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Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Attenuate Renal Fibrosis by Suppressing Fibroblast
Meiling Chen1,2,3, Chenxi Jia1,2,3, Zhuocheng Shi1,2,3
1Ministry of Education Key Laboratory of Child Development and Disorders, Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders Chongqing China.
Abstract:
Renal fibrosis is a common pathological feature and key driver of progression to end-stage renal disease in various chronic kidney diseases, with effective treatments remaining scarce. Exosomes derived from mesenchymal stem cells (MSC-Exos) have demonstrated tremendous potential in tissue and organ repair and antifibrosis treatment. This study investigated the therapeutic effects and mechanisms of MSC-Exo derived from human umbilical cord (HucMSC-Exo) on renal fibrosis. HucMSC-Exo was applied to intervene in a mouse model of renal fibrosis induced by unilateral ureteral obstruction (UUO) or cocultured with TGF-β-stimulated rat renal fibroblasts (NRK-49F). Results showed that HucMSC-Exo conspicuously alleviated pathological damage, inflammatory response, fibroblast proliferation/activation, and extracellular matrix deposition in UUO kidneys. Single-cell sequencing revealed a prominent upregulation of Inhba gene in UUO kidneys, whereas HucMSC-Exo treatment effectively inhibited its expression. Further mechanistic studies showed that knocking down Inhba mimicked the antifibrotic effects of HucMSC-Exo, whereas exogenously adding INHBA weakened its protective effects. Transcriptome sequencing results revealed that the downstream effects of Inhba involve regulating the PI3K/AKT signaling pathway, and HucMSC-Exo treatment markedly inhibited the activation of this pathway. Collectively, HucMSC‑Exo exerts antifibrotic effects by regulating the INHBA/PI3K/AKT signaling axis to inhibit renal fibroblast activation.
Insights
Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSC-Exos) show promise for treating kidney fibrosis. These exosomes alleviate fibrosis by inhibiting the INHBA/PI3K/AKT pathway, offering a potential new therapeutic strategy.
Area of Science:
- Nephrology
- Regenerative Medicine
- Cell Biology
Background:
- Renal fibrosis is a major cause of chronic kidney disease progression, with limited treatment options.
- Mesenchymal stem cell-derived exosomes (MSC-Exos) show potential for tissue repair and antifibrotic therapies.
Purpose of the Study:
- To investigate the therapeutic effects of human umbilical cord MSC-Exos (HucMSC-Exos) on renal fibrosis.
- To elucidate the underlying mechanisms of HucMSC-Exo's antifibrotic action.
Main Methods:
- Renal fibrosis was induced in mice via unilateral ureteral obstruction (UUO) and in rat renal fibroblasts (NRK-49F) using TGF-β.
- HucMSC-Exo treatment was applied to these models.
- Single-cell and transcriptome sequencing were used to analyze gene expression and signaling pathways.
- Gene knockdown and exogenous protein addition were employed to validate mechanistic findings.
Main Results:
- HucMSC-Exo treatment significantly reduced pathological damage, inflammation, fibroblast activation, and extracellular matrix deposition in UUO kidneys.
- Single-cell sequencing identified upregulation of the Inhba gene in fibrotic kidneys, which was inhibited by HucMSC-Exo.
- Knocking down Inhba mimicked HucMSC-Exo's antifibrotic effects, while adding INHBA diminished them.
- Transcriptome analysis revealed that Inhba regulates the PI3K/AKT pathway, which was inhibited by HucMSC-Exo.
Conclusions:
- HucMSC-Exos effectively alleviate renal fibrosis by targeting the INHBA/PI3K/AKT signaling axis.
- This mechanism involves inhibiting renal fibroblast activation and extracellular matrix accumulation.
- HucMSC-Exos represent a promising cell-free therapeutic strategy for renal fibrosis.
