MFGE8 in exosomes derived from mesenchymal stem cells prevents esophageal stricture after endoscopic submucosal dissection in pigs.

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 (ChGelMSC-Exo) for the prevention of esophageal stenosis after ESD in a porcine model. RESULTS: Pigs were randomly assigned into (1) ChGelMSC-Exo treatment group, (2) ChGelPBS 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. ChGelMSC-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 ChGelPBS 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 TGFß1 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.

Wirelessly powered deformable electronic stent for noninvasive electrical stimulation of lower esophageal sphincter.

Electrical stimulation is a promising method to modulate gastrointestinal disorders. However, conventional stimulators need invasive implantation and removal surgeries associated with risks of infection and secondary injuries. Here, we report a battery-free and deformable electronic esophageal stent for wireless stimulation of the lower esophageal sphincter in a noninvasive fashion. The stent consists of an elastic receiver antenna infilled with liquid metal (eutectic gallium-indium), a superelastic nitinol stent skeleton, and a stretchable pulse generator that jointly enables 150% axial elongation and 50% radial compression for transoral delivery through the narrow esophagus. The compliant stent adaptive to the dynamic environment of the esophagus can wirelessly harvest energy through deep tissue. Continuous electrical stimulations delivered by the stent in vivo using pig models significantly increase the pressure of the lower esophageal sphincter. The electronic stent provides a noninvasive platform for bioelectronic therapies in the gastrointestinal tract without the need for open surgery.

Nanoparticle-assembled bioadhesive coacervate coating with prolonged gastrointestinal retention for inflammatory bowel disease therapy.

A key challenge for the effective treatment of gastrointestinal diseases including inflammatory bowel disease is to develop an orally administered drug delivery system capable of prolonged retention in the gastrointestinal tract. Herein we report a bioadhesive liquid coacervate based on hydrogen bonding-driven nanoparticle assembly. Free from electrostatic interactions, our fluid nanoparticle-assembled coacervate demonstrates significant pH- and salt-independent structural stability and forms a physically adhesive coating on a large surface area of intestinal tract with an extended residence time of more than 2 days to mediate the sustained release of preloaded water-soluble small molecule drugs in vivo. The orally administered drug-laden nanoparticle-assembled coacervate significantly mitigates the symptoms of inflammatory bowel disease, restores the diversity of gut microbiota, reduces systemic drug exposure, and improves the therapeutic efficacy in a rat acute colitis model compared with the oral administration of the same amount of drug in solution form. We suggest that the nanoparticle-assembled coacervate provides a promising drug delivery platform for management and treatment of numerous gastrointestinal diseases where controlled drug release with extended residence time is desired.

Transplantation of mesenchymal stem cells to the brain by topical application in an experimental traumatic brain injury model.

Mesenchymal stem cells (MSCs) have been shown in various animal models to be capable of neurorepair and neuroprotection. To carry out a therapeutic function, MSCs must be delivered to the target organ. MSCs are administered to patients via systemic infusion, which has many drawbacks, including a low engraftment rate and the migration of MSCs to non-target organs. However, other approaches such as direct intracerebral injection of MSCs might cause cerebral bleeding. In this study, a traumatic brain injury (TBI) was induced over the right parietal cerebral cortex in Sprague Dawley rats, and green fluorescent protein (GFP)-expressing MSCs (GFP-MSCs), together with a thin layer of fibrin, were applied to the external surface of the contralateral side 2 days later. Within 5 days of topical application, the GFP-MSCs had migrated from the site of application on the cortical surface, through the white matter, and had emerged at the cortical surface of the TBI site on the contralateral cerebral hemisphere, apparently following axons along the corpus callosum. In sham-injured control animals, the topically applied GFP-MSCs proliferated superficially on the cortex at the site of application, and no GFP-MSCs were found at the contralateral cortical surface. In all instances, GFP-MSCs were not detected in other organs of either the test or the control animals. Our study demonstrated that MSCs topically applied to the brain surface can migrate to a TBI site.