Obesity impairs therapeutic efficacy of mesenchymal stem cells by inhibiting cardiolipin-dependent mitophagy and intercellular mitochondrial transfer in mouse models of airway allergic inflammation

Mesenchymal stem cell (MSC) transplantation alleviates metabolic defects in diseased recipient cells by intercellular mitochondrial transport (IMT). However, the effect of host metabolic conditions on MSCs in general, and IMT in particular, has largely remained unexplored. This study has identified a molecular pathway that primarily governs the metabolic function and IMT of MSCs. We found underlying mitochondrial dysfunction, impaired mitophagy, and reduced IMT in MSCs derived from high-fat diet (HFD)-induced obese mice (MSC-Ob). Mechanistically, MSC-Ob failed to sequester their damaged mitochondria into LC3-dependent autophagosomes due to decrease in mitochondrial cardiolipin content, which we propose as a putative mitophagy receptor for LC3 in MSCs. Functionally, MSC-Ob exhibited diminished potential to rescue metabolic deficits and cell death in stress-induced epithelial cells. In a small molecule screen, we found pyrroloquinoline quinone (PQQ) as a regulator of mitophagy and IMT. Long-term culture of MSC-Ob with PQQ (MSC-ObPQQ) restored cardiolipin content and sequestration of mitochondria to autophagosomes with concomitant activation of mitophagy. Upon co-culture, MSC-ObPQQ rescued cell death in stress-induced epithelial cells by enhancing IMT. The beneficial effect of PQQ was also evident in MSCs derived from human subjects in an in vitro model. In two independent mice models, the transplantation of MSC-ObPQQ restored IMT to airway epithelial cells, improved their mitochondrial metabolism and attenuated features of allergic airway inflammation (AAI). However, unmodulated MSC-Ob failed to do so. In summary, we uncover the molecular mechanism leading to the therapeutic decline of obese-derived MSCs and highlight the importance of pharmacological modulation of these cells for therapeutic intervention.

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In vitro susceptibility to rhinovirus infection is greater for bronchial than for nasal airway epithelial cells in human subjects

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2009.03.010 ◽

2009 ◽

Vol 123 (6) ◽

pp. 1384-1390.e2 ◽

Cited By ~ 139

Author(s):

Nilceia Lopez-Souza ◽

Silvio Favoreto ◽

Hofer Wong ◽

Theresa Ward ◽

Shigeo Yagi ◽

...

Keyword(s):

Epithelial Cells ◽

Human Subjects ◽

Airway Epithelial Cells ◽

Nasal Airway ◽

Airway Epithelial ◽

In Vitro Susceptibility ◽

Rhinovirus Infection

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Eosinophil Responses at the Airway Epithelial Barrier during the Early Phase of Influenza a Virus Infection in C57BL/6 Mice

Cells ◽

10.3390/cells10030509 ◽

2021 ◽

Vol 10 (3) ◽

pp. 509 ◽

Cited By ~ 1

Author(s):

Meenakshi Tiwary ◽

Robert J. Rooney ◽

Swantje Liedmann ◽

Kim S. LeMessurier ◽

Amali E. Samarasinghe

Keyword(s):

Epithelial Cells ◽

Influenza A Virus ◽

Early Phase ◽

Influenza A ◽

Airway Epithelial Cells ◽

Epithelial Barrier ◽

Virus Infectivity ◽

Airway Epithelial ◽

In Vivo Models

Eosinophils, previously considered terminally differentiated effector cells, have multifaceted functions in tissues. We previously found that allergic mice with eosinophil-rich inflammation were protected from severe influenza and discovered specialized antiviral effector functions for eosinophils including promoting cellular immunity during influenza. In this study, we hypothesized that eosinophil responses during the early phase of influenza contribute to host protection. Using in vitro and in vivo models, we found that eosinophils were rapidly and dynamically regulated upon influenza A virus (IAV) exposure to gain migratory capabilities to traffic to lymphoid organs after pulmonary infection. Eosinophils were capable of neutralizing virus upon contact and combinations of eosinophil granule proteins reduced virus infectivity through hemagglutinin inactivation. Bi-directional crosstalk between IAV-exposed epithelial cells and eosinophils occurred after IAV infection and cross-regulation promoted barrier responses to improve antiviral defenses in airway epithelial cells. Direct interactions between eosinophils and airway epithelial cells after IAV infection prevented virus-induced cytopathology in airway epithelial cells in vitro, and eosinophil recipient IAV-infected mice also maintained normal airway epithelial cell morphology. Our data suggest that eosinophils are important in the early phase of IAV infection providing immediate protection to the epithelial barrier until adaptive immune responses are deployed during influenza.

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417: Cyclosporine does not penetrate, but accumulates at high concentrations within, differentiated human airway epithelial cells in vitro: Possible implications for the use of inhaled cyclosporine

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2006.11.439 ◽

2007 ◽

Vol 26 (2) ◽

pp. S210

Author(s):

R. Aris ◽

P. McNeillie ◽

O. Olusesi ◽

S. Thomas ◽

M. Paine ◽

...

Keyword(s):

Epithelial Cells ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Human Airway ◽

High Concentrations ◽

Human Airway Epithelial Cells

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The wound healing capacity of undifferentiated and differentiated airway epithelial cells in vitro

International Journal of Pediatric Otorhinolaryngology ◽

10.1016/j.ijporl.2018.07.006 ◽

2018 ◽

Vol 112 ◽

pp. 163-168 ◽

Cited By ~ 2

Author(s):

Cynthia M. Schwartz ◽

Braedyn A. Dorn ◽

Selam Habtemariam ◽

Cynthia L. Hill ◽

Tendy Chiang ◽

...

Keyword(s):

Wound Healing ◽

Epithelial Cells ◽

Airway Epithelial Cells ◽

Airway Epithelial

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In Vitro Investigations on Optimizing and Nebulization of IVT-mRNA Formulations for Potential Pulmonary-Based Alpha-1-Antitrypsin Deficiency Treatment

Pharmaceutics ◽

10.3390/pharmaceutics13081281 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1281

Author(s):

Shan Guan ◽

Max Darmstädter ◽

Chuanfei Xu ◽

Joseph Rosenecker

Keyword(s):

Epithelial Cells ◽

Transfection Efficiency ◽

Genetic Diseases ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Significant Toxicity ◽

Antitrypsin Deficiency ◽

Alpha 1 Antitrypsin Deficiency ◽

Alpha 1 Antitrypsin

In vitro-transcribed (IVT) mRNA has come into focus in recent years as a potential therapeutic approach for the treatment of genetic diseases. The nebulized formulations of IVT-mRNA-encoding alpha-1-antitrypsin (A1AT-mRNA) would be a highly acceptable and tolerable remedy for the protein replacement therapy for alpha-1-antitrypsin deficiency in the future. Here we show that lipoplexes containing A1AT-mRNA prepared in optimum conditions could successfully transfect human bronchial epithelial cells without significant toxicity. A reduction in transfection efficiency was observed for aerosolized lipoplexes that can be partially overcome by increasing the initial number of components. A1AT produced from cells transfected by nebulized A1AT-mRNA lipoplexes is functional and could successfully inhibit the enzyme activity of trypsin as well as elastase. Our data indicate that aerosolization of A1AT-mRNA therapy constitutes a potentially powerful means to transfect airway epithelial cells with the purpose of producing functional A1AT, while bringing along the unique advantages of IVT-mRNA.

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Induction of B7-H1 and B7-DC expression on airway epithelial cells by the Toll-like receptor 3 agonist double-stranded RNA and human rhinovirus infection: In vivo and in vitro studies

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2008.02.009 ◽

2008 ◽

Vol 121 (5) ◽

pp. 1155-1160 ◽

Cited By ~ 35

Author(s):

Lowella Heinecke ◽

David Proud ◽

Scherer Sanders ◽

Robert P. Schleimer ◽

Jean Kim

Keyword(s):

Epithelial Cells ◽

Airway Epithelial Cells ◽

In Vitro Studies ◽

Human Rhinovirus ◽

Airway Epithelial ◽

Toll Like Receptor ◽

Double Stranded Rna ◽

Rhinovirus Infection

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Ozone-induced release of cytokines and fibronectin by alveolar macrophages and airway epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1994.266.6.l612 ◽

1994 ◽

Vol 266 (6) ◽

pp. L612-L619 ◽

Cited By ~ 28

Author(s):

R. B. Devlin ◽

K. P. McKinnon ◽

T. Noah ◽

S. Becker ◽

H. S. Koren

Keyword(s):

Epithelial Cells ◽

Cell Line ◽

Alveolar Macrophages ◽

Airway Epithelial Cells ◽

Airway Hyperreactivity ◽

Ozone Exposure ◽

Airway Epithelial ◽

Human Airway ◽

Human Airway Epithelial Cells

Acute exposure of animals and humans to ozone results in decrements in lung function, development of airway hyperreactivity, inflammation, edema, damage to pulmonary cells, and production of several compounds with tissue damaging, fibrinogenic or fibrotic potential. The contribution of airway epithelial cells and alveolar macrophages to these processes is unclear. In this study we have directly exposed human alveolar macrophages and human airway epithelial cells to ozone in vitro and measured the cytotoxic effects of ozone, as well as the production of the inflammatory cytokines interleukin-6 (IL-6) and interleukin-8 (IL-8), and fibronectin, all of which are substantially elevated in the bronchoalveolar lavage fluid of humans exposed to ozone. Cells were grown on rigid, collagen-impregnated filter supports, and the interaction of cells with ozone facilitated by exposing them to the gas with medium below the support but no medium on top of the cells. The results show that, although macrophages are much more sensitive to ozone than epithelial cells, they do not produce increased amounts of IL-6, IL-8, or fibronectin following ozone exposure. In contrast, epithelial cells produce substantially more of all three proteins following ozone exposure, and both IL-6 and fibronectin are secreted vectorially. An immortalized human airway epithelial cell line (BEAS 2B) was used in these experiments since human airway epithelial cells are infrequently available for in vitro studies. Data from this study extend previous findings which suggest that the BEAS cell line is a useful model to study the interaction between airway epithelial cells and environmental toxicants.

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IL-4/IL-13 upregulates Sonic hedgehog expression to induce allergic airway epithelial remodeling

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00186.2019 ◽

2020 ◽

Vol 318 (5) ◽

pp. L888-L899 ◽

Cited By ~ 1

Author(s):

Xiangzhi Wang ◽

Chengyun Xu ◽

Junyan Ji ◽

Yuqing Cai ◽

Yingying Shu ◽

...

Keyword(s):

Epithelial Cells ◽

Sonic Hedgehog ◽

Goblet Cell ◽

Intratracheal Instillation ◽

Allergic Airway Inflammation ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Airway Epithelia ◽

Shh Signaling ◽

Epithelial Remodeling

We have previously demonstrated that upregulation of Sonic hedgehog (SHH) expression in allergic airway epithelia essentially contributes to the goblet cell metaplasia and mucous hypersecretion. However, the mechanism underlying the upregulation of SHH expression remains completely unknown. In cultured human airway epithelial cells, IL-4/IL-13 but not IL-5 robustly induces the mRNA and protein expression of SHH and in turn activates SHH signaling by promoting the JAK/STAT6-controlling transcription of SHH gene. Moreover, intratracheal instillation of IL-4 and/or IL-13 robustly activates STAT6 and concomitantly upregulates SHH expression in mouse airway epithelia, whereas, in Club cell 10-kDa protein (CC10)-positive airway epithelial cells of children with asthma, activated STAT6 closely correlates with the increased expression of SHH and high activity of SHH signaling. Finally, intratracheal inhibition of STAT6 by AS-1517499 significantly diminished the allergen-induced upregulation of SHH expression, goblet cell phenotypes, and airway hyperresponsiveness, in an ovalbumin- or house dust mite-induced mouse model with allergic airway inflammation,. Together, upregulation of SHH expression by IL-4/IL-13-induced JAK/STAT6 signaling contributes to allergic airway epithelial remodeling, and this study thus provides insight into how morphogen signaling is coordinated with Th2 cytokine pathways to regulate tissue remodeling in chronic airway diseases.

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