# Mechanisms governing the physiologic regulation of cell fate: Hypoxia-induced differentiation of neuroendocrine cells from stem cells

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $615,150

## Abstract

Project Summary
Decades of studies have suggested that pulmonary neuroendocrine cells perform multiple functions including
oxygen sensing, mechanotransduction, regulation of pulmonary blood flow, regulation of airway diameter,
chemosensation, and most recently the regulation of inflammation. Additionally, increased NE cell abundance
has been documented in several respiratory diseases including pulmonary hypertension, neuroendocrine
hyperplasia of infancy (NEHI), sudden infant death syndrome, asthma, bronchopulmonary dysplasia, congenital
pneumonia, cystic fibrosis, COPD, and congenital diaphragmatic hernia. However, it remains unclear whether
these NE cells are a cause of disease or whether they represent a protective regenerative response to injury.
Prior research has largely been conducted on neuroendocrine bodies (NEBs) which are clustered NE cells
occurring at airway branch points. Herein, we focus on the role of solitary neuroendocrine cells which may
represent a distinct population of NE cells that, like NEBs, are increased in diseases associated with NE cell
hyperplasia.
We provide evidence that hypoxia, frequently encountered in severe lung disease, stimulates neuroendocrine
differentiation as a protective response. Using lineage tracing, we will test whether hypoxia-induced NE cells are
plastic and capable of differentiating into other cell types following injury. We will also assess whether NE cell
hyperplasia is reversible following the restoration of normoxia using a novel airway explant system coupled to
long term 2 photon imaging. We hypothesize that hypoxia-dependent neuroendocrine differentiation is mediated
through the HIF signaling cascade localized to the basal stem cell compartment, and will test whether airway
stem cells possess this oxygen sensing machinery which in turn is responsible for triggering the onset of NE cell
differentiation. We will further examine whether HIF signaling independent of hypoxia is required for the normal
maintenance of tissue resident NE cells. Using genetic cell ablation, we will assess the functional relevance of
hypoxia-induced neuroendocrine differentiation in injury models. We will then test whether the abundant peptide
CGRP is a protective neuropeptide that ameliorates hypoxia-induced epithelial injury by promoting progenitor
cell proliferation and preventing cell death. To address NE cell heterogeneity, we have identified Tuj1 as an
epithelial marker of solitary NE cells that is absent in NEBs. We show that hyperplastic NE cells in
Neuroendocrine Hyperplasia of Infancy (NEHI) are positive for this marker. Lastly, we will establish a system for
studying human primary airway stem cell differentiation into Tuj1+ solitary NE cells following hypoxia.

## Key facts

- **NIH application ID:** 9971676
- **Project number:** 1R01HL148351-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JAYARAJ RAJAGOPAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $615,150
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971676

## Citation

> US National Institutes of Health, RePORTER application 9971676, Mechanisms governing the physiologic regulation of cell fate: Hypoxia-induced differentiation of neuroendocrine cells from stem cells (1R01HL148351-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9971676. Licensed CC0.

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