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Myofibroblast contraction is essential for generating and regenerating the gas-exchange surface
Rongbo Li, Xiaoping Li, James Hagood, Min-Sheng Zhu, Xin Sun
Rongbo Li, Xiaoping Li, James Hagood, Min-Sheng Zhu, Xin Sun
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Myofibroblast contraction is essential for generating and regenerating the gas-exchange surface

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Abstract

A majority (~95%) of the gas-exchange surface area is generated through septa formation during alveologenesis. Disruption of this process leads to alveolar simplification and bronchopulmonary dysplasia (BPD), a prevalent disorder in premature infants. Although several models have been proposed, the mechanism of septa formation remains under debate. Here we show that inactivation of myosin light chain kinase (MLCK), a key factor required for myofibroblast contraction, disrupted septa formation, supporting the myofibroblast contraction model of alveologenesis. The alveoli simplification phenotype was accompanied by decreased yes-associated protein (YAP), a key effector in the Hippo mechanotransduction pathway. Expression of activated YAP in Mlck-mutant lungs led to partial reversal of alveolar simplification. In the adult, although Mlck inactivation did not lead to simplification, it prevented reseptation during compensatory regrowth in the pneumonectomy model. These findings revealed that myofibroblast reactivation and contraction are requisite steps toward regenerating the gas-exchange surface in diseases such as BPD and chronic obstructive pulmonary disease (COPD).

Authors

Rongbo Li, Xiaoping Li, James Hagood, Min-Sheng Zhu, Xin Sun

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Figure 1

Mlck inactivation leads to decreased myofibroblast contraction.

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Mlck inactivation leads to decreased myofibroblast contraction.
(A) Tim...
(A) Timeline of dox treatment and analysis of PdgfrartTA tetO-Cre RosamTmG pups for assessment of cell morphology. (B–G) Representative images of reconstructed 70-μm z-stacks of GFP pattern (green) in the alveolar region of lungs at P8 (B–D) and P15 (E–G). (H) Quantification for images in B–G. ****P = 0.0000005 (n = 20 cells per stage selected from 3 samples at P8 and 2 samples at P15). (I) Timeline of dox-mediated gene inactivation and analysis. (J–M) Representative immunofluorescence staining for MLCK (J and K) and p-MLC (L and M) in the alveolar region of control and mutant lungs at P8. (N) Western blot analysis of lung tissues using antibodies against MLCK, β-actin, p-MLC, and MLC. (O) Western blot quantification indicated that MLCK levels were decreased in mutant compared with control lungs at P8. ####P = 0.000033 (n = 3). (P) Western blot quantification indicated a decrease in the ratio of p-MLC to MLC levels in mutant compared with control lungs at P8. *P = 0.0133 (n = 3). (Q–V) Representative collagen gel images for no cells, control PdgfraGFP-positive myofibroblasts and mutant PdgfraGFP-positive myofibroblasts at 0 hours and 48 hours. (W) Quantification for images in Q–V. ††††P < 0.0001, control versus Tbx4-rtTA tetO-Cre Mlckfl/fl at 24 hours (n = 3); ††††P < 0.0001, control versus Tbx4-rtTA tetO-Cre Mlckfl/fl at 48 hours (n = 3); ††††P < 0.0001, control versus Tbx4-rtTA tetO-Cre Mlckfl/fl at 72 hours (n = 3). Scale bars: 50 μm (B, E, and J–M), 10 μm (C, D, F, and G), and 1 mm (Q–V). Data represent the mean ± SEM. P values were determined by 2-tailed Student’s t test (H, O, and P) and 2-way ANOVA with Tukey’s method to adjust for multiple comparisons (W).

Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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