Loss of Hox5 function results in myofibroblast mislocalization and distal lung matrix defects during postnatal development  

作　　者：Steven M.Hrycaj Leilani Marty-Santos ANDrew J.Rasky Nicholas W.Lukacs Deneen M.Wellik 

机构地区：[1]Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan [2]Department of Pathology, University of Michigan [3]Department of Cell and Developmental Biology, University of Michigan

出　　处：《Science China(Life Sciences)》2018年第9期1030-1038,共9页中国科学（生命科学英文版）

基　　金：supported by a Ruth L. Kirschstein National Research Service Award (NSRA) training Grant 5 T32 HL 7749-20 to S.M.H;supported by MICHR PTSP UL1TR002240 to L.M.S;the National Heart, Lung, and Blood Institute (NHLBI) R01-HL119215 to D.M.W

摘　　要：Alveologenesis is the final stage of lung development and is responsible for the formation of the principle gas exchange units called alveoli. The lung mesenchyme, in particular the alveolar myofibroblasts, are drivers of alveolar development, however,few key regulators that govern the proper distribution and behavior of these cells in the distal lung during alveologenesis have been identified. While Hox5 triple mutants(Hox5 aabbcc) exhibit neonatal lethality, four-allele, compound mutant mice(Hox5 AabbCc) are born in Mendelian ratios and are phenotypically normal at birth. However, they exhibit defects in alveologenesis characterized by a BPD-like phenotype by early postnatal stages that becomes more pronounced at adult stages. Invasive pulmonary functional analyses demonstrate significant increases in total lung volume and compliance and a decrease in elastance in Hox5 compound mutants. SMA+ myofibroblasts in the distal lung are distributed abnormally during peak stages of alveologenesis and aggregate, resulting in the formation of a disrupted elastin network. Examination of other key components of the distal lung ECM, as well as other epithelial cells and lipofibroblasts reveal no differences in distribution. Collectively, these data indicate that Hox5 genes play a critical role in alveolar development by governing the proper cellular behavior of myofibroblasts during alveologenesis.Alveologenesis is the final stage of lung development and is responsible for the formation of the principle gas exchange units called alveoli. The lung mesenchyme, in particular the alveolar myofibroblasts, are drivers of alveolar development, however,few key regulators that govern the proper distribution and behavior of these cells in the distal lung during alveologenesis have been identified. While Hox5 triple mutants（Hox5 aabbcc） exhibit neonatal lethality, four-allele, compound mutant mice（Hox5 AabbCc） are born in Mendelian ratios and are phenotypically normal at birth. However, they exhibit defects in alveologenesis characterized by a BPD-like phenotype by early postnatal stages that becomes more pronounced at adult stages. Invasive pulmonary functional analyses demonstrate significant increases in total lung volume and compliance and a decrease in elastance in Hox5 compound mutants. SMA＋ myofibroblasts in the distal lung are distributed abnormally during peak stages of alveologenesis and aggregate, resulting in the formation of a disrupted elastin network. Examination of other key components of the distal lung ECM, as well as other epithelial cells and lipofibroblasts reveal no differences in distribution. Collectively, these data indicate that Hox5 genes play a critical role in alveolar development by governing the proper cellular behavior of myofibroblasts during alveologenesis.

关 键 词：Hox5 alveologenesis alveolar myofibroblasts lung ECM postnatal lung development 

分 类 号：R563[医药卫生—呼吸系统]