Small Intestinal Submucosa Induces Loss of Mitochondrial Integrity and Caspase-Dependent Apoptosis in Human T Cells

Abstract

Porcine small intestinal submucosa (SIS) is a cell-free biomaterial used in humans for wound healing and as scaffold material for constructive remodeling of damaged or missing tissue. We have previously shown that SIS contains a factor that suppresses human helper T cell subset differentiation and expansion by inducing programmed cell death. Our aims here were to identify in detail the processes involved in SIS-induced T cell apoptosis and to perform the first characterization of the apoptosis-inducing factor present in SIS. In in vitro experiments, we utilized human T cell lines, Jurkat and CEM, to identify the processes involved in SIS-induced T cell apoptosis. Two types of sterile SIS material were used: hydrated sheets and rehydrated clinical-grade sheets. We found that SIS-mediated apoptosis as detected by induction of membrane annexin V staining involved the loss of mitochondrial membrane potential and was dependent on caspase activation. We eliminated transforming growth factor beta (TGF-beta), Fas ligand (FasL), and galectin family members as factors in SIS-mediated T cell apoptosis. We further established that processes required to prepare SIS for clinical use, freeze-drying, and gas sterilization destroyed the apoptosis-inducing factor. SIS contains a factor that induces loss of mitochondrial integrity and caspase-dependent apoptosis in human T cells. This factor is destroyed by freeze-drying and gas sterilization and is not TGF-beta, FasL, or a galectin family member. Normal T cell homeostasis in gut-associated tissues may be regulated in part by this unknown factor.

Understanding Roles of Porcine Small Intestinal Submucosa in Urinary Bladder Regeneration: Identification of Variable Regenerative Characteristics of Small Intestinal Submucosa

“…73 In contrast to results reported by Allman et al, SIS completely abolishes the generation of Th2 cells in vitro; and the suppression of Th cell activation by SIS involved the induction of Th cell apoptosis through a caspase-dependent pathway(s), but independent of TGF-b, Fas ligand (FasL), or galectin family members. 74 Other studies showed that SIS appears to have no effects on proinflammatory cytokines (IL-6, IL-1b, TNF-a) or NLRP3 expression, but promotes both Th1 and Th2 responses under different conditions. 70 Sterilization methods such as freeze-drying and gas sterilization may have significant impacts by activating or inactivating unidentified bioactive molecules in SIS and eliciting differential biological responses.…”

Development of hypoparathyroidism animal model and the feasibility of small intestinal submucosa application on the parathyroid autotransplantation

“…Its efficacy in promoting tissue growth, differentiation and angiogenesis has been well documented [5]. In addition, it has also been reported to possess some immunosuppressive factors [5,7,8]. Based on this, we have speculated that angiogenic potential and immunosuppressive properties of SIS would promote the graft survival of autotransplanted parathyroid tissue.…”

Small Intestine Submucosa Is a Potential Material for Intrauterine Adhesions Treatment in a Rat Model

“…In addition, the integrity of endometrium in the SIS group was better than that in the control group. It has been reported that SIS contains factors with immunosuppressive properties and suppresses the T-helper cell activation [15,16]. Furthermore, it was observed that the implantation of SIS is associated with fewer infections than other graft materials [14].…”