Abstract
Diabetes mellitus is a chronic metabolic disorder affecting millions worldwide, characterized by hyperglycemia resulting from defects in insulin secretion or action. While current treatments range from pharmacotherapy to experimental cell-based therapies, progress remains hampered by donor scarcity and an incomplete understanding of islet stress responses. This dissertation investigates cellular stress responses in pancreatic islets and strategies to improve stem cell-derived islet (SC-islet) transplantation. The first chapter provides an overview of diabetes pathophysiology, modeling approaches, and treatment options. In the second chapter, we use single-cell RNA sequencing to investigate cell-type-specific responses to diabetes-associated stress in primary human islets exposed to endoplasmic reticulum and inflammatory stress. Notable, we found that not only do β-cells exhibit a robust response to stress, but α-cells and ductal cells do as well. We also characterized β-cell-specific responses to stress. Building on these findings, the dataset enabled the identification of drug and gene candidates to enhance islet stress resilience, leading to the discovery of CIB1 as a regulator of SC-islet function and apoptosis. The third chapter employs whole-genome CRISPR screening to identify genes that improve SC-islet transplantation in mouse models. FCAMR overexpression significantly reduced blood glucose and increased C-peptide in subcutaneous transplantations, and induced weight gain in intramuscular and kidney transplantation models. Overall, this dissertation analyzes cell-type-specific responses to diabetic-associated stress and establishes FCAMR as a target for enhancing SC-islet transplantation therapy.
Committee Chair
Jeffrey Millman
Committee Members
Farshid Guilak; Fumihiko Urano; Irfan Lodhi; Monika Bambouskova
Degree
Doctor of Philosophy (PhD)
Author's Department
Biology & Biomedical Sciences (Developmental, Regenerative, & Stem Cell Biology)
Document Type
Dissertation
Date of Award
12-18-2025
Language
English (en)
DOI
https://doi.org/10.7936/40zq-a796
Author's ORCID
0000-0002-5135-0938
Recommended Citation
Maestas, Marlie Maria, "Understanding Pancreatic Islet Stress Responses and Developing Strategies to Improve Transplantation Grafts" (2025). Arts & Sciences Theses and Dissertations. 3683.
The definitive version is available at https://doi.org/10.7936/40zq-a796