# HIGH-RESOLUTION CHARACTERIZATION OF HUMAN DUCTAL PROGENITOR CELLS AND THEIR REGENERATION POTENTIAL

> **NIH NIH U01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $230,250

## Abstract

PROJECT SUMMARY
 The existence of progenitor cells in the non-endocrine compartments of the adult human pancreas
(ductal/acinar) has been hypothesized for decades, but their characterization has proven elusive. We
hypothesized that BMP-7 (a TGF-β ligand with dual TGF-β inhibition/BMP activation abilities) would induce the
proliferation of putative resident pancreatic progenitors. Indeed, exposure of human non-endocrine tissue
(hNEPT) to BMP-7 led to the formation and growth of colonies that, upon BMP-7 withdrawal, differentiated into
multiple pancreatic tissues. In vitro lineage tracing showed that BMP-7-responsive cells in hNEPT express
pancreatic duodenal homeobox (PDX1) and the BMP receptor 1A (also known as activin-like kinase-3, ALK3).
However, they were negative for insulin and other mature pancreatic markers, including carbonic anhydrase II
(CAII, previosuly considered a panductal marker). These cells can be sorted using ALK3 (bright fraction) and
the purinergic receptor P2Y1 (P2RY1), a surrogate surface marker for PDX1+ cells. Sorted P2RY1+/ALK3bright+
cells can be cultured in defined conditions. They respond to BMP-7 by expanding as PDX1+/NKX6.1+
progenitor-like colonies, and differentiate into multiple pancreatic cell types (including β-like cells) upon BMP-7
withdrawal. qRT-PCR and RNAseq further confirmed the BMP-7-induced transcriptional activation of Inhibition
of Differentiation (ID) proteins associated with progenitor cell proliferation, as well as the upregulation of
markers of all adult pancreatic lineages following BMP-7 withdrawal. We have further identified the anatomic
location of PDX1+/ALK3bright+ cells in the human pancreas within the major pancreatic ducts and pancreatic duct
glands.
 Our goal is to dissect the role and biology of these cells in the context of pancreatic tissue
plasticity/regeneration, both in health and type 1 diabetes (T1D). Based on our data, we hypothesize that only
specific subsets of ductal cells respond to ALK3 agonism by proliferating and, upon interruption of this
stimulation, differentiating along multiple adult endocrine and exocrine pancreatic lineages. To test this
hypothesis and its multiple ramifications, we will pursue the following specific aims: (1) High-resolution
characterization of pancreatic ductal sub-populations obtained from healthy and T1D donors by single-cell
RNAseq as well as mass spectrometry-based label-free proteomics. In this context, we will also characterize
other potentially supportive cells in the progenitor cell niche, including those at the ductal stroma that may have
roles in proliferation/migration/differentiation of epithelial progenitors. (2) Dynamic imaging and characterization
of regeneration phenomena using virally-transduced reporter systems in live human pancreatic slice cultures.
(3) Characterization and quantification of progenitor cells in healthy controls and T1D samples representative
of various stages of the disease. (4) Determination of the in vivo re...

## Key facts

- **NIH application ID:** 10186697
- **Project number:** 5U01DK120393-03
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Juan Dominguez-Bendala
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $230,250
- **Award type:** 5
- **Project period:** 2018-09-25 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186697

## Citation

> US National Institutes of Health, RePORTER application 10186697, HIGH-RESOLUTION CHARACTERIZATION OF HUMAN DUCTAL PROGENITOR CELLS AND THEIR REGENERATION POTENTIAL (5U01DK120393-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10186697. Licensed CC0.

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