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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2025-07-01
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| author | Simin Jiang Dian Chen Liangliang Tian Zihang Pan Huanyu Long Lanhe Chu Weijing Kong Qiyang Yao Xiaojing Ma Yun Zhao Kai Wang Yahong Chen |
| author_facet | Simin Jiang Dian Chen Liangliang Tian Zihang Pan Huanyu Long Lanhe Chu Weijing Kong Qiyang Yao Xiaojing Ma Yun Zhao Kai Wang Yahong Chen |
| author_sort | Simin Jiang |
| collection | DOAJ |
| description | <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. |
| format | Article |
| id | doaj-art-d2ec42fa6bfd4f08bb4cf6ee63a4778e |
| institution | DOAJ |
| issn | 2227-9059 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
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| series | Biomedicines |
| spelling | doaj-art-d2ec42fa6bfd4f08bb4cf6ee63a4778e2025-08-20T03:02:48ZengMDPI AGBiomedicines2227-90592025-07-01137162310.3390/biomedicines13071623Role of BMPR2 Mutation in Lung Organoid DifferentiationSimin Jiang0Dian Chen1Liangliang Tian2Zihang Pan3Huanyu Long4Lanhe Chu5Weijing Kong6Qiyang Yao7Xiaojing Ma8Yun Zhao9Kai Wang10Yahong Chen11Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, ChinaDepartment of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, ChinaBeijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Clinical Stem Cell Research Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing 100191, ChinaBeijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Clinical Stem Cell Research Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing 100191, ChinaDepartment of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, ChinaDepartment of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, ChinaBeijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Clinical Stem Cell Research Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing 100191, ChinaBeijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Clinical Stem Cell Research Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing 100191, ChinaBeijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Clinical Stem Cell Research Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing 100191, ChinaBeijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Clinical Stem Cell Research Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing 100191, ChinaBeijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Clinical Stem Cell Research Center, State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University, Beijing 100191, ChinaDepartment of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China<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.https://www.mdpi.com/2227-9059/13/7/1623induced pluripotent stem cellairway organoidalveolar organoidpulmonary hypertensionBMPR2 |
| spellingShingle | Simin Jiang Dian Chen Liangliang Tian Zihang Pan Huanyu Long Lanhe Chu Weijing Kong Qiyang Yao Xiaojing Ma Yun Zhao Kai Wang Yahong Chen Role of BMPR2 Mutation in Lung Organoid Differentiation Biomedicines induced pluripotent stem cell airway organoid alveolar organoid pulmonary hypertension BMPR2 |
| title | Role of BMPR2 Mutation in Lung Organoid Differentiation |
| title_full | Role of BMPR2 Mutation in Lung Organoid Differentiation |
| title_fullStr | Role of BMPR2 Mutation in Lung Organoid Differentiation |
| title_full_unstemmed | Role of BMPR2 Mutation in Lung Organoid Differentiation |
| title_short | Role of BMPR2 Mutation in Lung Organoid Differentiation |
| title_sort | role of bmpr2 mutation in lung organoid differentiation |
| topic | induced pluripotent stem cell airway organoid alveolar organoid pulmonary hypertension BMPR2 |
| url | https://www.mdpi.com/2227-9059/13/7/1623 |
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