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.

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.

scholarly journals Origin of Myofibroblasts in Lung Fibrosis

2020 ◽  
Vol 1 (4) ◽  
pp. 155-162
Author(s):  
CF Hung
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Epithelial Cells ◽  
Lung Fibrosis ◽  
Cell Types ◽  
Mesenchymal Cells ◽  
Lineage Tracing ◽  
Alveolar Epithelial Cells ◽  
Multiple Sources ◽  
Alveolar Epithelial

Abstract Purpose of Review In this brief review, we will highlight important observational and experimental data in the literature that address the origin of scar-forming cells in lung fibrosis. Recent Findings Several cellular sources of activated scar-forming cells (myofibroblasts) have been postulated including alveolar epithelial cells; circulating fibrocytes; and lung stromal cell subpopulations including resident fibroblasts, pericytes, and resident mesenchymal stem cells. Recent advances in lineage-tracing models, however, fail to provide experimental evidence for epithelial and fibrocyte origins of lung myofibroblasts. Resident mesenchymal cells of the lung, which include various cell types including resident fibroblasts, pericytes, and resident mesenchymal stem cells, appear to be important sources of myofibroblasts in murine models of lung injury and fibrosis. Summary Lung myofibroblasts likely originate from multiple sources of lung-resident mesenchymal cells. Their relative contributions may vary depending on the type of injury. Although lineage-tracing experiments have failed to show significant contribution from epithelial cells or fibrocytes, they may play important functional roles in myofibroblast activation through paracrine signaling.

scholarly journals Nrf2/Keap1/ARE Signaling Mediated an Antioxidative Protection of Human Placental Mesenchymal Stem Cells of Fetal Origin in Alveolar Epithelial Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Xiurui Yan ◽  
Xue Fu ◽  
Yuanyuan Jia ◽  
Xiaona Ma ◽  
Jin Tao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Epithelial Cells ◽  
Caspase 3 ◽  
Antioxidative Activity ◽  
A549 Cells ◽  
Oxidative Injury ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Fetal Origin

The oxidative stresses are a major insult in pulmonary injury such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), two clinical manifestations of acute respiratory failure with substantially high morbidity and mortality. Mesenchymal stem cells (MSCs) hold a promise in treatments of many human diseases, mainly owing to their capacities of immunoregulation and antioxidative activity. The strong immunoregulatory role of human placental MSCs of fetal origin (hfPMSCs) has been previously demonstrated; their antioxidant activity, however, has yet been interrogated. In this report, we examined the antioxidative activity of hfPMSCs by accessing the ability to scavenge oxidants and radicals and to protect alveolar epithelial cells from antioxidative injury using both a cell coculture model and a conditioned culture medium (CM) of hfPMSCs. Results showed a comparable antioxidative capacity of the CM with 100 μM of vitamin C (VC) in terms of the total antioxidant capacity (T-AOC), scavenging abilities of free radicals DPPH, hydroxyl radical (·OH), and superoxide anion radical (O2-), as well as activities of antioxidant enzymes of SOD and GSH-PX. Importantly, both of the CM alone and cocultures of hfPMSCs displayed a protection of A549 alveolar epithelial cells from oxidative injury of 600 μM hydrogen peroxide (H2O2) exposure, as determined in monolayer and transwell coculture models, respectively. Mechanistically, hfPMSCs and their CM could significantly reduce the apoptotic cell fraction of alveolar epithelial A549 cells exposed to H2O2, accompanied with an increased expression of antiapoptotic proteins Bcl-2, Mcl-1, Nrf-2, and HO-1 and decreased proapoptotic proteins Bax, caspase 3, and Keap1, in comparison with naïve controls. Furthermore, hfPMSCs-CM (passage 3) collected from cultures exposed an inhibition of the Nrf2/Keap1/ARE signaling pathway which led to a significant reduction in caspase 3 expression in A549 cells, although the addition of Nrf2 inhibitor ML385 had no effect on the antioxidative activity of hfPMSCs-CM. These data clearly suggested that hfPMSCs protected the H2O2-induced cell oxidative injury at least in part by regulating the Nrf2-Keap1-ARE signaling-mediated cell apoptosis. Our study thus provided a new insight into the antioxidative mechanism and novel functions of hfPMSCs as antioxidants in disease treatments, which is warranted for further investigations.

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.

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