# A Unified Map of Airway Interactions: Secretome and Mechanotransduction Loops from Development to Disease

## TL;DR

This paper maps how airway cells interact through mechanical and chemical signals, offering new ways to treat diseases like asthma and COPD.

## Contribution

The first unified model of bidirectional secretome–mechanotransduction feedback in airways, revealing cellular roles and YAP/TAZ signaling loops.

## Key findings

- Epithelial cells act as environmental activators, smooth muscle as mechanical actuators, and chondrocytes as calcium-dependent regulators in airway homeostasis.
- YAP/TAZ signaling and TRPV4 channels link matrix stiffness to cytokine release, forming a closed-loop feedback system.
- Diseases like asthma and COPD involve pathological stiffness traps driven by YAP/TAZ-mediated hypercontractility and inflammation.

## Abstract

What are the main findings?

First closed-loop model mapping bidirectional secretome–mechanotransduction feedback in airways, where mechanical cues trigger cytokine release and vice versa through YAP/TAZ signalling.

A novel cellular specialization framework defining epithelial cells as environmental activators, smooth muscle as mechanical actuators, and chondrocytes as calcium-dependent regulators in airway homeostasis.

What is the implication of the main finding?

Enables targeted therapy of airway diseases by interrupting pathological feedback loops (e.g., YAP/TAZ-mediated feed-forward stiffness traps in asthma/COPD).

Provides a system-based framework for airway tissue engineering by incorporating mechanotransduction feedback loops essential for functional airway constructs.

Human airways maintain homeostasis through intricate cellular interactomes combining secretome-mediated signalling and mechanotransduction feedback loops. This review presents the first unified map of bidirectional mechanobiology–secretome interactions between airway epithelial cells (AECs), smooth muscle cells (ASMCs), and chondrocytes. We unify a novel three-component regulatory architecture: epithelium functioning as environmental activators, smooth muscle as mechanical actuators, and cartilage as calcium-dependent regulators. Critical mechanotransduction pathways, particularly YAP/TAZ signalling and TRPV4 channels, directly couple matrix stiffness to cytokine release, creating a closed-loop feedback system. During development, ASM-driven FGF-10 signalling and peristaltic contractions orchestrate cartilage formation and epithelial differentiation through mechanically guided morphogenesis. In disease states, these homeostatic circuits become pathologically dysregulated; asthma and COPD exhibit feed-forward stiffness traps where increased matrix rigidity triggers YAP/TAZ-mediated hypercontractility, perpetuating further remodelling. Aberrant mechanotransduction drives smooth muscle hyperplasia, cartilage degradation, and epithelial dysfunction through sustained inflammatory cascades. This system-level understanding of airway cellular networks provides mechanistic frameworks for targeted therapeutic interventions and tissue engineering strategies that incorporate essential mechanobiological signalling requirements.