Mesodermal ALK5 controls lung myofibroblast versus lipofibroblast cell fate

BMC Biology

Research Article

Aimin Li¹  Susan M. Smith¹  Shudong Ma¹  Matt K. Lee¹  Ashley Fischer¹  Changgong Li¹  Saverio Bellusci²  Parviz Minoo³  Zea Borok⁴ 

[1] Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, 90033, Los Angeles, CA, USA;Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, 90033, Los Angeles, CA, USA;Excellence Cluster Cardio Pulmonary System, University Justus Liebig Giessen, 39352, Giessen, Germany;Institute of Fundamental Medicine and Biology, Kazan Federal University, Kremlevskaya St 18, 420008, Kazan, Russia;Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, 90033, Los Angeles, CA, USA;Hastings Center for Pulmonary Research, Keck School of Medicine of USC, 90033, Los Angeles, CA, USA;Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine of USC, 90033, Los Angeles, CA, USA;Hastings Center for Pulmonary Research, Keck School of Medicine of USC, 90033, Los Angeles, CA, USA;

关键词: Lipofibroblast;    Lung development;    Mesoderm;    Myofibroblast;    Pdgfrα;    Pparβ;    Zfp423;   

DOI  :  10.1186/s12915-016-0242-9

 received in 2015-10-14, accepted in 2016-02-26,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundEpithelial-mesenchymal cross talk is centerpiece in the development of many branched organs, including the lungs. The embryonic lung mesoderm provides instructional information not only for lung architectural development, but also for patterning, commitment and differentiation of its many highly specialized cell types. The mesoderm also serves as a reservoir of progenitors for generation of differentiated mesenchymal cell types that include αSMA-expressing fibroblasts, lipofibroblasts, endothelial cells and others. Transforming Growth Factor β (TGFβ) is a key signaling pathway in epithelial-mesenchymal cross talk. Using a cre-loxP approach we have elucidated the role of the TGFβ type I receptor tyrosine kinase, ALK5, in epithelial-mesenchymal cross talk during lung morphogenesis.ResultsTargeted early inactivation of Alk5 in mesodermal progenitors caused abnormal development and maturation of the lung that included reduced physical size of the sub-mesothelial mesoderm, an established source of specific mesodermal progenitors. Abrogation of mesodermal ALK5-mediated signaling also inhibited differentiation of cell populations in the epithelial and endothelial lineages. Importantly, Alk5 mutant lungs contained a reduced number of αSMApos cells and correspondingly increased lipofibroblasts. Elucidation of the underlying mechanisms revealed that through direct and indirect modulation of target signaling pathways and transcription factors, including PDGFRα, PPARγ, PRRX1, and ZFP423, ALK5-mediated TGFβ controls a process that regulates the commitment and differentiation of αSMApos versus lipofibroblast cell populations during lung development.ConclusionALK5-mediated TGFβ signaling controls an early pathway that regulates the commitment and differentiation of αSMApos versus LIF cell lineages during lung development.

【 授权许可】

CC BY   
© Li et al. 2016