HucMSC-sEV-derived miR-320d alleviates IBD by inhibiting macrophage ferroptosis through m6A-mediated BCAT2
Naijian Wang1, Jintao Yuan2, Xiu Wang3
1Department of Laboratory Medicine, Affiliated People's Hospital, Jiangsu University, Zhenjiang 212002, Jiangsu, PR China; Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China.
Abstract:
N6-methyladenosine(m6A) modification has garnered significant attention due to its dynamic and reversible post-transcriptional regulation, playing a crucial role in the pathogenesis and progression of inflammatory bowel disease (IBD). Previous studies have demonstrated that human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-sEV) alleviate IBD severity by dampening excessive immune responses and fostering a balanced immune environment. Although hucMSC-sEV has been shown to alleviate IBD, whether its effects involve m6A modification remains unclear. Our findings reveal that hucMSC-sEV modulates m6A modification levels in macrophages and attenuates the inflammatory response in IBD by inhibiting the expression of m6A "eraser" ALKBH5 and "reader" YTHDF2. Branched chain amino acid transaminase 2 (BCAT2) was identified as a key target of hucMSC-sEV-mediated m6A modification, participating in the inhibition of ferroptosis in macrophages. Mechanistically, hucMSC-sEV increased the level of m6A modification by reducing the amount of ALKBH5 and YTHDF2 binding to the BCAT2 mRNA complex, thereby promoting BCAT2 expression and inhibiting ferroptosis in macrophages. We further identified that miR-320d is enriched in hucMSC-sEV and exerts its regulatory effects by targeting both ALKBH5 and YTHDF2. Taken together, these findings indicate that hucMSC-sEV delivers miR-320d to enhance BCAT2 m6A modification and expression, thereby inhibiting macrophage ferroptosis and alleviating inflammation. This finding provides a new theoretical basis for the application of engineered exosomes in the targeted treatment of IBD.
Insights
Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-sEV) alleviate inflammatory bowel disease (IBD) by regulating N6-methyladenosine (m6A) modification. This process inhibits macrophage ferroptosis and reduces inflammation, offering a new therapeutic avenue for IBD.
Area of Science:
- Epigenetics and RNA biology
- Immunology and Inflammation
- Cell biology and extracellular vesicles
Background:
- N6-methyladenosine (m6A) modification is a key post-transcriptional regulator implicated in inflammatory bowel disease (IBD) pathogenesis.
- Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-sEV) are known to mitigate IBD by modulating immune responses.
- The precise role of m6A modification in hucMSC-sEV-mediated IBD treatment remains largely unexplored.
Purpose of the Study:
- To investigate the involvement of m6A modification in the therapeutic effects of hucMSC-sEV on IBD.
- To elucidate the molecular mechanisms by which hucMSC-sEV influences m6A levels and inflammatory responses in macrophages.
- To identify key molecular targets and pathways mediating the anti-inflammatory effects of hucMSC-sEV in IBD.
Main Methods:
- Analysis of m6A modification levels in macrophages treated with hucMSC-sEV.
- Investigation of the expression of m6A-related enzymes (ALKBH5, YTHDF2) and their binding to target mRNAs.
- Identification of downstream targets, such as Branched chain amino acid transaminase 2 (BCAT2), and assessment of ferroptosis inhibition.
- Characterization of microRNA (miR-320d) content in hucMSC-sEV and its regulatory role on target genes.
Main Results:
- hucMSC-sEV treatment modulated m6A modification levels in macrophages, reducing the expression of m6A eraser ALKBH5 and reader YTHDF2.
- BCAT2 was identified as a key target, with hucMSC-sEV-mediated m6A modification inhibiting ferroptosis in macrophages by promoting BCAT2 expression.
- miR-320d, enriched in hucMSC-sEV, was found to target both ALKBH5 and YTHDF2, thereby enhancing BCAT2 expression and suppressing macrophage ferroptosis.
- hucMSC-sEV delivery of miR-320d led to increased BCAT2 m6A modification and expression, ultimately inhibiting macrophage ferroptosis and alleviating inflammation.
Conclusions:
- hucMSC-sEV exerts therapeutic effects in IBD by delivering miR-320d, which enhances BCAT2 m6A modification and expression.
- This mechanism inhibits macrophage ferroptosis and reduces inflammation, providing a novel insight into exosome-based IBD therapy.
- The findings support the potential of engineered exosomes for targeted IBD treatment by modulating epigenetic mechanisms.
