Lai Huasheng,Yip Hon-Chi,Gong Yu,Chan Kai-Fung,Leung Kevin Kai-Chung,Chan Melissa Shannon,Xia Xianfeng,Chiu Philip Wai-Yan
Background Endoscopic submucosal dissection (ESD) is the current standard treatment for early-stage esophageal neoplasms. However, the postoperative esophageal stricture after extensive mucosal dissection remains a severe challenge with limited effective treatments available. In this study, we introduced a chitosan/gelatin (ChGel) sponge encapsulating the adipose mesenchymal stem cells (ADMSCs)-derived exosomes (ChGel MSC−Exo ) for the prevention of esophageal stenosis after ESD in a porcine model. Results Pigs were randomly assigned into (1) ChGel MSC−Exo treatment group, (2) ChGel PBS group, and (3) the controls. Exosome treatments were applied immediately on the day after ESD as well as on day 7. Exosome components crucial for wound healing were investigated by liquid chromatography-tandem mass spectrometry (LC–MS/MS) and small RNA sequencing. ChGel MSC−Exo treatment significantly reduced mucosal contraction on day 21, with less fiber accumulation and inflammatory infiltration, and enhanced angiogenesis when compared with the control and ChGel PBS groups. The anti-fibrotic effects following MSC-Exo treatment were further found to be associated with the anti-inflammatory M2 polarization of the resident macrophages, especially within the M2b subset characterized by the reduced TGFβ1 secretion, which sufficiently inhibited inflammation and prevented the activation of myofibroblast with less collagen production at the early stage after ESD. Moreover, the abundant expression of exosomal MFGE8 was identified to be involved in the transition of the M2b-macrophage subset through the activation of MFGE8/STAT3/Arg1 axis. Conclusions Our study demonstrates that exosomal MFGE8 significantly promotes the polarization of the M2b-macrophage subset, consequently reducing collagen deposition. These findings suggest a promising potential for MSC-Exo therapy in preventing the development of esophageal stricture after near-circumferential ESD. Graphical Abstract
Yunfei Li,Cheng Cheng,Mingfei Li,Yi Hou,Jie Li,Shichao Duan,Enyi Gao,Ke Liu,Zhipeng Dai
Osteoarthritis (OA) is a common degenerative joint disease. Cysteine-rich intestinal protein 1(CRIP1) is involved in many biological processes, but its role in OA remains unclear. OA-related datasets from the GEO database revealed that CRIP1 expression was upregulated in OA patient cartilage. This upregulation was also confirmed in our collected clinical samples and OA mice. CRIP1 knockdown increased the expression of collagen II and tissue inhibitor of metalloproteinases 3, but reduced the levels of matrix metalloproteinase 13 and phosphorylated p65 in IL-1β-induced primary mouse chondrocytes. In contrast, CRIP1 overexpression had the opposite effects. CRIP1 knockdown alleviated cartilage damage, reduced extracellular matrix (ECM) degradation, and inhibited p65 phosphorylation in OA mice. To investigate the CRIP1 mechanism in OA, proteins regulated by CRIP1 were screened by label-free quantitative proteomics, and the milk fat globule-epidermal growth factor 8 (MFGE8) protein was identified in the search for CRIP1-specific binding proteins in chondrocytes using immunoprecipitation/mass spectrometry. CRIP1 knockdown increased MFGE8 expression in OA mouse cartilage and IL-1β-induced chondrocytes. CRIP1 overexpression resulted in a shortened half-life of MFGE8 in chondrocytes. The proteasome inhibitor reversed the MFGE8 downregulation in CRIP1 overexpressing chondrocytes. Immunoprecipitation and rescue experiments verified that CRIP1 regulated MFGE8 degradation by promoting its binding to E3 ubiquitin-protein ligase 3A (UBE3A). Meanwhile, CRIP1 affected ECM degradation and NF-κB pathway through MFGE8. In summary, CRIP1 knockdown attenuated cartilage damage in OA mice and inhibited the ECM degradation and p65 activation in vivo and in vitro . This effect may be mediated by inhibiting the interaction between UBE3A and MFGE8.
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