Transplantation sites for human and murine islets

Abstract

Aims/hypothesis Beta cell replacement is a potential cure for type 1 diabetes. In humans, islet transplants are currently infused into the liver via the portal vein, although this site has disadvantages. Here, we investigated alternative transplantation sites for human and murine islets in recipient mice, comparing the portal vein with quadriceps muscle and kidney, liver and spleen capsules. Methods Murine islets were isolated from C57BL6/J mice and transplanted into syngeneic recipients. Human islets were isolated and transplanted into either severe combined immunodeficiency (SCID) or recombination-activating gene 1 (RAG-1) immunodeficient recipient mice. All recipient mice were 8-12 weeks of age and had been rendered diabetic (defined as blood glucose concentrations ≥20 mmol/l on two consecutive days before transplantation) by alloxan tetrahydrate treatment. Islets were transplanted into five different sites (portal vein, quadriceps muscle, kidney, liver and spleen capsules). Blood glucose concentrations were monitored twice weekly until mice were killed. Dose-response studies were also performed to determine the minimum number of islets required to cure diabetes ('cure' is defined for this study as random fed blood glucose of <15 mmol/l). Results For transplantation of murine islets into the different sites, the kidney yielded 100% success, followed by muscle (70%), portal vein (60%), spleen capsule (29%) and liver capsule (0%). For human islets, transplantation into the kidney cured diabetes in 75-80% of recipient mice. Transplantation into muscle and portal vein had intermediate success (both 29% at 2000 islet equivalents), while transplantation into liver and spleen capsule failed (0%). With increased islet mass, success rates for muscle grafts improved to 52-56%. Conclusions/interpretation For both human and murine islets, equivalent or superior glucose lowering results were obtained for transplantation into skeletal muscle, compared with the portal vein. Unfortunately, kidney grafts are not feasible in human recipients. Skeletal muscle offers easier access and greater potential for protocol biopsies. This study suggests that human trials of muscle as a transplant site may be warranted.

Tissue‐engineering approaches in pancreatic islet transplantation

“…Moreover, this tissue shows a high oxygen tension, which is ideal for islet engraftment. Some studies support the hypothesis that this site is one of the most suitable sites for islet transplantation (Stokes et al, ), but results regarding its efficacy are heterogeneous, highlighting the need to use additional strategies to improve islet engraftment and to reduce the fibrotic process (Fransson et al, ; Tsuchiya et al, ; Yoshimatsu et al, ). The bone medullary cavity is a well vascularized and easily accessible space occupied by the bone marrow that offers sufficient space for multiple infusions with minimal trauma and spares the islets from IBMIR (Salazar‐Bañuelos, Wright, Sigalet, & Benítez‐Bribiesca, ). Islets survive and engraft successfully after intrabone marrow islet transplantation in both animal models (Cantarelli et al, ; Kover et al, ; K. C. Yang, Wu, et al, ) and humans (Maffi et al, ).…”

“…Islets transplanted into the epididymal fat produced similar results to islets transplanted intraportally, although encapsulation or tissue‐engineered strategies are required (Buitinga et al, ; Manzoli et al, ; D. Mao et al, ; Rios, Zhang, Luo, & Shea, ; K. Wang, Wang, Han, Chen, & Luo, ; X. Wang, Wang, Zhang, Qiang, & Luo, ; Weaver et al, ). The renal subcapsular space has been considered one of the best sites for islet transplantation for more than 3 decades (Mellgren, Schnell Landström, Petersson, & Andersson, ) and is used as a positive control in most studies instead of the liver (Ar’Rajab, Ahrén, Alumets, Lögdberg, & Bengmark, ; Halberstadt et al, ; Medarova et al, ; Pepper et al, ). Compared to intraportally transplanted islets, renal subcapsular islet grafts show a faster vascular engraftment that increases success rates (Olsson, Olerud, Pettersson, & Carlsson, ; Stokes et al, ). Nevertheless, several physiological and anatomical concerns (such as poor blood supply or reduced space to home islet grafts) make the transplantation of islets into the renal subcapsular space a nonfeasible option in humans. The spleen has been considered an alternative to the liver for islet transplantation since the 1970s (Koncz, Zimmerman, DeLellis & Davidoff, ), and several studies comparing the results of islet transplantation performed in the spleen and in the liver were published in that decade (Feldman et al, ; Kolb, Ruckert, Largiadèr, & Largiadèr, ; Reckard, Franklin, & Schulak, ; D. E. Sutherland, Frenzel, Payne, Matas, & Najarian, ).…”

“…Moreover, this tissue shows a high oxygen tension, which is ideal for islet engraftment. Some studies support the hypothesis that this site is one of the most suitable sites for islet transplantation (Stokes et al, 2017), but results regarding its efficacy are heterogeneous, highlighting the need to use additional strategies to improve islet engraftment and to reduce the fibrotic process (Fransson et al, 2015;Tsuchiya et al, 2015;Yoshimatsu et al, 2015).…”

“…(e) The renal subcapsular space has been considered one of the best sites for islet transplantation for more than 3 decades (Mellgren, Schnell Landström, Petersson, & Andersson, 1986) and is used as a positive control in most studies instead of the liver (Ar 'Rajab, Ahrén, Alumets, Lögdberg, & Bengmark, 1990;Halberstadt et al, 2005;Medarova et al, 2009;Pepper et al, 2015). Compared to intraportally transplanted islets, renal subcapsular islet grafts show a faster vascular engraftment that increases success rates (Olsson, Olerud, Pettersson, & Carlsson, 2011;Stokes et al, 2017). Nevertheless, several physiological and anatomical concerns (such as poor blood supply or reduced space to home islet grafts) make the transplantation of islets into the renal subcapsular space a nonfeasible option in humans.…”

Immunological aspects of allogeneic pancreatic islet transplantation: a comparison between mouse and human

“…Investigators have looked at the kidney capsule, omental pouch, gastric submucosa, peritoneal space, spleen, bone, and muscle among other potential sites for islet transplantation, some of which have been tested in humans . The advantages and disadvantages of several islet transplantation sites have been cataloged and compared between humans and other animal species and efforts to improve engraftment in easily accessible islet graft sites are warranted .…”