# Pluripotent stem cell-based modeling of cigarette smoke injury

> **NIH NIH F30** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $51,752

## Abstract

Abstract
Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality in the US and
worldwide. COPD encompasses disease of the airways as well as alveolar epithelial destruction, but the
response of the alveolar epithelium to cigarette smoke has been much less well-studied than that of the airway
epithelium. This is a result of poor accessibility of alveolar epithelial cells compared to airway cells, the latter of
which can be obtained by bronchoscopy and brushing, and a lack of in vitro culture systems that can support the
study of cigarette smoke exposure of the human alveolar epithelium. Primary human alveolar epithelial type 2
cells (AEC2s) can be cultured in three-dimensional organoids, but are difficult to culture at air-liquid interface
(ALI) due to their tendency to transdifferentiate and senesce in culture. This project proposes the establishment
of a novel model system to interrogate alveolar epithelial injury in response to cigarette smoke based on human
induced pluripotent stem cells (iPSCs) differentiated to alveolar epithelial type 2 cells (iAEC2s) and cultured at
ALI. We hypothesize that iAEC2s exhibit a distinct molecular response to cigarette smoke injury relative to
syngeneic airway epithelial cells and that AATD alveolar epithelial cells are intrinsically more susceptible to
cigarette smoke injury than their wild type counterparts. In aim 1, we will define the iAEC2 transcriptomic
response to cigarette smoke injury. We will generate iAEC2s and expose them to gas-phase cigarette smoke at
ALI. The response will be assessed by single-cell RNA sequencing of iAEC2 ALI cultures with and without
cigarette smoke exposure, in comparison to the response of airway epithelial ALI cultures from the same patient.
This will result in the elucidation of an alveolar epithelial-specific smoke response transcriptional signature when
compared to airway epithelial cells from the same genetic background. In aim 2, we will extend our model to the
only monogenic form of COPD, alpha-1 antitrypsin deficiency (AATD). We will utilize AATD-specific iPSCs that
are homozygous for the polymerizing form of AAT, a genotype known as “PiZZ”, alongside their CRISPR-edited
wild type isogenic counterparts (“PiMM”). We hypothesize that alpha-1 antitrypsin (AAT) is upregulated in the
alveolar epithelium in response to cigarette smoke, and that PiZZ iAEC2s exhibit increased susceptibility to
cigarette smoke compared to isogenic PiMM iAEC2s due to gain-of-function toxicity of the Z form of AAT that
manifests as activation of the unfolded protein response and ER stress pathways. In aim 3, we will establish a
PiZZ-specific transcriptomic disease signature using patient distal lung tissue. We will leverage an existing
microarray dataset from PiZZ and PiMM COPD patient lung parenchymal tissue. Importantly, all patients in this
study have a history of smoke exposure. We hypothesize that transcriptomic differences between the disease
states wi...

## Key facts

- **NIH application ID:** 10406380
- **Project number:** 5F30HL147426-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Kristine Abo
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406380

## Citation

> US National Institutes of Health, RePORTER application 10406380, Pluripotent stem cell-based modeling of cigarette smoke injury (5F30HL147426-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10406380. Licensed CC0.

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