Fibrin supports subcutaneous neonatal porcine islet transplantation without the need for pre‐vascularization

Abstract

Background Neonatal porcine islets (NPIs) are a promising tissue source for clinical islet xenotransplantation. To facilitate graft monitoring and recovery if needed, an extra‐hepatic transplant site would be optimal. In addition, islet transplantation into the portal vein has been associated with life‐threatening intraperitoneal bleeding, portal vein thrombosis, hepatic steatosis, and loss of islet graft function. Although it is hypoxic, the subcutaneous space is a potential extra‐hepatic location for clinical islet transplantation. In this study, we explore the benefits of fibrin scaffolds in enhancing the engraftment and long‐term function of NPI grafts in this ectopic site. Methods Diabetic immune‐compromised mice were transplanted with 5000 NPIs under the kidney capsule (KC), and subcutaneously with or without fibrin (SC + F, SC, respectively). All mice were monitored for reversal of hyperglycemia and long‐term metabolic function. Results All mice transplanted with NPI under the KC or SC + F (12/12 and 17/17, respectively) achieved normal fasting blood glucose levels between 5 and 22 weeks post‐transplantation and displayed normal glucose tolerance during an intraperitoneal glucose tolerance test. In contrast, NPIs transplanted SC with no fibrin (n = 7) failed to obtain normoglycemia. Conclusion Fibrin matrix facilitates engraftment of NPIs in the subcutaneous site of diabetic mice. These data support further investigation of the subcutaneous site for clinical islet xenotransplantation.

Characterization and reduction of non-endocrine cells accompanying islet-like endocrine cells differentiated from human iPSC

“…To investigate the cell maturation and function of iPIC in vivo, we implanted iPIC embedded in fibrin gel, which is known to support the engraftment of porcine islets 18 , 19 , into the subcutaneous spaces of mice with streptozotocin-induced diabetes. The grafts of iPIC formed granulation tissue and could be easily retrieved from the host 25–36 weeks after implantation (Fig.…”

Bioabsorption of Subcutaneous Nanofibrous Scaffolds Influences the Engraftment and Function of Neonatal Porcine Islets

“…This was mainly due to the islets in an unmodified space experiencing hypoxic conditions, resulting in apoptosis [ 41 ]. Our group recently showed that NPI transplanted without a fibrin scaffold in subcutaneous space did not achieve optimal graft function [ 37 ]. Therefore, preconditioning of the subcutaneous space has been pursued.…”

“…Porcine pancreases were surgically obtained from 1- to 3-day-old male and female Duroc neonatal piglets (University of Alberta Swine Research Centre, Edmonton, AB, Canada). Neonatal porcine islets (NPIs) were isolated and cultured for seven days as described previously [ 8 , 37 ]. A total of eight independent NPI isolations were used for the transplant studies.…”

“…Scaffold-only grafts (no NPI) recovered at four weeks were fixed in 10% w / v zinc-buffered formalin (Thermo Fisher, Waltham, MA, USA), embedded in paraffin blocks and subsequently stained using hematoxylin and eosin (H&E) [ 37 , 39 ]. Similarly, NPI grafts were processed and embedded in paraffin blocks for histological assessment.…”

Xenotransplantation literature update, July/August 2020

“…T cell‐ and natural killer cell‐mediated xenograft rejection is also a known immunological obstacle, which necessitates heavy immunosuppression in xenotransplantation 7 . It has shown that dendritic cell (DC)‐based cell therapy has a potential to promote transplantation tolerance and could help to reduce/replace immunosuppressive treatments 8 .…”