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Pulmonary Fibrosis and Cell Therapy
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Pulmonary Fibrosis and Cell Therapy

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cell Microenvironment".

Viewed by 29326

Editor

Dr. Anna Serrano-Mollar

E-Mail Website1 Website2
Collection Editor
Department of Experimental Pathology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, Institut d'Investigacions Biomédiques August Pi i Sunyer, 08036 Barcelona, Spain
Interests: pulmonary fibrosis; cell therapy; type II alveolar cells; pulmonary macrophages; fibroblasts; lung cells; cell cultures; lung surfactant; lung inflammation; experimental models of lung disease
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

During these last two decades, cell therapies for the treatment of pulmonary fibrosis have been considered a promising treatment. Since then, different types of stem cells or lung progenitor cells have been evaluated, mostly in animal models and only in a few human clinical trials. However, although both preclinical and human clinical data support the safety of cell therapies, they have not been translated into routine clinical practice. The reasons are diverse, since many key unanswered questions remain, such as doubts about the type of cells to be transplanted, the origin of these cells (autologous or heterologous), the route of administration (intravenous or endotracheal), the dose, the best time for transplantation and others. Additionally, the concern about side effects, such as unwanted differentiation of the grafted stem cells, cannot be forgotten. In addition to answering these questions, it is essential to know the mechanisms by which cell therapies exert their positive effects. Recent studies indicate that most of the positive effects can be attributed to the cellular secretome, composed of free soluble proteins and extracellular vesicles. The use of the secretome would avoid the side effects associated with cells, as well as the difficulty in obtaining and expanding them. Therefore, it is not only important to answer these questions, but also to know the mechanisms by which cell therapies exert their positive effects. All of this knowledge would help consolidate cell therapies in clinical practice.

This Topical Collection aims to summarize the updated knowledge on different cell therapies and the mechanisms involved in their potential therapeutic effect in pulmonary fibrosis.

The Topical Collection, entitled "Pulmonary Fibrosis and Cell Therapy", will include both review and original research papers covering key topics related to different cell therapies for pulmonary fibrosis, such as (1) different types of stem cells, induced pluripotent stem cells (iPSC), non-derived and derived to pulmonary cells; (2) lung progenitor cells; (3) other types of pulmonary cells; (4) cell secretome; (5) cell–cell interactions; (6) investigating mechanisms of lung tissue regeneration, cell engraftment or cell secretome. We hope that our readers from various disciplines will benefit from this Topical Collection, which will serve as a gateway to the amazing world of cell therapies for fibrotic diseases.

We look forward to your contributions.

Dr. Anna Serrano-Mollar
Collection Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • stem and progenitor cells
  • induced pluripotent stem cells (iPSC)
  • induced pluripotent stem cell-derived pulmonary cells (iPSC-PC)
  • spheroids
  • organoids
  • cell secretome
  • cell dose
  • cell route of administration
  • cell-derived drugs
  • molecular mechanism
  • tissue regeneration mechanism

Published Papers (8 papers)

Download All Papers

2022

Jump to: 2021

29 pages, 2370 KiB  
Review
Promises and Challenges of Cell-Based Therapies to Promote Lung Regeneration in Idiopathic Pulmonary Fibrosis
by Alejandro Egea-Zorrilla, Laura Vera, Borja Saez and Ana Pardo-Saganta
Cells 2022, 11(16), 2595; https://doi.org/10.3390/cells11162595 - 20 Aug 2022
Cited by 7 | Viewed by 4104
Abstract
The lung epithelium is constantly exposed to harmful agents present in the air that we breathe making it highly susceptible to damage. However, in instances of injury to the lung, it exhibits a remarkable capacity to regenerate injured tissue thanks to the presence [...] Read more.
The lung epithelium is constantly exposed to harmful agents present in the air that we breathe making it highly susceptible to damage. However, in instances of injury to the lung, it exhibits a remarkable capacity to regenerate injured tissue thanks to the presence of distinct stem and progenitor cell populations along the airway and alveolar epithelium. Mechanisms of repair are affected in chronic lung diseases such as idiopathic pulmonary fibrosis (IPF), a progressive life-threatening disorder characterized by the loss of alveolar structures, wherein excessive deposition of extracellular matrix components cause the distortion of tissue architecture that limits lung function and impairs tissue repair. Here, we review the most recent findings of a study of epithelial cells with progenitor behavior that contribute to tissue repair as well as the mechanisms involved in mouse and human lung regeneration. In addition, we describe therapeutic strategies to promote or induce lung regeneration and the cell-based strategies tested in clinical trials for the treatment of IPF. Finally, we discuss the challenges, concerns and limitations of applying these therapies of cell transplantation in IPF patients. Further research is still required to develop successful strategies focused on cell-based therapies to promote lung regeneration to restore lung architecture and function. Full article
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17 pages, 691 KiB  
Review
Stem-Cell Therapy for Bronchopulmonary Dysplasia (BPD) in Newborns
by Said A. Omar, Amal Abdul-Hafez, Sherif Ibrahim, Natasha Pillai, Mohammed Abdulmageed, Ranga Prasanth Thiruvenkataramani, Tarek Mohamed, Burra V. Madhukar and Bruce D. Uhal
Cells 2022, 11(8), 1275; https://doi.org/10.3390/cells11081275 - 09 Apr 2022
Cited by 19 | Viewed by 5151
Abstract
Premature newborns are at a higher risk for the development of respiratory distress syndrome (RDS), acute lung injury (ALI) associated with lung inflammation, disruption of alveolar structure, impaired alveolar growth, lung fibrosis, impaired lung angiogenesis, and development of bronchopulmonary dysplasia (BPD) with severe [...] Read more.
Premature newborns are at a higher risk for the development of respiratory distress syndrome (RDS), acute lung injury (ALI) associated with lung inflammation, disruption of alveolar structure, impaired alveolar growth, lung fibrosis, impaired lung angiogenesis, and development of bronchopulmonary dysplasia (BPD) with severe long-term developmental adverse effects. The current therapy for BPD is limited to supportive care including high-oxygen therapy and pharmacotherapy. Recognizing more feasible treatment options to improve lung health and reduce complications associated with BPD is essential for improving the overall quality of life of premature infants. There is a reduction in the resident stem cells in lungs of premature infants with BPD, which strongly suggests a critical role of stem cells in BPD pathogenesis; this warrants the exploration of the potential therapeutic use of stem-cell therapy. Stem-cell-based therapies have shown promise for the treatment of many pathological conditions including acute lung injury and BPD. Mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) including exosomes are promising and effective therapeutic modalities for the treatment of BPD. Treatment with MSCs and EVs may help to reduce lung inflammation, improve pulmonary architecture, attenuate pulmonary fibrosis, and increase the survival rate. Full article
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12 pages, 271 KiB  
Review
Autologous Haematopoietic Stem Cell Transplantation and Systemic Sclerosis: Focus on Interstitial Lung Disease
by Gianluca Bagnato, Antonio Giovanni Versace, Daniela La Rosa, Alberta De Gaetano, Egidio Imbalzano, Marianna Chiappalone, Carmelo Ioppolo, William Neal Roberts, Alessandra Bitto, Natasha Irrera, Alessandro Allegra, Giovanni Pioggia and Sebastiano Gangemi
Cells 2022, 11(5), 843; https://doi.org/10.3390/cells11050843 - 01 Mar 2022
Cited by 2 | Viewed by 2576
Abstract
Autologous hematopoietic stem cells transplantation (AHSCT) has been employed as treatment for severe systemic sclerosis (SSc) with high risk of organ failure. In the last 25 years overall survival and treatment-related mortality have improved, in accordance with a better patient selection and mobilization [...] Read more.
Autologous hematopoietic stem cells transplantation (AHSCT) has been employed as treatment for severe systemic sclerosis (SSc) with high risk of organ failure. In the last 25 years overall survival and treatment-related mortality have improved, in accordance with a better patient selection and mobilization and conditioning protocols. This review analyzes the evidence from the last 5 years for AHSCT-treated SSc patients, considering in particular the outcomes related to interstitial lung disease. There are increasing data supporting the use of AHSCT in selected patients with rapidly progressive SSc. However, some unmet needs remain, such as an accurate patient selection, pre-transplantation analysis to identify subclinical conditions precluding the transplantation, and the alternatives for post-transplant ILD recurrence. Full article
22 pages, 12510 KiB  
Article
Niclosamide Ethanolamine Salt Alleviates Idiopathic Pulmonary Fibrosis by Modulating the PI3K-mTORC1 Pathway
by Xiaolin Pei, Fangxu Zheng, Yin Li, Zhoujun Lin, Xiao Han, Ya Feng, Zhenhuan Tian, Dunqiang Ren, Ke Cao and Chenggang Li
Cells 2022, 11(3), 346; https://doi.org/10.3390/cells11030346 - 20 Jan 2022
Cited by 12 | Viewed by 3465
Abstract
Idiopathic pulmonary fibrosis (IPF) is an interstitial pneumonia characterized by chronic progressive fibrosis, ultimately leading to respiratory failure and early mortality. Although not fully explored, the major causative factors in IPF pathogenesis are dysregulated fibroblast proliferation and excessive accumulation of extracellular matrix (ECM) [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is an interstitial pneumonia characterized by chronic progressive fibrosis, ultimately leading to respiratory failure and early mortality. Although not fully explored, the major causative factors in IPF pathogenesis are dysregulated fibroblast proliferation and excessive accumulation of extracellular matrix (ECM) deposited by myofibroblasts differentiated from pulmonary fibroblasts. More signalling pathways, including the PI3K-Akt-mTOR and autophagy pathways, are involved in IPF pathogenesis. Niclosamide ethanolamine salt (NEN) is a highly effective multitarget small-molecule inhibitor reported in antitumor studies. Here, we reported that in an IPF animal model treated with NEN for 14 days, attractive relief of pulmonary function and hydroxyproline content were observed. To further explore, the therapeutic effect of NEN in IPF and pathological changes in bleomycin-challenged mouse lung sections were assessed. Additionally, the effects of NEN on abnormal proliferation and ECM production in IPF cell models established with TGF-β1-stimulated A549 cells or DHLF-IPF cells were studied. In nonclinical studies, NEN ameliorated lung function and histopathological changes in bleomycin-challenged mice, and the lung hydroxyproline content was significantly diminished with NEN treatment. In vitro, NEN inhibited PI3K-mTORC1 signalling and arrested the cell cycle to prevent uncontrolled fibroblast proliferation. Additionally, NEN inhibited TGF-β1-induced epithelial–mesenchymal transition (EMT) and ECM accumulation via the mTORC1-4EBP1 axis. Furthermore, NEN-activated noncanonical autophagy resensitized fibroblasts to apoptosis. The above findings demonstrated the potential antifibrotic effect of NEN mediated via modulation of the PI3K-mTORC1 and autophagy pathways. These data provide strong evidence for a therapeutic role for NEN in IPF. Full article
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2021

Jump to: 2022

15 pages, 3000 KiB  
Article
Vardenafil Activity in Lung Fibrosis and In Vitro Synergy with Nintedanib
by Michael H. Bourne, Jr., Theodore J. Kottom, Deanne M. Hebrink, Malay Choudhury, Edward B. Leof and Andrew H. Limper
Cells 2021, 10(12), 3502; https://doi.org/10.3390/cells10123502 - 11 Dec 2021
Cited by 6 | Viewed by 2564
Abstract
Idiopathic pulmonary fibrosis (IPF) remains an intractably fatal disorder, despite the recent advent of anti-fibrotic medication. Successful treatment of IPF, like many chronic diseases, may benefit from the concurrent use of multiple agents that exhibit synergistic benefit. In this light, phosphodiesterase type 5 [...] Read more.
Idiopathic pulmonary fibrosis (IPF) remains an intractably fatal disorder, despite the recent advent of anti-fibrotic medication. Successful treatment of IPF, like many chronic diseases, may benefit from the concurrent use of multiple agents that exhibit synergistic benefit. In this light, phosphodiesterase type 5 inhibitors (PDE5-Is), have been studied in IPF primarily for their established pulmonary vascular effects. However, recent data suggest certain PDE5-Is, particularly vardenafil, may also reduce transforming growth factor beta 1 (TGF-β1) activation and extracellular matrix (ECM) accumulation, making them a potential target for therapy for IPF. We evaluated fibroblast TGF-β1-driven extracellular matrix (ECM) generation and signaling as well as epithelial mesenchymal transformation (EMT) with pretreatment using the PDE5-I vardenafil. In addition, combinations of vardenafil and nintedanib were evaluated for synergistic suppression of EMC using a fibronectin enzyme-linked immunosorbent assay (ELISA). Finally, the effects of vardenafil on fibrosis were investigated in a bleomycin mouse model. Our findings demonstrate that vardenafil suppresses ECM generation alone and also exhibits significant synergistic suppression of ECM in combination with nintedanib in vitro. Interestingly, vardenafil was shown to improve fibrosis markers and increase survival in bleomycin-treated mice. Vardenafil may represent a potential treatment for IPF alone or in combination with nintedanib. However, additional studies will be required. Full article
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24 pages, 646 KiB  
Review
Treatable Traits in Chronic Respiratory Disease: A Comprehensive Review
by Yong Qin Lee, Asvin Selvakumar and Kay Choong See
Cells 2021, 10(11), 3263; https://doi.org/10.3390/cells10113263 - 22 Nov 2021
Cited by 3 | Viewed by 2612
Abstract
Chronic respiratory diseases are major contributors to the global burden of disease. While understanding of these diseases has improved, treatment guidelines have continued to rely on severity and exacerbation-based approaches. A new personalised approach, termed the “treatable traits” approach, has been suggested to [...] Read more.
Chronic respiratory diseases are major contributors to the global burden of disease. While understanding of these diseases has improved, treatment guidelines have continued to rely on severity and exacerbation-based approaches. A new personalised approach, termed the “treatable traits” approach, has been suggested to address the limitations of the existing treatment strategies. We aim to systematically review the current evidence regarding treatable traits in chronic respiratory diseases and to identify gaps in the current literature. We searched the PubMed and Embase databases and included studies on treatable traits and chronic respiratory diseases. We then extracted information on prevalence, prognostic implications, treatment options and benefits from these studies. A total of 58 papers was included for review. The traits identified were grouped into five broad themes: physiological, biochemical, psychosocial, microbiological, and comorbidity traits. Studies have shown advantages of the treatable traits paradigm in the clinical setting. However, few randomised controlled trials have been conducted. Findings from our review suggest that multidisciplinary management with therapies targeted at treatable traits has the potential to be efficacious when added to the best practices currently implemented. This paradigm has the potential to improve the holistic care of chronic respiratory diseases. Full article
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Graphical abstract

30 pages, 7666 KiB  
Article
Deleterious Role of Th9 Cells in Pulmonary Fibrosis
by Kui Miao Deng, Xiang Sheng Yang, Qun Luo, Yi Xin She, Qing Yang Yu and Xiao Xiao Tang
Cells 2021, 10(11), 3209; https://doi.org/10.3390/cells10113209 - 17 Nov 2021
Cited by 13 | Viewed by 2910
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Immune disorders play an important role in IPF pathogenesis. Here, we show that Th9 cells differentiate and activate in the lung tissue of patients with IPF and bleomycin (BLM)-induced [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Immune disorders play an important role in IPF pathogenesis. Here, we show that Th9 cells differentiate and activate in the lung tissue of patients with IPF and bleomycin (BLM)-induced lung fibrosis mice. Moreover, we found that Th9 cells promote pulmonary fibrosis in two ways. On the one hand, Th9 cells promote fibroblast differentiation, activation, and collagen secretion by secreting IL-9. On the other hand, they promote differentiation of Th0 cells into Th2 cells by secreting IL-4. Th9 cells and Th2 cells can promote each other, accelerating the Th1/Th2 imbalance and eventually forming a positive feedback of pulmonary fibrosis. In addition, we found that neutralizing IL-9 in both preventive and therapeutic settings ameliorates bleomycin-induced pulmonary fibrosis. Furthermore, we identified several critical signaling pathways involved in the effect of neutralizing IL-9 on pulmonary fibrosis by proteomics study. From an immunological perspective, we elucidated the novel role and underlying mechanism of Th9 cells in pulmonary fibrosis. Our study suggested that Th9-based immunotherapy may be employed as a treatment strategy for IPF. Full article
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Graphical abstract

13 pages, 610 KiB  
Review
Basophils and Mast Cells in COVID-19 Pathogenesis
by Giuseppe Murdaca, Mario Di Gioacchino, Monica Greco, Matteo Borro, Francesca Paladin, Claudia Petrarca and Sebastiano Gangemi
Cells 2021, 10(10), 2754; https://doi.org/10.3390/cells10102754 - 14 Oct 2021
Cited by 40 | Viewed by 4815
Abstract
Basophils and mast cells are among the principal inducers of Th2 responses and have a crucial role in allergic and anti-parasitic protective immunity. Basophils can function as antigen-presenting cells that bind antigens on their surface and boost humoral immune responses, inducing Th2 cell [...] Read more.
Basophils and mast cells are among the principal inducers of Th2 responses and have a crucial role in allergic and anti-parasitic protective immunity. Basophils can function as antigen-presenting cells that bind antigens on their surface and boost humoral immune responses, inducing Th2 cell differentiation. Their depletion results in lower humoral memory activation and greater infection susceptibility. Basophils seem to have an active role upon immune response to SARS-CoV-2. In fact, a coordinate adaptive immune response to SARS-CoV-2 is magnified by basophils. It has been observed that basophil amount is lower during acute disease with respect to the recovery phase and that the grade of this depletion is an important determinant of the antibody response to the virus. Moreover, mast cells, present in a great quantity in the nasal epithelial and lung cells, participate in the first immune response to SARS-CoV-2. Their activation results in a hyperinflammatory syndrome through the release of inflammatory molecules, participating to the “cytokine storm” and, in a longer period, inducing pulmonary fibrosis. The literature data suggest that basophil counts may be a useful prognostic tool for COVID-19, since their reduction is associated with a worse prognosis. Mast cells, on the other hand, represent a possible therapeutic target for reducing the airway inflammation characteristic of the hyperacute phase of the disease. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Single Cell Deconvolution of Pulmonary Fibrosis（tentative title）
Authors: Amir Abdollahi; Jennifer Furkel; Mahmoud Moustafa; Max Knoll
Affiliation: Division of Molecular and Translational Radiation Oncology Heidelberg Faculty of Medicine (MFHD) Heidelberg University Hospital (UKHD) Heidelberg Ion-Beam Therapy Center (HIT) Im Neuenheimer Feld 450 Director: Radiation Oncology Programs Head: Personalized Radiation Oncology (NCT-PRO) National Center for Tumor Disease (NCT) Im Neuenheimer Feld 460 Clinical Cooperation Unit Translational Radiation Oncology (E210) National Coordinator: Radiation Oncology Program German Cancer Consortium (DKTK) German Cancer Research Center (DKFZ) Im Neuenheimer Feld 223 69120 Heidelberg Germany
Abstract: Our manuscript will describe pitfalls and the methodological developments needed to achieve a comprehensive cellular diversity representation in normal vs. fibrotic lungs via extrocoporal perfusion of two preclinical mouse lung models etc. and 10X NGS single cell transcriptomics.

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