Exploring miRNA heterogeneity within pancreatic beta-cell subpopulations to improve beta-cell therapies

Pancreatic β-cells within islets are molecularly and functionally heterogeneous.

Single-cell RNA sequencing (scRNA-Seq) has revealed distinct β-cell subpopulations with unique transcriptional profiles, that have been linked to their secretory and regenerative capacities.

ScRNA-seq has also detected transcriptional changes within specific β-cell subpopulations in prediabetes and T1D, suggesting distinct susceptibilities to disease progression.

In vitro generated stem-cell derived islets (SC-islets) also contain transcriptionally distinct β-cell subpopulations, but these subpopulations aren’t identical to primary islets.

This may contribute to their reduced functionality, which is one of the important limitations for the clinical use of SC-islets in replacement therapies. Most scRNA-Seq protocols cannot detect microRNAs (miRNAs).

Thus, whether miRNA expression is heterogeneous within islet β-cells or whether miRNA action contributes to their molecular and functional heterogeneity remains unexplored.

MiRNAs are negative regulators of gene expression essential for the development, survival and function of pancreatic β-cells.

Given recent findings showing heterogeneous presence and action of miRNAs within other cell types, we hypothesize that miRNAs contribute to the molecular and functional heterogeneity of pancreatic β-cells.

Accordingly, we propose a collaborative approach using cutting-edge molecular and imaging techniques to explore and compare miRNA expression and targeting at high-throughput and single-cell levels between SC-islets, human islets and pancreatic tissue in health and T1D.

This project will provide novel understanding of the molecular mechanisms underlying heterogeneous susceptibility of β-cells to T1D development and progression and why SC-derived islets aren’t as functional as primary islets. This knowledge could enhance current efforts in preserving and generating β-cells for treating T1D.