Small molecule activator of LYN improved the outcome of islet transplantation in mice

• Author / Creator

  Akbari Motlagh, Roozbeh

• Islet transplantation can achieve insulin independence in individuals with type 1 diabetes. However, islets derived from multiple donors are often required, and functional β-cells are lost early after transplantation. Notably, up to 80% of newly transplanted islets are lost due to cell death during the acute post-transplant period, which can be attributed to poor vascularization and the instant blood-mediated inflammatory reaction. Thus, strategies are needed to improve graft survival and function, particularly in light of these challenges. Our lab has recently characterized LYN as a critical regulator of β-cell proliferation and survival. We herein sought to test the hypothesis that pharmacological activation of LYN improves the outcome of islet transplantation in mice.
  Male BALB/c islets were isolated and transplanted (marginal mass of 125 islets) into syngeneic diabetic mice recipients under the left kidney capsule. Recipients were thereafter injected intraperitoneally once daily with a specific activator of LYN (MLR-1023) or vehicle for 7 days. An intraperitoneal glucose tolerance test was performed at days 8 and 28. The graft-bearing kidneys and pancreas were also harvested for immunohistochemical analysis.
  A brief 7-day treatment with MLR-1023 was sufficient to stimulate β-cell proliferation in islet recipients. However, β-cell mass was not significantly altered, due to inter-individual variations. MLR treatment accelerated revascularization at day 8 compared to the control group. Remarkably, these results translated into better glucose tolerance in the MLR-treated group compared to controls at day 8, without increased insulin secretion. Although MLR-1023 exhibited a sustained effect on revascularization at day 28, the majority of its effects dissipated after drug withdrawal.

  This finding could hold significant clinical implications, as MLR-1023 could potentially be utilized in clinical islet transplantation to reduce the required islet mass for achieving insulin independence or to expedite the attainment of normoglycemia. Moreover, our study demonstrated a notable increase in revascularization, although it did not reach statistical significance. Notably, we observed accelerated neovascularization independent of VEGF-A. These results suggest that MLR-1023 may potentially enable stimulating revascularization through a distinct pathway.

• Subjects / Keywords

  • Islet transplantation
  • MLR-1023
  • LYN

• Graduation date

  Fall 2023

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-cwyx-8476

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.