# Sources and Regulation of Epithelial Stem/Progenitor Cells in Alveolar Regeneration

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $157,680

## Abstract

PROJECT SUMMARY/ABSTRACT
Recapitulation of normal lung function following a severe acute injury implies an inherent regenerative ability of
the lung. However, sources and relative regenerative capacities of lung epithelial stem/progenitor cells remain
unclear, especially in the human lung. Depending on the injury type and severity, several distinct progenitors
are activated and respond by proliferating and differentiating to aid in near complete recovery. Both airway and
alveolar stem/progenitor cells are activated and contribute to alveolar repair following severe injuries such as
influenza or bleomycin. To this end, recent studies from our lab have uncovered an airway epithelial progenitor
cell marked by elevated levels of Major Histocompatibility Complex (MHC) Class I protein, H2-K1. Despite
having a transcriptome highly similar to the mature club cells, the H2-K1high progenitors, unlike mature club
cells, selectively proliferate post injury and aid in improved oxygenation in injured mice after orthotopic
transplantation. However, mechanisms underlying early and selective activation of these progenitors remain
unknown. In addition, there are several more aspects of distal lung regeneration that are yet unclear. The chief
among them is whether the distal epithelial progenitor hierarchy that we observe in mouse lungs is maintained
in distal human lungs. The distal human lung airways have a higher proportion of basal cells and have more
heterogeneous secretory cell populations than the mouse airway epithelium. Furthermore, the human type 2
alveolar epithelial cells (AEC2s) have remarkable in vitro proliferative and regenerative capacity. Therefore,
there is an unmet need to understand the identity and regulation of distal human airway and alveolar
progenitors. To this end, our preliminary data show that a distal human secretory subpopulation that is
analogous to the mouse H2-K1high club-like progenitors can give rise to AEC2s in vitro. Conversely, we have
uncovered a novel and unexpected ability of mature human AEC2s to differentiate towards airway lineages in
vitro and in vivo, suggesting at least two sources of distal epithelial regeneration in the human. Therefore, it is
critical to clarify the identity and characteristics of both distal mouse and human epithelial progenitors primed
for alveolar repair. This proposal seeks to answer these questions through three aims: 1) Determine the
mechanisms underlying activation of H2-K1high progenitors in alveolar repair. 2) To identify distal secretory cells
as a source of alveolar cells post injury in the distal human lung. 3) Determine whether a subpopulation of
mature human AEC2s has reversible bi-directional potential to differentiate into alveolar basal cells. These
aims will utilize single cell mRNA and open chromatin sequencing, in vitro and in vivo manipulation of proposed
signaling pathways, and orthotopic transplantation of progenitor cells to clarify the epithelial stem/progenitor
cell hierar...

## Key facts

- **NIH application ID:** 10105222
- **Project number:** 1K99HL155785-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jaymin J Kathiriya
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $157,680
- **Award type:** 1
- **Project period:** 2021-04-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105222

## Citation

> US National Institutes of Health, RePORTER application 10105222, Sources and Regulation of Epithelial Stem/Progenitor Cells in Alveolar Regeneration (1K99HL155785-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10105222. Licensed CC0.

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