thereby decrease the pro-inflammatory cytokine storm. Emerging evidence indicates that extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) control and modulate immunity. The therapeutic potential of MSC-EVs has not been investigated in acquired AA. Hence, in this study, we constructed an AA mice model through irradiation and splenocyte infusion to test the benefits of hypoxic MSC-EVs (Hx-EVs) and normoxic MSC-EVs (Nx-EVs). We found that MSC-EVs treatment significantly prolonged the survival rate and increased the platelet (PLT) counts of the AA mice. Immunohistochemical staining and colony assay confirmed amelioration of hypoplasia in the BM and increased numbers of hematopoietic stem cells (HSCs). These effects of MSC-EVs were mediated by T cell suppression and inhibition of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) production in the AA mouse model. In addition, an in vitro study revealed that MSC-EVs led to reduced IFN-gamma and TNF-alpha levels and there was an association with decreased splenocyte viability. Previous studies examined the diagnostic and prognostic values of microRNAs (miRNAs) in AA and identified miR-199a, miR-146a, miR-223, and miR-126. We used quantitative real-time PCR to evaluate the expression of these miRNAs on isolated BM mononuclear cells (BM-MNCs) from treated and untreated AA mice. miR-223, miR-146a, and miR-199a expressions increased in the MSC-EVs treated AA mice. Treatment with MSC-EVs increased expression of miR-223 and miR-146a. Our findings showed that treatment with MSC-EVs significantly ameliorated immune destruction of HSCs in the AA mouse model and confirmed the importance of miRNAs in the clinical status of this model.

Automated summary

The study showed that treatment with hypoxic MSC-EVs and normoxic MSC-EVs significantly prolonged the survival rate, increased platelet counts, and ameliorated BM hypoplasia in a mouse model of AA. The effects of MSC-EVs were mediated by T cell suppression and inhibition of interferon-gamma and tumor necrosis factor-alpha production. Additionally, there was an association between reduced pro-inflammatory cytokine levels and decreased splenocyte viability in vitro.