title: Mesodermal ALK5 controls lung myofibroblast versus lipofibroblast cell fate.
abstract: BACKGROUND
  Epithelial-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.
  
  
  RESULTS
  Targeted 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 αSMA(pos) 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 αSMA(pos) versus lipofibroblast cell populations during lung development.
  
  
  CONCLUSIONS
  ALK5-mediated TGFβ signaling controls an early pathway that regulates the commitment and differentiation of αSMA(pos) versus LIF cell lineages during lung development.
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.
authors.forename: Aimin
authors.initials: A
authors.lastname: Li
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.
authors.forename: Shudong
authors.initials: S
authors.lastname: Ma
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Smith
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.
authors.forename: Matt K
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.|Hastings Center for Pulmonary Research, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.
authors.forename: Zea
authors.initials: Z
authors.lastname: Borok
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.|Excellence Cluster Cardio Pulmonary System, University Justus Liebig Giessen, Giessen, 39352, Germany.|Institute of Fundamental Medicine and Biology, Kazan Federal University, Kremlevskaya St 18, Kazan, 420008, Russia.
authors.forename: Saverio
authors.initials: S
authors.lastname: Bellusci
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.
authors.forename: Changgong
authors.initials: C
authors.lastname: Li
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA. minoo@usc.edu.|Hastings Center for Pulmonary Research, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA. minoo@usc.edu.
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D008168:Lung / Q000002:abnormalities / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D008648:Mesoderm / Q000002:abnormalities / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000002:abnormalities / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C484557:Ebfaz protein, mouse; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse
keywords: Lipofibroblast; Lung development; Mesoderm; Myofibroblast; Pdgfrα; Pparβ; Zfp423