scholarly journals Modeling of fibrotic lung disease using 3D organoids derived from human pluripotent stem cells

2019 ◽  
Author(s):  
Hans-Willem Snoeck ◽  
Alexandros Strikoudis ◽  
Lucas Loffredo ◽  
Ya-Wen Chen
Keyword(s):  
Stem Cells ◽  
Epithelial Cells ◽  
Lung Disease ◽  
Lung Tissue ◽  
Embryonic Stem ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Recessive Mutations ◽  
Genome Expression ◽  
Fibrotic Lung Disease

Idiopathic pulmonary fibrosis (IPF) is an intractable interstitial lung disease for which no curative treatment is available except for lung transplantation. Its pathogenesis is unclear, but a role for injury to type 2 alveolar epithelial cells is hypothesized. Recessive mutations in some, but not all genes implicated in Hermansky-Pudlak Syndrome (HPS) cause HPS-associated interstitial pneumonia (HPSIP), a clinical entity similar to IPF. We previously reported that mutation in HPS1 in embryonic stem cells-derived 3D lung organoids caused fibrotic changes. Here we show that introduction of all HPS mutations associated with HPSIP (HPS1, 2 and 4) promote fibrosis in lung organoids, while mutation in HSP8, which is not associated with HPSIP, does not. Furthermore, genome-expression analysis of epithelial cells derived from these organoids revealed significant overlap with similar analyses of both affected and unaffected lung tissue of non-HPS IPF patients. Importantly, this analysis showed upregulation of interleukin-11 in HPS-mutant fibrotic organoids and in fibrotic and unaffected lung tissue from IPF patients. Furthermore, IL-11 induced fibrosis in WT organoids, while its deletion prevented fibrosis in fibrotic HPS4-mutant organoids, suggesting IL-11 as a therapeutic target in IPF and HPSIP. hPSC-derived 3D lung organoids are therefore a valuable resource to model fibrotic lung disease.

Derivation of Type II Alveolar Epithelial Cells from Murine Embryonic Stem Cells

2002 ◽  
Vol 8 (4) ◽  
pp. 541-550 ◽  
Author(s):  
Nadire N. Ali ◽  
Alasdair J. Edgar ◽  
Ali Samadikuchaksaraei ◽  
Catherine M. Timson ◽  
Hanna M. Romanska ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Epithelial Cells ◽  
Embryonic Stem ◽  
Alveolar Epithelial Cells ◽  
Type Ii ◽  
Alveolar Epithelial ◽  
Murine Embryonic Stem Cells

scholarly journals Differentiation of Bone Marrow Mesenchymal Stem Cells into Alveolar Epithelial Cells Reduces Radiation-Induced Lung Injury by Regulating Angii/ACE2/Ang(1-7) Axis and Suppressing NF-Κb/MAPK Pathway

2021 ◽  
Author(s):  
shiying niu ◽  
changsheng cong ◽  
zhaopeng wang ◽  
meili sun ◽  
yueying zhang
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Lung Tissue ◽  
Mapk Pathway ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Qrt Pcr ◽  
Radiation Induced

Abstract Background Radiation-induced lung injury (RILI) is one of the most common complications of thoracic tumors radiotherapy. Since therapeutic strategies remains limited, the exploration of new approaches to treat RILI is on high demands. The use of bone mesenchymal stem cells (BMSCs) to treat RILI holds great promise thanks to their multidifferentiation and anti-inflammatory potential after injury. Here, we investigate the therapeutic potential of BMSCs in RILI. Methods Forty five C57BL/6 mice were randomly divided into groups. Except for the control group, all mice received chest irradiation. Within 24 hours after irradiation, BMSCs were injected into the tail vein of mice in BMSCs group. At 4 weeks after irradiation, all mice were dissected. HE staining and immunohistochemistry were used to observe the pathological changes of lung tissue and the expression of inflammatory factors. Immunofluorescence technique was used to detect whether BMSCs migrated to lung tissue and to verify their differentiation potential. The expression of Ang II and Ang (1-7) in lung tissue was detected by ELISA. The expression of MasR mRNA in lung tissue was detected by qRT-PCR. Western blotting was used to detect the expression of ACE2, ACE, AT1R and MAPK related proteins. Results we found that BMSCs significantly reduced RILI by HE and immunohistochemistry. Immunofluorescence results showed that BMSCs migrated to injuried lung tissue and differentiated into alveolar epithelial cells. Combined with qRT-PCR and Western blotting results showed BMSCs significantly up-regulated ACE2/Ang(1-7)/MasR axis and suppressed NF-κB/MAPK pathway. Conclusions The study demonstrated that BMSCs may be transplanted into damaged lung tissue where they differentiated into AEC II to regulate AngII/ACE2/Ang(1-7) axis and suppress NF-κB/MAPK pathway to alleviate RILI.

Tenascin in rat lung development: in situ localization and cellular sources

1995 ◽  
Vol 269 (4) ◽  
pp. L482-L491 ◽  
Author(s):  
Y. Zhao ◽  
S. L. Young
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Epithelial Cells ◽  
Lung Tissue ◽  
Lung Development ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
Rat Lung ◽  
Alveolar Epithelial

Tenascin (TN) is a hexameric extracellular matrix glycoprotein that may play an important role during lung development. TN protein is temporally and spatially restricted during lung organogenesis. The temporo-spatial and cellular expression of TN mRNA in lung remains unclear. Localization of message expression of TN in rat lung tissue was first investigated by using in situ hybridization performed with an antisense RNA probe. TN mRNA was present primarily within the mesenchyme of day 16 gestational age fetal rat lung tissue, whereas immunoreactive TN protein was found along the basement membrane. In postnatal day 3 rat lung tissue, TN mRNA was detected along alveolar septal walls and was concentrated at secondary septal tips. Expression of TN message was consistent with localization of immunoreactive TN protein. Accumulation of TN mRNA in alveolar septal tips suggests that mesenchyme may be the major source of TN mRNA. To investigate the cellular source of TN in rat lung, we studied the expression of TN in cultured rat lung fibroblasts, endothelial cells, and alveolar epithelial cells. Two TN isoforms having molecular mass of 230 and 180 kDa were in conditioned medium and in cellular extracts of lung fibroblasts and endothelial cells. TN was secreted and deposited in the extracellular matrix closely associated with the surface of lung fibroblasts and endothelial cells. Lung alveolar epithelial cells showed undetectable or barely detectable amounts of TN. These studies demonstrated that TN isoforms are expressed not only by lung fibroblasts but also by lung endothelial cells. The unique spatial localization of TN mRNA during lung development and expression of TN by different lung cell types suggested TN may be involved in matrix organization and cell-cell interactions during lung development.

scholarly journals Characterization of Early Stages of Human Alveolar Infection by the Q Fever AgentCoxiella burnetii

2019 ◽  
Vol 87 (5) ◽  
Author(s):  
Amanda L. Dragan ◽  
Richard C. Kurten ◽  
Daniel E. Voth
Keyword(s):  
Epithelial Cells ◽  
Lung Tissue ◽  
Alveolar Macrophages ◽  
Human Lung ◽  
Q Fever ◽  
Cell Types ◽  
Alveolar Epithelial Cells ◽  
Human Lung Tissue ◽  
Content Type ◽  
Alveolar Epithelial

ABSTRACTHuman Q fever is caused by the intracellular bacterial pathogenCoxiella burnetii. Q fever presents with acute flu-like and pulmonary symptoms or can progress to chronic, severe endocarditis. After human inhalation,C. burnetiiis engulfed by alveolar macrophages and transits through the phagolysosomal maturation pathway, resisting the acidic pH of lysosomes to form a parasitophorous vacuole (PV) in which to replicate. Previous studies showed thatC. burnetiireplicates efficiently in primary human alveolar macrophages (hAMs) inex vivohuman lung tissue. AlthoughC. burnetiireplicates in most cell typesin vitro, the pathogen does not grow in non-hAM cells of human lung tissue. In this study, we investigated the interaction betweenC. burnetiiand other pulmonary cell types apart from the lung environment.C. burnetiiformed a prototypical PV and replicated efficiently in human pulmonary fibroblasts and in airway, but not alveolar, epithelial cells. Atypical PV expansion in alveolar epithelial cells was attributed in part to defective recruitment of autophagy-related proteins. Further assessment of theC. burnetiigrowth niche showed that macrophages mounted a robust interleukin 8 (IL-8), neutrophil-attracting response toC. burnetiiand ultimately shifted to an M2-polarized phenotype characteristic of anti-inflammatory macrophages. Considering our findings together, this study provides further clarity on the uniqueC. burnetii-lung dynamic during early stages of human acute Q fever.

scholarly journals Adipose Tissue-Derived Stem Cells Have the Ability to Differentiate into Alveolar Epithelial Cells and Ameliorate Lung Injury Caused by Elastase-Induced Emphysema in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Eriko Fukui ◽  
Soichiro Funaki ◽  
Kenji Kimura ◽  
Toru Momozane ◽  
Atsuomi Kimura ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Alveolar Epithelial Cells ◽  
Chronic Obstructive ◽  
Alveolar Cells ◽  
Alveolar Epithelial

Chronic obstructive pulmonary disease is a leading cause of mortality globally, with no effective therapy yet established. Adipose tissue-derived stem cells (ADSCs) are useful for ameliorating lung injury in animal models. However, whether ADSCs differentiate into functional cells remains uncertain, and no study has reported on the mechanism by which ADSCs improve lung functionality. Thus, in this study, we examined whether ADSCs differentiate into lung alveolar cells and are able to ameliorate lung injury caused by elastase-induced emphysema in model mice. Here, we induced ADSCs to differentiate into type 2 alveolar epithelial cells in vitro. We demonstrated that ADSCs can differentiate into type 2 alveolar epithelial cells in an elastase-induced emphysematous lung and that ADSCs improve pulmonary function of emphysema model mice, as determined with spirometry and 129Xe MRI. These data revealed a novel function for ADSCs in promoting repair of the damaged lung by direct differentiation into alveolar epithelial cells.

scholarly journals Radiation Induces Pulmonary Fibrosis by Promoting the Fibrogenic Differentiation of Alveolar Stem Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Lu-Kai Wang ◽  
Tsai-Jung Wu ◽  
Ji-Hong Hong ◽  
Fang-Hsin Chen ◽  
John Yu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Tissue Growth ◽  
Alveolar Epithelial Cells ◽  
Type I ◽  
Alveolar Cells ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Radiation Induced

The lung is a radiosensitive organ, which imposes limits on the therapeutic dose in thoracic radiotherapy. Irradiated alveolar epithelial cells promote radiation-related pneumonitis and fibrosis. However, the role of lung stem cells (LSCs) in the development of radiation-induced lung injury is still unclear. In this study, we found that both LSCs and LSC-derived type II alveolar epithelial cells (AECII) can repair radiation-induced DNA double-strand breaks, but the irradiated LSCs underwent growth arrest and cell differentiation faster than the irradiated AECII cells. Moreover, radiation drove LSCs to fibrosis as shown with the elevated levels of markers for epithelial-mesenchymal transition and myofibroblast (α-smooth muscle actin (α-SMA)) differentiation in in vitro and ex vivo studies. Increased gene expressions of connective tissue growth factor and α-SMA were found in both irradiated LSCs and alveolar cells, suggesting that radiation could induce the fibrogenic differentiation of LSCs. Irradiated LSCs showed an increase in the expression of surfactant protein C (SP-C), the AECII cell marker, and α-SMA, and irradiated AECII cells expressed SP-C and α-SMA. These results indicated that radiation induced LSCs to differentiate into myofibroblasts and AECII cells; then, AECII cells differentiated further into either myofibroblasts or type I alveolar epithelial cells (AECI). In conclusion, our results revealed that LSCs are sensitive to radiation-induced cell damage and may be involved in radiation-induced lung fibrosis.

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