What question did this study set out to answer?

The research aims to improve the functional maturation of stem cell-derived islets by integrating regional developmental signaling cues.

June 7, 2026

2428-P: Cross-Species Decoding of Pancreatic Spatial Identity Uncovers Regional Cues during Development to Improve SC-islet Function

Key Points

The research aims to improve the functional maturation of stem cell-derived islets by integrating regional developmental signaling cues.
Established a directed differentiation protocol for SC-islets from human pluripotent stem cells.
Isolated dorsal and ventral pancreatic buds from a fluorescent reporter mouse line at embryonic day 12.5.
Performed bulk RNA sequencing on isolated pancreatic tissues to validate and identify regional molecular features.
SC-islets expressed endocrine and maturation markers but showed limited MAFA induction, indicating immature beta-cell characteristics.
Transcriptomic analysis revealed the D-bud had higher expression of alpha-cell and insulin secretion genes.
The V-bud exhibited enrichment in BMP and JAK-STAT target genes.

Abstract

Introduction and Objective: Pancreas originates from spatially distinct dorsal (D) and ventral (V) domains that are exposed to unique developmental signaling cues and generate islets with distinct functionalities. However, current human stem cell-derived islet (SC-islet) differentiation protocols for type 1 diabetes (T1D) cell therapy do not fully incorporate these regional developmental inputs, potentially compromising the functional maturation of SC-islets. Methods: To address this gap, we established a directed differentiation protocol to generate SC-islets from human pluripotent stem cells and assembled a comprehensive collection of donated human and mouse pancreatic tissues preserving D and V domains across embryonic and adult stages. Using a fluorescent reporter mouse line, we precisely isolated embryonic day (E)12.5 dorsal and ventral pancreatic buds and performed bulk RNA sequencing to validate known regional differences and identify novel domain-specific molecular features. Results: Our SC-islets show robust expression of endocrine and maturation markers but limited induction of MAFA, consistent with immature beta (β)-cells. Transcriptomic analysis of murine tissues confirmed known regional differences and identified new differentially expressed genes. The D-bud showed higher α-cell-associated and insulin secretion gene expression, while V-bud displayed enriched BMP and JAK-STAT targets. Conclusion: Together, these finding validated our fluorescence guided mouse model to investigate pancreatic D/V development and established a robust SC-islet differentiation protocol. These platforms, along with our growing repository of donated human tissues, will allow us to determine how regional developmental cues can enhance SC-islet function and advance cell therapies for T1D. Disclosure M. Bandral: None. D. Lorberbaum: None. Funding American Diabetes Association (1-26-PDF-0739), P&F P30-DK020572 NIH R00 DK128537

Mark Helpful

Bookmark

Relay