Isolation Of Alveolar Epithelial Type II Progenitor Cells From The Adult Human Lungs

Fujino, Naoya; Kubo, Hiroshi; Suzuki, Takaya; Hegab, Ahmed E.; Me, He; Yamada, Mitsuhiro; Yamaya, Mutsuo

doi:10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a4913

Cited by 9 publications

(13 citation statements)

References 18 publications

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“…Similarly, we found co-expression of ATII and ATI cell marker as well as single ATI cells expressing podoplanin upon Wnt/β-catenin activation. Taken together, these data from mouse and human tissue support the notion that ATI cells might originate not only from ATII cells, but also from other -in human lung tissue, yet to be further defined -alveolar progenitor cells [8,9,11,38]. To proof this unequivocally, future studies are needed that conduct fate-mapping and ex vivo tracking in transgene animals, however, these analyses are limited in human lung tissue with current techniques.…”

Section: Discussionsupporting

confidence: 52%

Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures

et al. 2015

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Chronic obstructive pulmonary disease (COPD) is characterised by a progressive loss of lung tissue. Inducing repair processes within the adult diseased lung is of major interest and Wnt/β-catenin signalling represents a promising target for lung repair. However, the translation of novel therapeutic targets from model systems into clinical use remains a major challenge.We generated murine and patient-derived three-dimensional (3D) ex vivo lung tissue cultures (LTCs), which closely mimic the 3D lung microenvironment in vivo. Using two well-known glycogen synthase kinase-3β inhibitors, lithium chloride (LiCl) and CHIR 99021 (CT), we determined Wnt/β-catenin-driven lung repair processes in high spatiotemporal resolution using quantitative PCR, Western blotting, ELISA, (immuno)histological assessment, and four-dimensional confocal live tissue imaging.Viable 3D-LTCs exhibited preserved lung structure and function for up to 5 days. We demonstrate successful Wnt/β-catenin signal activation in murine and patient-derived 3D-LTCs from COPD patients. Wnt/β-catenin signalling led to increased alveolar epithelial cell marker expression, decreased matrix metalloproteinase-12 expression, as well as altered macrophage activity and elastin remodelling. Importantly, induction of surfactant protein C significantly correlated with disease stage ( per cent predicted forced expiratory volume in 1 s) in patient-derived 3D-LTCs.Patient-derived 3D-LTCs represent a valuable tool to analyse potential targets and drugs for lung repair. Enhanced Wnt/β-catenin signalling attenuated pathological features of patient-derived COPD 3D-LTCs. @ERSpublications Patient-derived 3D-LTCs are a powerful tool for preclinical drug validation and imaging of Wnt-induced lung repair

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Section: Discussionsupporting

confidence: 52%

Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures

et al. 2015

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“…Because all cells in this murine model are deficient in Thy-1, we cannot isolate its role in fibroblast lipid accumulation in vivo from the effects exerted by neighboring cells. Alveolar Type II cells also express Thy-1 (44), and the epithelium overlying Thy-1 (2) fibroblasts in idiopathic pulmonary fibrosis demonstrates an increased expression of Thy-1 (45). Because alveolar epithelial-mesenchymal signaling is important in lipofibroblast differentiation and function (18), and the potential effects of Thy-1 on epithelial cell functions are unknown, a fibroblastspecific Thy-1 knockout mouse would be required to determine the cell-specific effects of Thy-1 on fibroblast phenotype in vivo.…”

Section: Discussionmentioning

confidence: 99%

Thy-1 Signals through PPARγ to Promote Lipofibroblast Differentiation in the Developing Lung

Varisco

Ambalavanan

Whitsett

et al. 2012

Am J Respir Cell Mol Biol

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Thy-1 is a glycosylphosphytidylinositol-linked cell-surface glycoprotein present on a subset of lung fibroblasts, which plays an important role in postnatal alveolarization. In the present study, we define the role of Thy-1 in pulmonary lipofibroblast differentiation and in the regulation of lipid homeostasis via peroxisome proliferator-activated receptor-g (PPARg). Thy-1 was associated with interstitial cells containing lipid droplets in vivo. The transfection of Thy-1 into Thy-1 (2) fibroblasts increased triglyceride content, fatty-acid uptake, and the expression of the lipofibroblast marker adipocyte differentiationrelated protein. Thy-1 (1) fibroblasts exhibited 2.4-fold higher PPARg activity, and the inhibition or activation of PPARg reduced and increased triglyceride content, respectively. Thy-1 (2) fibroblasts were not responsive to either of the PPARg agonists ciglitazone or prostaglandin J 2 , supporting the importance of Thy-1 in signaling via PPARg. Thy-1 (1) fibroblasts expressed significantly higher concentrations of fatty-acid transporter protein-3 mRNA, and demonstrated higher rates of fatty-acid uptake and increased triglyceride content. The inhibition of fatty-acid transporter protein function reduced Thy-1 (1) fibroblast lipid content. The expression of Thy-1 in C57BL/6 lung fibroblasts increased during the neonatal period, coinciding with the onset of alveolarization. Thy-1 promoted lipofibroblast differentiation via the expression of PPARg, stimulated lipid accumulation via fatty-acid esterification, and enhanced the fatty-acid uptake mediated by fattyacid transporter proteins. Thy-1 is important in the regulation of lipofibroblast differentiation in the developing lung.Keywords: Thy-1; lipofibroblast; PPARg; lipid metabolismBeginning at 35 weeks after conception and continuing for up to 8 years after birth, the alveolar stage of lung development is marked by the sequential division of larger airspaces into smaller ones by secondary alveolar septa (1, 2). From term birth until adulthood, the 5-fold increase in the number of alveoli and the 20-fold increase in alveolar surface area are critical in meeting the increasing oxygenation and ventilation needs of human growth and activity (2, 3). Premature birth, exposure to high concentrations of inspired oxygen, and mechanical ventilation lead to impaired alveolar development and chronic lung disease (4). The impaired lung function of chronic lung disease results in significant morbidity, mortality, and healthcare costs from early life through adulthood (5-8). Understanding how the different tissues of the lung behave during normal and impaired alveolar development is a key first step toward restoring alveolarization and attenuating the burden of respiratory disease after premature birth.Pulmonary lipofibroblasts comprise an incompletely characterized population of lipid-containing interstitial cells that play an important role in alveolarization. Hyperoxia, hypoxia, and nicotine exposure stimulate lipofibroblasts to myofibroblast differentiation a...

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“…Alveolar epithelial progenitor cells isolated from adult human lungs possess a phenotype characteristic of mesenchymal stem cells [83]. The transitional phenotype of alveolar epithelial progenitor cells between the epithelium and mesenchyme suggests that these cells may act as endogenous stem cells in lung tissue repair.…”

Section: Stem Cell Exhaustionmentioning

confidence: 99%

Mechanisms of development of multimorbidity in the elderly

2015

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In ageing populations many patients have multiple diseases characterised by acceleration of the normal ageing process. Better understanding of the signalling pathways and cellular events involved in ageing shows that these are characteristic of many chronic degenerative diseases, such as chronic obstructive pulmonary disease (COPD), chronic cardiovascular and metabolic diseases, and neurodegeneration. Common mechanisms have now been identified in these diseases, which show evidence of cellular senescence with telomere shortening, activation of PI3K-AKT-mTOR signalling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence and low grade chronic inflammation ("inflammaging"). Many of these pathways are driven by chronic oxidative stress. There is also a reduction in anti-ageing molecules, such as sirtuins and Klotho, which further accelerates the ageing process. Understanding these molecular mechanisms has identified several novel therapeutic targets and several drugs have already been developed that may slow the ageing process, as well as lifestyle interventions, such as diet and physical activity. This indicates that in the future new treatment approaches may target the common pathways involved in multimorbidity and this area of research should be given high priority. Thus, COPD should be considered as a component of multimorbidity and common disease pathways, particularly accelerated ageing, should be targeted. @ERSpublications Multimorbidities share many common underlying mechanisms that may be linked to common causes such as oxidative stress

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Isolation Of Alveolar Epithelial Type II Progenitor Cells From The Adult Human Lungs

Cited by 9 publications

References 18 publications

Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures

Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures

Thy-1 Signals through PPARγ to Promote Lipofibroblast Differentiation in the Developing Lung

Mechanisms of development of multimorbidity in the elderly

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