BM-derived mesenchymal stem cell microvesicles protect enteric neural precursor cells and alleviate diabetes-associated enteric neuropathy
Huiying Shi, Hailing Yao, Yilin Liu, Mengke Fan, Sicheng Cai, Shizhao Xu, Chen Jiang, Yurui Zhang, Weiwei Jiang, Wei Qian, Rong Lin
Huiying Shi, Hailing Yao, Yilin Liu, Mengke Fan, Sicheng Cai, Shizhao Xu, Chen Jiang, Yurui Zhang, Weiwei Jiang, Wei Qian, Rong Lin
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Research Article Gastroenterology Neuroscience

BM-derived mesenchymal stem cell microvesicles protect enteric neural precursor cells and alleviate diabetes-associated enteric neuropathy

Abstract

Enteric nervous system (ENS) injury, characterized by progressive degeneration of enteric neurons and glial cells, is a common diabetic complication with no effective cure beyond symptomatic management. Enteric neural precursor cells (ENPCs) play a key role in maintaining neurogenesis and gliogenesis within the adult ENS. Here, we demonstrate that bone marrow mesenchymal stem cell–derived microvesicles (BMSC-MVs) alleviate diabetic ENS injury. In both diabetic patients and mouse models, gastrointestinal transit was delayed, ENS structure was impaired, and neurogenesis and gliogenesis from ENPCs were elevated yet remained functionally insufficient. Transcriptomic profiling revealed activation of ER stress and the pro-apoptotic PERK branch of the unfolded protein response in ENPCs. BMSC-MVs homed to the colon, were internalized by ENPCs, and suppressed ER stress, thereby enhancing functional neurogenesis and gliogenesis, restoring ENS structure, and improving gastrointestinal motility. Mechanistically, vinculin on BMSC-MVs bound talin-1 on ENPCs, activating the ERK pathway to suppress diabetic ER stress. These results identify BMSC-MVs as a promising cell-free therapeutic strategy for diabetic ENS injury.

Authors

Huiying Shi, Hailing Yao, Yilin Liu, Mengke Fan, Sicheng Cai, Shizhao Xu, Chen Jiang, Yurui Zhang, Weiwei Jiang, Wei Qian, Rong Lin

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Figure 8

Surface VCL on BMSC-MVs mediates internalization by binding to TLN1 on ENPCs.

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Surface VCL on BMSC-MVs mediates internalization by binding to TLN1 on E...
(A and B) Screening of ENPC surface proteins interacting with BMSC-MVs by far Western blot (A) and biotin pull-down (B). Far Western analysis revealed 5 candidate bands, with band 1 identified as TLN1 by LC-MS/MS; biotin pull-down showed 3 bands, with band 1 confirmed as TLN1. CBB, Coomassie blue. (C) Peptide-based ranking of ENPC surface proteins interacting with BMSC-MVs from far Western blot. (D and E) Screening of BMSC-MV surface proteins by far Western blot (D) and biotin pull-down (E). Far Western showed 3 candidates, with band 1 identified as VCL; biotin pull-down revealed 5 bands, with band 1 identified as VCL by LC-MS/MS. (F) Venn diagram of overlapping ENPC surface proteins identified by far Western and biotin pull-down assays. (G) Western blot analysis and qualification of VCL in BMSC-MVs after Vcl knockdown (shVCL) or overexpression (oeVCL). n = 4. (H) Western blot analysis of TLN1 in ENPCs after Tln1 knockdown (siTLN1) or overexpression (oeTLN1). n = 3. (I and J) Coimmunoprecipitation assay to assess the binding of HA-tagged VCL in BMSC-MVs to FLAG-tagged TLN1 in ENPCs. IgG control is shown. Data are presented as mean ± SD. Statistical significance was determined by unpaired 2-tailed Student’s t test. ****P < 0.0001.