# Engraftment of PSC-Derived Lung Lineages to Reconstitute in vivo Airway and Alveolar Stem Cell Function

> **NIH NIH P01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $526,492

## Abstract

SUMMARY: PROJECT 1
A variety of devastating lung diseases are initiated by dysfunction or damage to the diverse epithelia of the
proximal airways or distal alveoli. While these tissues are composed of many epithelial cell types, the vast
majority are continually replenished by the stem/progenitor cells of each compartment: airway basal cells or
alveolar epithelial type 2 cells (AT2s), respectively. Implicit in this biology is recognition that durably
reconstituting these stem cell compartments with exogenously-derived normal cells might result in life-long
replenishment of their many differentiated cell derivatives. In this proposal we develop approaches for
reconstituting endogenous airway and alveolar stem/progenitor cell compartments by transplanting engineered
lung epithelial progenitors derived in culture from pluripotent stem cells. We present methods for the directed
differentiation of pluripotent stem cells into airway basal cells (iBCs) and distal alveolar bud tip progenitors
(iTPs) followed by intra-airway instillation of these cells into recipient mice. We test the hypothesis that iBCs or
iTPs can be engrafted in vivo into the stem cell compartments of airways and alveoli, respectively, thus durably
reconstituting epithelial function and providing future treatments for genetic lung diseases that result from
airway or alveolar dysfunction. In aim 1 we test the capacity of engrafted iTPs to functionally rescue alveolar
epithelial cell dysfunction in vivo in 2 genetic mouse models that recapitulate distal human lung diseases. In
Aim 2 we develop a novel in vivo “competitive lung repopulation assay” able to determine which candidate
stem/progenitor cell phenotype is best able to reconstitute in vivo airway epithelial stem cell function, and we
apply this assay to functionally test the hypothesis that the subset of PSC-derived basal cells expressing the
BMP antagonist, Nbl1, possesses more potent reconstitution capacity than other iBCs, as a result of
suppressed BMP signaling activity. Finally in aim 3, we evaluate the functional capacity of engrafted mouse
iBCs to rescue motile ciliary function in a mouse model of primary ciliary dyskinesia (PCD), and we test the
human translational potential of iBCs using normal or PCD patient-specific human iPSC lines that will be
gene-corrected, differentiated into iBCs, and xenogeneically transplanted into NSG mice.

## Key facts

- **NIH application ID:** 10768965
- **Project number:** 1P01HL170952-01
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Darrell N. Kotton
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $526,492
- **Award type:** 1
- **Project period:** 2024-03-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10768965

## Citation

> US National Institutes of Health, RePORTER application 10768965, Engraftment of PSC-Derived Lung Lineages to Reconstitute in vivo Airway and Alveolar Stem Cell Function (1P01HL170952-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10768965. Licensed CC0.

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