# Improving human pluripotent stem cell derived beta cell transplantation using genetic lineage tracing.

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $385,420

## Abstract

Project summary:
Type one diabetes (T1D) is characterized by the destruction of insulin-producing beta cells by an autoimmune
attack. Currently there is no cure available and T1D patients rely on supply of endogenous insulin via injections,
but long-term complications and the risk of hypoglycemia due to poor insulin control persist. Transplantation of
isolated cadaveric islets into long-standing T1D patients results in ~35 months of insulin independence,
tremendously improving quality of life. While this beta cell replacement therapy has emerged as a potential cure
for T1D, its advancement has been hampered by the lack of an abundant beta cell source. We have recently
demonstrated the large-scale production of glucose responsive insulin producing beta-like cells from human
pluripotent stem cells. These cells can correct diabetes in animal models, thus directly addressing donor
shortage with this viable approach. However, a largely neglected aspect of current cell therapy research
efforts is the dramatic and immediate loss of stem cell derived beta cells (sBCs) upon transplantation.
This is a critical problem that, if successfully resolved, will tremendously increase the efficacy of virtually
all current approaches proposing to deliver sBCs for cell replacement therapy purposes, both naked and
encapsulated. Our overall hypothesis is that transplantation of sBCs results in the loss of a large proportion of
these cells, due to several mechanisms, including: (1) hypoxia and nutrition deprivation mediated cell death, (2)
transdifferentiate into other hormone expressing cell types and (3) that part of the remaining sBCs adopt a less
functional beta cell phenotype. The focus of this grant application is two-fold: (1) accurately and comprehensively
elucidate the fate of sBCs upon transplantation employing genetic lineage tracing and (2) to prevent phenotypical
changes and sBC death by temporal expression of the anti-apoptotic gene BCL2 using mRNAs in combination
with physiological oxygen adaption shown by us to significantly improve graft survival. Specifically, our lineage
tracing analysis will comprehensively define the cellular changes of sBC upon transplantation. We further
anticipate to accurately define the associated molecular changes driving them, thus likely providing
unacknowledged targets to improve sBC survival thereafter. Furthermore, we except to provide an effective and
simple way to prevent the loss of functional sBC mass that is currently occurring upon transplantation. Taken
together, the timely approach outlined within this proposal combined with our unique expertise is poised
to successfully address a critical problem of cell replacement therapy for T1D patients, the preservation
of sBC survival and function immediately upon transplantation.

## Key facts

- **NIH application ID:** 9970221
- **Project number:** 5R01DK120444-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Holger A. Russ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,420
- **Award type:** 5
- **Project period:** 2018-09-30 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970221

## Citation

> US National Institutes of Health, RePORTER application 9970221, Improving human pluripotent stem cell derived beta cell transplantation using genetic lineage tracing. (5R01DK120444-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970221. Licensed CC0.

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