Role of BMPR2 Mutation in Lung Organoid Differentiation

Role of BMPR2 Mutation in Lung Organoid Differentiation

<b>Background</b>: The bone morphogenetic protein (BMP) signaling pathway is essential for lung development. BMP4, a key regulator, binds to type I (BMPR1) and type II (BMPR2) receptors to initiate downstream signaling. While the inactivation of <i>Bmpr1a</i> and <i>Bmp...

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Main Authors: Simin Jiang, Dian Chen, Liangliang Tian, Zihang Pan, Huanyu Long, Lanhe Chu, Weijing Kong, Qiyang Yao, Xiaojing Ma, Yun Zhao, Kai Wang, Yahong Chen
Format: Article
Language:English
Published: MDPI AG 2025-07-01
Series:Biomedicines
Subjects:
induced pluripotent stem cell
airway organoid
alveolar organoid
pulmonary hypertension
BMPR2
Online Access:https://www.mdpi.com/2227-9059/13/7/1623
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Summary:<b>Background</b>: The bone morphogenetic protein (BMP) signaling pathway is essential for lung development. BMP4, a key regulator, binds to type I (BMPR1) and type II (BMPR2) receptors to initiate downstream signaling. While the inactivation of <i>Bmpr1a</i> and <i>Bmpr1b</i> leads to tracheoesophageal fistulae, the role of <i>BMPR2</i> mutations in lung epithelial development remains unclear. <b>Methods</b>: We generated induced pluripotent stem cells (iPSCs) from a patient carrying a BMPR2 mutation (c.631C>T), and gene-corrected isogenic controls were created using CRISPR/Cas9. These iPSCs were differentiated into lung progenitor cells and subsequently cultured to generate alveolar and airway organoids. The differentiation efficiency and epithelial lineage specification were assessed using immunofluorescence, flow cytometry, and qRT-PCR. <b>Results</b>: BMPR2-mutant iPSCs showed no impairment in forming a definitive or anterior foregut endoderm. However, a significant reduction in lung progenitor cell differentiation was observed. Further, while alveolar epithelial differentiation remained largely unaffected, airway organoids derived from BMPR2-mutant cells exhibited impaired goblet and ciliated cell development, with an increase in basal and club cell markers, indicating skewing toward undifferentiated airway cell populations. <b>Conclusions</b>: BMPR2 dysfunction selectively impairs late-stage lung progenitor specification and disrupts airway epithelial maturation, providing new insights into the developmental impacts of BMPR2 mutations.
ISSN:2227-9059

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