Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization

Abstract

Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation. Transplanting an islet equivalent (IEQ):HUCPVC ratio of 1:30 under the kidney capsule in diabetic NSG mice demonstrated the fastest return to normoglycemia by 3 days after transplant: Superior glycemic control was seen at both early (2.7 weeks) and later stages (7, 12, and 16 weeks) versus ratios of 1:0, 1:10, and 1:50, respectively. Syngeneic islet transplantation in immunocompetent mice using the clinically relevant hepatic portal route with a marginal islet mass showed that mice transplanted with an IEQ:HUCPVC ratio of 1:150 had superior glycemic control versus ratios of 1:0, 1:90, and 1:210 up to 6 weeks after transplant. Immunodeficient mice transplanted with human islets (IEQ:HUCPVC ratio of 1:150) exhibited better glycemic control for 7 weeks after transplant versus islet transplant alone, and islets transplanted via the hepatic portal vein in an allogeneic mouse model using a curative islet mass demonstrated delayed rejection of islets when cotransplanted with HUCPVCs (IEQ:HUCPVC ratio of 1:150). The immunosuppressive and proregenerative properties of HUCPVCs demonstrated long-term positive effects on graft function in vivo, indicating that they may improve long-term human islet allotransplantation outcomes.

Cell therapy for advanced liver diseases: Repair or rebuild

“…Long-term improvements were made in the engraftment of allogenic pancreatic islet cells into the liver when co-transplanted with GMPcompatible umbilical cord perivascular MSCs, enabling delayed rejection of islet grafts. 56 The immunomodulatory function of MSCs alters macrophage phenotype and enhances the proregenerative effect of macrophage therapy (discussed later) in pre-clinical murine fibrosis, 57 and co-transplantation of MSCs improves foetal hepatocyte engraftment in retrorsine-injured mouse livers. 58 Hydrogels have been used to coat cells in substances containing growth factors and matrix proteins to maintain the cells in a pro-regenerative state.…”

The use of mesenchymal stromal cells in the treatment of coronavirus disease 2019

“…The benefits of MSCs have since been assessed for many other conditions in both pre-clinical and clinical trial settings. Notable examples include exploring the reduction of inflammation in patients with osteoarthritis [84], multiple sclerosis [85,86], as well as their use in the treatment of type 1 diabetes mellitus either alone [87] or together with transplanted pancreatic islets to promote integration and survival [88].…”

“…UC-MSCs (including from Wharton's Jelly) are the most common source with 27 trials, followed by 9 from adipose tissue, 4 from dental pulp, 3 from placenta, 1 from menstrual blood, 1 from mesenchyme-angioblasts and 1 from olfactory mucosa with 14 not declaring their origin [107]. In recent years, the benefits of and relative ease with which UC-MSCs can be isolated and maintained compared with BM-MSCs has been widely recognised and thus far they have been the most readily adopted cellular therapeutic treatment for COVD-19 [88,108,109]. Interestingly, there are 5 trials utilising either MSC conditioned media or exosomes containing components of the MSC secretome, believed to execute the immunomodulatory benefits which have been documented in various studies [45,95,110].…”

Mesenchymal stromal cells and their derivatives – putative therapeutics in the management of autoimmune pancreatitis

“…A very recent example is the co‐administration of MSCs with pancreatic islets in immunocompetent type 1 diabetic wild‐type mice. Glycemic control was restored, using human mesenchymal cells, and a clear demonstration provided evidence of the suppression of T‐cell activation without the need for prior ex vivo licensing (stimulation) with the inflammatory cytokines interferon‐Υ (IFN‐Υ), interleukin‐1β (IL‐1β), and tumor necrosis factor‐α (TNF‐α) [16]. The first approval, with government reimbursement, for the treatment of an immune condition with MSCs was that in Japan in 2016, for the treatment of both pediatric disease and adult acute graft‐versus‐host disease (aGVHD) [17].…”