# Pathogenesis of Airway Stem Cell Abnormalities in Obliterative Bronchiolitis

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2022 · $589,618

## Abstract

Project Summary:
End-stage lung diseases are a major cause of morbidity and mortality worldwide. Lung transplantation is an
excellent treatment option for patients with this condition, yet 50% of recipients die within five years due to the
development of obliterative bronchiolitis (OB) in the allograft. Epithelial stem cell depletion is suggested to
contribute to the development of OB; however, there is little research being performed to test this hypothesis,
primarily due to the lack of animal models for OB that develop allograft pathology resembling that seen in
humans. We recently developed a novel orthotopic lung transplant model in the ferret that models human OB
very well. Using this model, we have shown for the first time in ferret and human allografts that the number of
clonogenic K5+p63+ basal stem cells (BSCs) progressively declines in proximal and distal airways of the allograft
as the severity of OB increases. Additionally, our research is the first to demonstrate that the proximal airway
submucosal gland (SMG), a facultative niche for BSCs in the surface airway epithelium (SAE), is an early target
of immune destruction in human and ferret allograft airways. In mice, the SMG stem cell niche serves only the
trachea; however, in larger mammals such as humans and ferrets, SMGs are present throughout the
cartilaginous airways. Using lineage tracing, we have shown that the myoepithelial cells (MECs) of SMGs are
precursors of multipotent K5+p63+ BSCs in the SAE. During the development of OB, the destruction of SMG
stem cell niches in the allograft occurs simultaneously with phenotypic and functional changes to multipotent
K5+p63+ BSCs in the SAE. We hypothesize that destruction of the denervated SMG in the allograft, and thus
depletion of MECs, leads to a decline in multipotent K5+p63+ BSCs in the SAE, and to increases in committed
multipotent (K5+p63+K14+), bipotent (K5+K14+, p63+K14+) and unipotent (K14+) basal cells, all of which have a
reduced capacity for self-renewal. The objective of the proposed research is to determine the functional
significance of the phenotypic changes in the MECS and the lineage-committed basal cells and how denervation
of the SMG alters Wnt signaling (Lef-1/TCF1) required for both the maintenance of the SMG stem cell niche and
lineage commitment of glandular MECs to SAE BSCs in the setting of injury. Additionally, a major preclinical
objective of this proposal is to elucidate the ability of stem cells to engraft into a transplanted lung and repair
injury, thus laying the foundation for the development of stem cell therapy to delay or prevent OB in lung
allografts. We will achieve these objectives by addressing the following specific aims: 1) Determine how
destruction of the SMG stem cell niche contributes to depletion of K5+p63+ BSCs. 2) Identify consequences of
lung denervation on airway stem cells and their niches. 3) Determine the potential for airway stem cell
transplantation in preventing or delaying OB. ...

## Key facts

- **NIH application ID:** 10372103
- **Project number:** 5R01HL136370-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Kalpaj Rajnikant Parekh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $589,618
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372103

## Citation

> US National Institutes of Health, RePORTER application 10372103, Pathogenesis of Airway Stem Cell Abnormalities in Obliterative Bronchiolitis (5R01HL136370-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10372103. Licensed CC0.

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