# Mechanical Control of Smooth Muscle Differentiation During Mouse Lung Branching

> **NIH NIH F30** · PRINCETON UNIVERSITY · 2020 · $50,520

## Abstract

Project Summary
Diseases arising from lung developmental disorders are widespread and often deadly. Our abilities to develop
therapies for these disorders or to engineer artificial lungs in the laboratory are limited by our incomplete
understanding of how the complex and stereotyped architecture of the lung develops. The smooth muscle that
surrounds the airways (airway smooth muscle, ASM) has recently been shown to play a role in the bifurcation
of epithelial buds, an important step in the development of the branched structure of the lung. To help drive
bifurcation, ASM must differentiate from the mesenchyme surrounding epithelial bud tips in a precise and
asymmetric pattern, but the mechanisms controlling this spatial pattern of differentiation are poorly understood.
Signaling molecules, like sonic hedgehog and bone morphogenic protein-4, and mechanical cues, like the
pressure inside the developing airway, are known to increase smooth muscle differentiation. I hypothesize that
the transpulmonary pressure causes a distribution of mechanical stress in the mesenchyme that specifies the
spatial pattern of smooth muscle differentiation around bud tips. Confirming this hypothesis would support a
model in which mesenchymal cells around bud tips are primed to be potential ASM precursors by signaling
molecules, but the precise pattern of mechanical stress determines which potential precursors differentiate into
ASM. To test the hypothesis, I will determine whether stretch can induce airway mesenchymal cells to adopt
an ASM phenotype in culture (Aim 1). I will then analyze RNA sequencing data of lungs cultured under high
and low pressure to understand potential molecular mechanisms by which transpulmonary pressure is
transduced into a morphogenetic signal (Aim 2). Finally, I will use computational models of lung volumetric
reconstructions to determine whether bud epithelial geometry and transpulmonary pressure are sufficient to
cause stress distributions in the mesenchyme that predict the pattern of ASM differentiation at bud tips (Aim 3).
Successfully completing these aims will deepen our understanding of how ASM differentiates and how
transpulmonary pressure affects lung development. This knowledge could inform future research into therapies
that modulate ASM differentiation to treat congenital lung diseases and future efforts to direct the differentiation
of smooth muscle in tissue-engineered lungs.

## Key facts

- **NIH application ID:** 9991896
- **Project number:** 5F30HL139039-04
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Jacob Michael Jaslove
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991896

## Citation

> US National Institutes of Health, RePORTER application 9991896, Mechanical Control of Smooth Muscle Differentiation During Mouse Lung Branching (5F30HL139039-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9991896. Licensed CC0.

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