Evidence for the involvement of fibroblast growth factor 10 in lipofibroblast formation during embryonic lung development.
Lipid-containing alveolar interstitial fibroblasts (lipofibroblasts) are increasingly recognized as an important component of the epithelial stem cell niche in the rodent lung. Although lipofibroblasts were initially believed merely to assist type 2 alveolar epithelial cells in surfactant production during neonatal life, recent evidence suggests that these cells are indispensable for survival and growth of epithelial stem cells during adulthood. Despite increasing interest in lipofibroblast biology, little is known about their cellular origin or the molecular pathways controlling their formation during embryonic development. Here, we show that a population of lipid-droplet-containing stromal cells emerges in the developing mouse lung between E15.5 and E16.5. This is accompanied by significant upregulation, in the lung mesenchyme, of peroxisome proliferator-activated receptor gamma (master switch of lipogenesis), adipose differentiation-related protein (marker of mature lipofibroblasts) and fibroblast growth factor 10 (previously shown to identify a subpopulation of lipofibroblast progenitors). We also demonstrate that although only a subpopulation of total embryonic lipofibroblasts derives from Fgf10(+) progenitor cells, in vivo knockdown of Fgfr2b ligand activity and reduction in Fgf10 expression lead to global reduction in the expression levels of lipofibroblast markers at E18.5. Constitutive Fgfr1b knockouts and mutants with conditional partial inactivation of Fgfr2b in the lung mesenchyme reveal the involvement of both receptors in lipofibroblast formation and suggest a possible compensation between the two receptors. We also provide data from human fetal lungs to demonstrate the relevance of our discoveries to humans. Our results reveal an essential role for Fgf10 signaling in the formation of lipofibroblasts during late lung development.
Department of Surgery, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Denise
D
Al Alam
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Department of Internal Medicine II, Klinikstrasse 36, Giessen, Hessen 35392, Germany.
Elie
E
El Agha
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA 90502, USA.
Reiko
R
Sakurai
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Department of Internal Medicine II, Klinikstrasse 36, Giessen, Hessen 35392, Germany.
Vahid
V
Kheirollahi
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Department of Internal Medicine II, Klinikstrasse 36, Giessen, Hessen 35392, Germany.
Alena
A
Moiseenko
Department of Surgery, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Soula
S
Danopoulos
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Department of Internal Medicine II, Klinikstrasse 36, Giessen, Hessen 35392, Germany.
Amit
A
Shrestha
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Department of Internal Medicine II, Klinikstrasse 36, Giessen, Hessen 35392, Germany.
Carole
C
Schmoldt
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Department of Internal Medicine II, Klinikstrasse 36, Giessen, Hessen 35392, Germany.
Jennifer
J
Quantius
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Department of Internal Medicine II, Klinikstrasse 36, Giessen, Hessen 35392, Germany.
Susanne
S
Herold
Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Department of Internal Medicine II, Klinikstrasse 36, Giessen, Hessen 35392, Germany.
Cho-Ming
CM
Chao
Division of Neonatology, Department of Pediatrics, Columbia University, New York, NY 10027, USA.
Caterina
C
Tiozzo
Department of Pediatrics, Division of Cell Biology, National Jewish Health, Denver, CO 80206, USA.
Stijn
S
De Langhe
Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, Center for Complex Biological Systems, University of California Irvine, Irvine, CA 92697, USA.
Maksim V
MV
Plikus
Maternal Fetal Medicine Division, University of Southern California, Los Angeles, CA 90033, USA.
Matthew
M
Thornton
Maternal Fetal Medicine Division, University of Southern California, Los Angeles, CA 90033, USA.
Brendan
B
Grubbs
Division of Neonatal Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Parviz
P
Minoo
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA 90502, USA vrehan@labiomed.org saverio.bellusci@innere.med.uni-giessen.de.
Virender K
VK
Rehan
Department of Surgery, Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA 90027, USA Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Department of Internal Medicine II, Klinikstrasse 36, Giessen, Hessen 35392, Germany Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia vrehan@labiomed.org saverio.bellusci@innere.med.uni-giessen.de.
Saverio
S
Bellusci
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002469:Cell Separation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology*; D005434:Flow Cytometry; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008168:Lung / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
C496463:FGF10 protein, human; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D008055:Lipids; D047495:PPAR gamma; D051497:Receptor, Fibroblast Growth Factor, Type 2
Fgf10; Lipofibroblasts; Lung; Mesenchyme