Mesenchymal stem cell secretome-loaded fibrin glue improves the healing of intestinal anastomosis

Abstract

Anastomotic leakage is a serious complication following gastrointestinal surgery and one of the leading causes of patient mortality. Despite the significant clinical and economic burden, there are currently no reliable treatment options to improve the healing of intestinal anastomosis and subsequently prevent anastomotic leakage. Recently, the development of regenerative medicine has shown promise for improving anastomotic healing. Recent studies have illustrated that stem cell-derived secretome can enhance tissue regeneration without the safety and ethical limitations of stem cell transplantation. Herein, we developed a fibrin glue topical delivery system loaded with mesenchymal stem cells (MSCs)-derived secretome for controlled delivery of bioactive factors, and evaluated its application potential in improving the healing of intestinal anastomosis. Under in vitro conditions, the MSCs secretome significantly promoted cell proliferation viability in a dose-dependent manner and resulted in the controlled release of growth factors via fibrin glue delivery. We established a rat surgical anastomotic model and experimentally found that MSCs secretome-loaded fibrin glue enhanced anastomotic bursting pressure, increased granulation tissue formation and collagen deposition, and significantly promoted anastomotic healing. Mechanistically, fibrin glue accelerated cell proliferation, angiogenesis, and macrophage M2 polarization at the surgical anastomotic site by releasing bioactive factors in the secretome, and it also alleviated the inflammatory response and cell apoptosis at the anastomotic site. Our results demonstrated for the first time that MSCs-derived secretome could promote the healing of intestinal anastomosis. Considering the accessibility and safety of the cell-free secretome, we believed that secretome-loaded fibrin glue would be a cell-free therapy to accelerate the healing of intestinal anastomosis with great potential for clinical translation.

The Role of Adipose Tissue Mesenchymal Stem Cells in Colonic Anastomosis Healing in Inflammatory Bowel Disease: Experimental Study in Rats

“…This is in agreement with studies that have shown that the administration of AdMSCs on the site of the anastomosis can help the properties of the AdMSCs work in a paracrine way on the organ target [34][35][36]40,50]. Most of the related studies agree that by using a parenteral administration method, MSCs hardly ever reach the organ target [34,62]. Further studies are needed to reveal whether mesenchymal cell properties can be amplified by using a different medium of application.…”

“…Lee et al have reported that intravenously injected MSCs were found to be trapped in the lungs [61]. Also, Yu et al have reported no therapeutic effect when they injected the secretome of MSCs intravenously, as compared to applying the therapy locally with the use of fibrin glue as a medium [62].…”

“…Yu et al have proposed a novel cell free therapy by using fibrin glue as a medium. They have demonstrated that it is possible to deliver the healing properties of MSCs by administering their secretome with fibrin glue, enabling the slow release of healing and growth factors for up to 10 days in rats with ischemic anastomoses [62].…”

“…Key to the therapeutic properties of AdMSCs is the secretome by which they seem to regulate inflammation as well as enhance the healing properties of the cells; this might indicate future experimental directions. As indicated by the studies of Park et al and Yu et al, using AdMSC secretome could be a way of using the properties of MSCs without using the actual cells [62,63]. More studies with secretome could potentially lead us to identify the molecule or the group of molecules produced by MSCs which have similar anti-inflammatory and regenerative properties as the cell culture of MSCs.…”