# Charting human islet maturation via combined soft nanoelectronics and single-cell spatial transcriptomics

> **NIH NIH DP1** · HARVARD UNIVERSITY · 2021 · $845,000

## Abstract

Pancreatic islets rely on spatiotemporally orchestrated interactions between heterogenous cells to maintain
blood glucose homeostasis. In type 1 diabetes, an islet-directed autoimmune attack leads to loss of functional β
cells, which is accompanied by defects in the other islet cell types. Diabetics suffer complications from chronic
glucose misregulation, which ultimately reduce life expectancy. Administering insulin itself can treat type 1
diabetes. However, daily insulin injection is expensive, onerous, and carries side effects including risk of
ketoacidosis and coma. Human stem cell-derived islet organoids (SC-islets) offer a chance to generate a limitless
human islet supply as potential therapeutics through transplantation. However, SC-islets lack the precision,
kinetics, and magnitude of insulin/glucagon secretion that natural islets show during adult life. Whether these
limitations reflect poor spatiotemporal coordination between (or within) populations of SC-islet cell types, or
intrinsic three-dimensional (3D) heterogeneity in development and maturation, is still unknown.
Here, we propose to address these fundamental questions by experimentally capturing the trajectories of cellular
activity and interaction across the 3D volume of developing SC-islets through the integration of novel
technologies from stem cell biology, soft thin-film nanoelectronics, tissue clearing and single-cell spatial
transcriptomics, and computational and system biology. Specifically, we have (1) exploited scalable cell
differentiation and purification methods to build “designer” SC-islets with custom α and β composition; (2) globally
embedded soft stretchable sensor arrays within SC-islets, building “cyborg islets” for chronically-stable tracing
of islet-wide α- and β-cell type specific electrical activities at single-cell resolution in vitro and in vivo; (3)
implemented 3D tissue clearing, staining, imaging, and in situ single-cell RNA sequencing to spatially map
hormones, biomarkers, gene expression, and cell types in the intact SC-islets at subcellular resolution; and (4)
used fluorescently-labeled electronic barcodes to identify sensor positions within cleared SC-islets and
computationally integrate chronic electrical recording with hormones, biomarker and gene expression data at the
single-cell level.
We propose to integrate and use these inventions to address major challenges in SC-islet maturation.
Specifically, we aim to employ such multimodal characterization of SC-islet development to address (1) the role
of Dec1 in islet maturation mediated by circadian entrainment; (2) the 3D heterogeneity in SC-islet maturation;
and (3) the role of nerve innervation and vascularization in the maturation of transplanted SC-islets. The success
of this proposal will result in a platform that can monitor the in situ single-cell activity of SC-islets in a chronically
stable manner, provide an understanding of the 3D heterogeneity during SC-islet development and maturation....

## Key facts

- **NIH application ID:** 10326565
- **Project number:** 1DP1DK130673-01
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Jia Liu
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $845,000
- **Award type:** 1
- **Project period:** 2021-09-17 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326565

## Citation

> US National Institutes of Health, RePORTER application 10326565, Charting human islet maturation via combined soft nanoelectronics and single-cell spatial transcriptomics (1DP1DK130673-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10326565. Licensed CC0.

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