Abstract
Transplantation of islets in type 1 diabetes (T1D) is limited by poor islet engraftment into the liver, with two to three donor pancreases required per recipient. We aimed to condition the liver to enhance islet engraftment to improve long‐term graft function. Diabetic mice received a non‐curative islet transplant (n = 400 islets) via the hepatic portal vein (HPV) with fibroblast growth factor 7‐loaded galactosylated poly(DL‐lactide‐co‐glycolic acid) (FGF7‐GAL‐PLGA) particles; 26‐µm diameter particles specifically targeted the liver, promoting hepatocyte proliferation in short‐term experiments: in mice receiving 0.1‐mg FGF7‐GAL‐PLGA particles (60‐ng FGF7) vs vehicle, cell proliferation was induced specifically in the liver with greater efficacy and specificity than subcutaneous FGF7 (1.25 mg/kg ×2 doses; ~75‐µg FGF7). Numbers of engrafted islets and vascularization were greater in liver sections of mice receiving islets and FGF7‐GAL‐PLGA particles vs mice receiving islets alone, 72 h posttransplant. More mice (six of eight) that received islets and FGF7‐GAL‐PLGA particles normalized blood glucose concentrations by 30‐days posttransplant, versus zero of eight mice receiving islets alone with no evidence of increased proliferation of cells within the liver at this stage and normal liver function tests. This work shows that liver‐targeted FGF7‐GAL‐PLGA particles achieve selective FGF7 delivery to the liver‐promoting islet engraftment to help normalize blood glucose levels with a good safety profile.
Highlights
Islets are clusters of polyhormonal cells including insulin secreting β-cells
Fibroblast Growth Factor 7 (FGF7) 1.25mg /kg s.c. was associated with the greatest total proliferation of liver cells versus hepatic growth factor (HGF) 250μg/ kg i.v., T3 4mg/ kg s.c., and all three growth factors in combination; all mice were given 2 injections of GFs, the first at the time of transplant and the second 48hrs later with liver cell proliferation assessed 48hrs following this (Figure 1A)
3.2 Subcutaneous FGF7 with islets did not control blood glucose levels more effectively than transplantation of islets alone Mice with diabetes transplanted with 400 islets plus FGF7 1.25mg/kg s.c (×2 injections), did not demonstrate improved glycemic control compared with mice transplanted with islets alone by 6 weeks, with no mice cured from their diabetes: glucose concentrations at 6 weeks:: 18.1±2.2 mmol/L vs. 19.2±1.8 mmol/L, respectively (p=0.80)
Summary
Islets are clusters of polyhormonal cells including insulin secreting β-cells. In Type 1 diabetes (T1D), destruction of pancreatic β-cells by autoimmune processes leads to insulin deficiency requiring insulin replacement. Preconditioning the host liver with growth factors (GFs) creates a receptive ‘‘niche’’ involving the re-modelling and proliferation of liver cells 14,15. We tested targeted GF delivery to the liver to promote short-term liver cell proliferation, enhance islet engraftment and improved metabolic control in a mouse model of T1D. In order to do this we: 1) characterized the biodistribution and release kinetics of several formulations and particle sizes in vivo; 2) identified an optimal particle size and dose; 3) co-transplanted GF-loaded galactosylated PLGA (GALPLGA) particles concurrently with a non-curative mass of islets via the clinically relevant hepatic portal vein (HPV) into diabetic mice and monitored glycemic control over a 6 week period with histological assessments of islet engraftment in the liver
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