WNT5a-ROR Signaling Is Essential for Alveologenesis

被引：32

作者：

Li, Changgong ^{[1
,2
]}

Smith, Susan M. ^{[1
,2
]}

Peinado, Neil ^{[1
,2
]}

Gao, Feng ^{[1
,2
]}

Li, Wei ^{[1
,2
]}

Lee, Matt K. ^{[1
,2
]}

Zhou, Beiyun ^{[3
,4
]}

Bellusci, Saverio ^{[1
,2
,5
]}

Pryhuber, Gloria S. ^{[6
]}

Ho, Hsin-Yi Henry ^{[7
]}

Borok, Zea ^{[3
,4
]}

Minoo, Parviz ^{[1
,2
]}

机构：

[1] LAC USC Med Ctr, Dept Pediat, Div Neonatol, Los Angeles, CA 90033 USA

[2] Childrens Hosp, Los Angeles, CA 90033 USA

[3] Keck Sch Med USC, Dept Med, Hastings Ctr Pulm Res, Los Angeles, CA 90033 USA

[4] Keck Sch Med USC, Dept Med, Div Pulm Crit Care & Sleep Med, Los Angeles, CA 90033 USA

[5] Justus Liebig Univ Giessen, German Ctr Lung Res DZL, UGMLC, D-35390 Giessen, Germany

[6] Univ Rochester, Med Ctr, Dept Pediat, Div Neonatol, Rochester, NY 14642 USA

[7] Univ Calif Davis, Sch Med, Dept Cell Biol & Human Anat, Davis, CA 95616 USA

来源：

CELLS | 2020年 / 9卷 / 02期

基金：

美国国家卫生研究院;

关键词：

WNT5a; ROR; lung; alveologenesis; secondary crest myofibroblast; migration; LUNG; CELLS; RECEPTOR; DIFFERENTIATION; MYOFIBROBLASTS; PROGENITORS; ACTIVATION; HYPEROXIA; PATHWAY; BETA;

D O I：

10.3390/cells9020384

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

WNT5a is a mainly "non-canonical" WNT ligand whose dysregulation is observed in lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma. Germline deletion of Wnt5a disrupts embryonic lung development. However, the temporal-specific function of WNT5a remains unknown. In this study, we generated a conditional loss-of-function mouse model (Wnt5a(CAG)) and examined the specific role of Wnt5a during the saccular and alveolar phases of lung development. The lack of Wnt5a in the saccular phase blocked distal airway expansion and attenuated differentiation of endothelial and alveolar epithelial type I (AT1) cells and myofibroblasts. Postnatal Wnt5a inactivation disrupted alveologenesis, producing a phenotype resembling human bronchopulmonary dysplasia (BPD). Mutant lungs showed hypoalveolization, but endothelial and epithelial differentiation was unaffected. The major impact of Wnt5a inactivation on alveologenesis was on myofibroblast differentiation and migration, with reduced expression of key regulatory genes. These findings were validated in vitro using isolated lung fibroblasts. Conditional inactivation of the WNT5a receptors Ror1 and Ror2 in alveolar myofibroblasts recapitulated the Wnt5a(CAG) phenotype, demonstrating that myofibroblast defects are the major cause of arrested alveologenesis in Wnt5a(CAG) lungs. Finally, we show that WNT5a is reduced in human BPD lung samples, indicating the clinical relevance and potential role for WNT5a in pathogenesis of BPD.

引用

页数：18

共 42 条

[41]

Yamaguchi TP, 1999, DEVELOPMENT, V126, P1211

[42] Loss of Endothelium-Derived Wnt5a Is Associated With Reduced Pericyte Recruitment and Small Vessel Loss in Pulmonary Arterial Hypertension [J].

Yuan, Ke ;

Shamskhou, Elya A. ;

Orcholski, Mark E. ;

Nathan, Abinaya ;

Reddy, Sushma ;

Honda, Hiroaki ;

Mani, Vigneshwaran ;

Zeng, Yitian ;

Ozen, Mehmet O. ;

Wang, Lingli ;

Demirci, Utkan ;

Tian, Wen ;

Nicolls, Mark R. ;

Perez, Vinicio A. de Jesus .

CIRCULATION, 2019, 139 (14) :1710-1724

← 1 2 3 4 5 →