# Reprogramming of type 2 alveolar epithelial cells in idiopathic pulmonary fibrosis and regulation by TGFb1.

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $72,630

## Abstract

Idiopathic Pulmonary Fibrosis (IPF) is the most common fibrotic interstitial lung disease among 
adults. The cause of IPF is not fully understood, and it is frequently progressive, often leading 
to death within several years of diagnosis. In IPF, there is loss of alveolar epithelial cells, 
including type 1 cells (AEC1s), which line the alveolar airspace surface, and type 2 (AEC2s), which 
secrete surfactant, self-renew, and give rise to AEC1s and development of honeycomb cysts. These 
cysts are lined by "bronchiolized" epithelium, so-called because of expression of airway and 
secretory cell markers such as p63, KRT5, KRT17, and MUC5B. The origin of the cells lining these 
cysts is not understood, but have generally been thought to be the result of migration of airway 
epithelial cells (basal and/or club), in a failed attempt at alveolar repair. Recent single-cell 
RNA (sc-RNA) sequencing studies have uncovered widespread AEC2 and other epithelial cell 
abnormalities in end-stage IPF tissue, such as intermediate/transitional cell states and ectopic 
expression of genes associated with airway cells (such as KRT5+ AEC2s). Our lab has recently shown 
that AEC2s are capable of reprogramming into KRT5+ basal-cell like cells in in vitro organoid 
cultures. These suggest a new hypothesis that the bronchiolized epithelium lining honeycomb cysts 
may actually be derived from reprogrammed AEC2s. This study seeks to characterize whether the 
epithelial abnormalities present in end-stage IPF tissue are also present earlier in the IPF 
disease course and to determine the role of TGFβ1 in regulating the aforementioned reprogramming. 
Samples from patients undergoing surgical biopsy for the purpose of clinical diagnosis will be 
analyzed by sc-RNA sequencing, to characterize the AEC2 and other epithelial cell populations and 
reconstruct estimated lineages, especially surrounding the induction of the basal-cell 
differentiation master- regulator Sox2 within AEC2s. These samples will be compared to normal and 
end-stage IPF tissue, in order to test the hypothesis that AEC2 reprogramming is an early feature 
of IPF. In addition, diagnostic biopsy samples will be obtained from patients who took 
epigallocatechin gallate (EGCG) for two weeks prior to biopsy. EGCG is a mesenchyme-specific 
inhibitor of TGFβ signaling under study in humans and will therefore allow us to examine the 
hypothesis that AEC2 reprogramming abnormalities seen in diagnostic biopsies can be reversed by 
TGFβ blockade. Finally, organoid co-cultures and precision-cut lung slices cultures will be used to 
examine the contribution of important signaling pathways, such as TGFβ, Wnt, and Notch, in driving 
AEC2 reprograming towards a SPC-/KRT5+ basal-cell like state. Knowledge of the mechanisms driving 
AEC2 reprograming in IPF may provide fundamental insight into the cause of this disorder and 
contribute to the development of targeted therapies for this incurable and frequently fatal 
disease. ...

## Key facts

- **NIH application ID:** 10140871
- **Project number:** 1F32HL156356-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Max Louis Cohen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $72,630
- **Award type:** 1
- **Project period:** 2021-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140871

## Citation

> US National Institutes of Health, RePORTER application 10140871, Reprogramming of type 2 alveolar epithelial cells in idiopathic pulmonary fibrosis and regulation by TGFb1. (1F32HL156356-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10140871. Licensed CC0.

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