# Linking human islet structural heterogeneity to beta cell state

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $403,750

## Abstract

Project Summary/Abstract
 The detailed structure of the beta cell niche, and that of the islet in general, remains poorly understood;
this is particularly the case for human islets. Islet structure appears heterogeneous across the pancreas, and
whether conserved structural features exist among islets is unknown. A detailed understanding of the
organizational principles of islets would advance our ability both to reconstitute stem-cell derived islets as a
cure for type 1 diabetes (T1D) and to block the progression of events that lead to the loss of beta cells during
the progression of diabetes. Therefore, the goal of this proposal is twofold: first, to identify and experimentally
validate the critical organizational principles of the islet in general and the beta cell niche in particular, and
second, to leverage these organizational principles to engineer more functional islets as a cure for T1D.
 Towards the first goal, we have developed a custom, semi-automated, 3D imaging and analysis
pipeline that permits quantification of the statistical properties of the beta cell niche at sub-micron resolution
and across hundreds of individual beta cells. Preliminary analyses of healthy mouse and human islets revealed
that (1) in both species beta and delta cells maintain at least one physical contact with a source of basement
membrane, whereas alpha cells do not, and (2) beta cells in engineered islets that contact sources of vascular
basement membrane have dramatically elevated insulin expression. We hypothesize that beta cell contact with
basement membrane is a conserved element of islet structure that must be incorporated into engineered islets
to optimize beta cell function. Towards the second goal, we have demonstrated that reconstituting stem cell-
derived beta cells into pseudo-islets in a manner that maximizes their contact with basement membrane
improves their response to glucose by at least two-fold in vitro and further extends their functionality in vivo.
 Building on these preliminary findings, we first aim to dramatically expand this analysis across tens of
thousands of individual cells in human and mouse islets, incorporating all endocrine cell types along with
immune cells, vascular cells, and nerves. This will result in the first quantitative assessment of the endocrine
cell structural niche that acknowledges the structural heterogeneity of islets and aims to identify conserved
structural motifs. Second, we aim to determine if conserved features of the beta cell niche are necessary and
sufficient for optimal beta cell function. We will test this hypothesis using in vitro reconstituted islets, primary
human islets cultured ex vivo, and engineered human islets transplanted into mice in vivo. Finally, we will use
genome editing techniques to test the necessity of specific pericyte-derived basement membrane molecules
for glucose homeostatic function in engineered islets. Taken together, our study will provide the first
quantitative structural b...

## Key facts

- **NIH application ID:** 10891735
- **Project number:** 5U01DK135019-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Zev Jordan Gartner
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $403,750
- **Award type:** 5
- **Project period:** 2022-09-20 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891735

## Citation

> US National Institutes of Health, RePORTER application 10891735, Linking human islet structural heterogeneity to beta cell state (5U01DK135019-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10891735. Licensed CC0.

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