# Systematic unlocking of airway stem cell differentiation program

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $200,660

## Abstract

Project Summary
Adult stem cells have the ability to turn into any cell type in their organ. Guiding their
differentiation to specific cell types holds great promise in modeling the genetic underpinnings of
disease and providing regenerative therapies. This differentiation occurs like a progressively
branching tree, as cells are coaxed by a sequence and combination of signals into the many
progeny cell types. Yet, we currently have a patchy understanding of this differentiation tree and
as a result cannot make most cell types from adult stem cells. Building this stem cell
differentiation tree by discovering what signals guide cells along each branch would unlock the
ability to produce a vast number of cell types in a dish that are currently inaccessible or
inefficient to derive.
We have developed a new technology that promises to transform our ability to map stem cell
trees and achieve new clinically valuable differentiated cell types. The key to this technology is a
method to introduce barcode tags into hundreds of cell populations at a time that we have
guided to sample all possible branches of a particular step of stem cell differentiation. We use a
high-throughput technology called single cell RNA sequencing to read out what each of
thousands of cells turned into, using the barcode tag to connect that fate to the sequence and
combination of signals that gave rise to it. We can then create a map of that particular step that
reveals the optimal sequence and combination of signals needed to turn adult stem cells into
many types of cells, all from a single experiment.
In this proposal, we will focus on developing our exhaustive profiling approach using adult
airway stem cells from humans and mice as our model system. Airway cell types have high
clinical utility in modeling and providing regenerative therapy for diseases such as Cystic
Fibrosis, asthma, bronchitis, and chronic obstructive pulmonary disease. In Aim 1 of this project,
we will optimize and explore the resolution of our barcoding technology and will develop
computational analysis and visualization tools to make sense of the data. In Aim 2, we will focus
our efforts on differentiating airway stem cells to the mature cell types in the airway, which are
currently inaccessible to study. This project promises to expedite stem cell disease modeling
and regenerative approaches.

## Key facts

- **NIH application ID:** 9849827
- **Project number:** 5R21OD025309-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Richard I Sherwood
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $200,660
- **Award type:** 5
- **Project period:** 2019-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849827

## Citation

> US National Institutes of Health, RePORTER application 9849827, Systematic unlocking of airway stem cell differentiation program (5R21OD025309-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9849827. Licensed CC0.

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