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UBC Theses and Dissertations

Prioritization of ligands and receptors in human islets and stem cell-derived cells Kamal, Sepehr


Diabetes is caused by the dysfunction and/or destruction of insulin-producing pancreatic β-cells, and curative therapy will require their repair, regeneration, or replacement. Beyond insulin, islets have been reported to contain transcripts for hundreds of other ligands and receptors. Some of these intercellular signals may have therapeutic benefit in diabetes, or in efforts to generate insulin-producing cells from stem cells. Over 90% of the small molecules and proteins used to generate stem cell-derived β-like cells (SCβ-cells) are activators or inhibitors of receptors, and modulation of signaling pathways can alter SCβ-cell differentiation. In this study, we systematically mapped intercellular signaling in human islets and stem cell-derived cells, and built prioritized lists of protein ligands and receptors to guide future screening studies. First, we created a custom ligand-receptor database of 422 protein ligands, 349 receptors, and 1552 interactions. We then integrated multiple datasets to rank ligands and receptors in stem cell-derived cells based on gene expression, protein abundance, and differential expression and abundance compared to human islets. We combined the ligand and receptor ranks to rank each interacting ligand-receptor pair. Finally, we presented three prioritized lists to guide future screens: scarce ligands with abundant receptors in stem cell-derived cells, scarce receptors with abundant ligands in stem cell-derived cells, and abundant receptors with abundant ligands in stem cell-derived cells. Collectively, we expect these data will enable future studies to define the roles of ligands and receptors in diabetes and diabetes therapies.

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