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Cells
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Cell Therapy for Lung Disease
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Cell Therapy for Lung Disease

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 21355

Special Issue Editors

Prof. Dr. Daniel J. Weiss

E-Mail Website
Guest Editor
Department of Medicine, University of Vermont, Burlington, VT, USA
Interests: lung disorders; lung biology; stem cells; mesenchymal stromal cells; bioengineering; cell therapy
Prof. Dr. Sara Rolandsson Enes

E-Mail Website
Guest Editor
Department of Experimental Medical Science, Lund University, Lund, Sweden
Interests: lung disorders; lung biology; lung repair; mesenchymal stromal cells; cell therapy; cell biology

Special Issue Information

Dear Colleagues, 

Chronic respiratory diseases such as acute respiratory distress syndrome (ARDS), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) remain a significant cause of morbidity and mortality worldwide. For many of these severe lung diseases, there is currently no cure, and it is becoming evident that new and innovative therapeutic strategies are needed. One such strategy involves cell-based therapy, utilizing administration of a variety of cell types, including mesenchymal stromal cells (MSCs), induced pluripotent stem cells (iPSCs), and epithelial- or endothelial progenitor cells either through a systemic or intratracheal route to repair damaged or dysfunctional lung tissue. Uncovering the mechanisms by which cell-therapeutic approaches may inhibit or reverse lung tissue destruction and stimulate proper tissue remodeling may promote the development of novel therapies against severe chronic lung diseases. 

Therefore, this Specific Issue aims to gather a comprehensive collection of basic, translational, and clinical original research articles and reviews that will stimulate continuing efforts to understand and develop effective and safe cell therapy for lung diseases. 

Prof. Dr. Daniel J. Weiss
Prof. Dr. Sara Rolandsson Enes
Guest Editors

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 special issue 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.

Dr. Daniel J Weiss
Prof. Dr. Sara Rolandsson Enes
Guest Editors

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 special issue 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

  • Lung disease
  • Cell therapy
  • Stem cells
  • Remodeling
  • Progenitors

Published Papers (7 papers)

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Research

Jump to: Review

13 pages, 4250 KiB  
Communication
hLMSC Secretome Affects Macrophage Activity Differentially Depending on Lung-Mimetic Environments
by Bryan Falcones, Zackarias Söderlund, Arturo Ibáñez-Fonseca, Isaac Almendros, Jordi Otero, Ramon Farré, Sara Rolandsson Enes, Linda Elowsson Rendin and Gunilla Westergren-Thorsson
Cells 2022, 11(12), 1866; https://doi.org/10.3390/cells11121866 - 8 Jun 2022
Cited by 7 | Viewed by 2021
Abstract
Mesenchymal stromal cell (MSC)-based therapies for inflammatory diseases rely mainly on the paracrine ability to modulate the activity of macrophages. Despite recent advances, there is scarce information regarding changes of the secretome content attributed to physiomimetic cultures and, especially, how secretome content influence [...] Read more.
Mesenchymal stromal cell (MSC)-based therapies for inflammatory diseases rely mainly on the paracrine ability to modulate the activity of macrophages. Despite recent advances, there is scarce information regarding changes of the secretome content attributed to physiomimetic cultures and, especially, how secretome content influence on macrophage activity for therapy. hLMSCs from human donors were cultured on devices developed in house that enabled lung-mimetic strain. hLMSC secretome was analyzed for typical cytokines, chemokines and growth factors. RNA was analyzed for the gene expression of CTGF and CYR61. Human monocytes were differentiated to macrophages and assessed for their phagocytic capacity and for M1/M2 subtypes by the analysis of typical cell surface markers in the presence of hLMSC secretome. CTGF and CYR61 displayed a marked reduction when cultured in lung-derived hydrogels (L-Hydrogels). The secretome showed that lung-derived scaffolds had a distinct secretion while there was a large overlap between L-Hydrogel and the conventionally (2D) cultured samples. Additionally, secretome from L-Scaffold showed an HGF increase, while IL-6 and TNF-α decreased in lung-mimetic environments. Similarly, phagocytosis decreased in a lung-mimetic environment. L-Scaffold showed a decrease of M1 population while stretch upregulated M2b subpopulations. In summary, mechanical features of the lung ECM and stretch orchestrate anti-inflammatory and immunosuppressive outcomes of hLMSCs. Full article
(This article belongs to the Special Issue Cell Therapy for Lung Disease)
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16 pages, 4575 KiB  
Communication
Ciliated (FOXJ1+) Cells Display Reduced Ferritin Light Chain in the Airways of Idiopathic Pulmonary Fibrosis Patients
by Sofia C. Wijk, Pavan Prabhala, Anna Löfdahl, Annika Nybom, Stefan Lang, Hans Brunnström, Leif Bjermer, Gunilla Westergren-Thorsson and Mattias Magnusson
Cells 2022, 11(6), 1031; https://doi.org/10.3390/cells11061031 - 18 Mar 2022
Cited by 2 | Viewed by 2699
Abstract
Cell-based therapies hold great promise in re-establishing organ function for many diseases, including untreatable lung diseases such as idiopathic pulmonary fibrosis (IPF). However, many hurdles still remain, in part due to our lack of knowledge about the disease-driving mechanisms that may affect the [...] Read more.
Cell-based therapies hold great promise in re-establishing organ function for many diseases, including untreatable lung diseases such as idiopathic pulmonary fibrosis (IPF). However, many hurdles still remain, in part due to our lack of knowledge about the disease-driving mechanisms that may affect the cellular niche and thereby possibly hinder the function of any transplanted cells by imposing the disease phenotype onto the newly generated progeny. Recent findings have demonstrated increased ciliation of lung cells from IPF patients, but how this affects ciliated cell function and the airway milieu is not well-known. Here, we performed single-cell RNA sequencing on primary ciliated (FOXJ1+) cells isolated from IPF patients and from healthy control donors. The sequencing identified multiple biological processes, such as cilium morphogenesis and cell signaling, that were significantly changed between IPF and healthy ciliated cells. Ferritin light chain (FTL) was downregulated in IPF, which suggests that iron metabolism may be affected in the IPF ciliated cells. The RNA expression was confirmed at the protein level with histological localization in lung tissue, prompting future functional assays to reveal the potential role of FTL. Taken together, our data demonstrate the importance of careful analyses in pure cell populations to better understand the IPF disease mechanism. Full article
(This article belongs to the Special Issue Cell Therapy for Lung Disease)
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17 pages, 6413 KiB  
Article
A Novel Bioreactor for Reconstitution of the Epithelium and Submucosal Glands in Decellularized Ferret Tracheas
by Albert C. Pai, Thomas J. Lynch, Bethany A. Ahlers, Vitaly Ievlev, John F. Engelhardt and Kalpaj R. Parekh
Cells 2022, 11(6), 1027; https://doi.org/10.3390/cells11061027 - 18 Mar 2022
Cited by 6 | Viewed by 1901
Abstract
Tracheal grafts introduce the possibility to treat airway pathologies that require resection. While there has been success with engraftment of the surface airway epithelium (SAE) onto decellularized tracheas, there has been minimal advancement in regenerating the submucosal glands (SMGs). We designed a cost-effective [...] Read more.
Tracheal grafts introduce the possibility to treat airway pathologies that require resection. While there has been success with engraftment of the surface airway epithelium (SAE) onto decellularized tracheas, there has been minimal advancement in regenerating the submucosal glands (SMGs). We designed a cost-effective open-system perfusion bioreactor to investigate the engraftment potential of ferret SAEs and murine myoepithelial cells (MECs) on a partly decellularized ferret trachea with the goal of creating a fully functional tracheal replacement. An air–liquid interface was also arranged by perfusing humidified air through the lumen of a recellularized conduit to induce differentiation. Our versatile bioreactor design was shown to support the successful partial decellularization and recellularization of ferret tracheas. The decellularized grafts maintained biomechanical integrity and chondrocyte viability, consistent with other publications. The scaffolds supported SAE basal cell engraftment, and early differentiation was observed once an air–liquid interface had been established. Lastly, MEC engraftment was sustained, with evidence of diffuse SMG reconstitution. This model will help shed light on SMG regeneration and basal cell differentiation in vitro for the development of fully functional tracheal grafts before transplantation. Full article
(This article belongs to the Special Issue Cell Therapy for Lung Disease)
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19 pages, 2954 KiB  
Article
Paracrine Regulation of Alveolar Epithelial Damage and Repair Responses by Human Lung-Resident Mesenchymal Stromal Cells
by Dennis M. L. W. Kruk, Marissa Wisman, Jacobien A. Noordhoek, Mehmet Nizamoglu, Marnix R. Jonker, Harold G. de Bruin, Karla Arevalo Gomez, Nick H. T. ten Hacken, Simon D. Pouwels and Irene H. Heijink
Cells 2021, 10(11), 2860; https://doi.org/10.3390/cells10112860 - 23 Oct 2021
Cited by 11 | Viewed by 3331
Abstract
COPD is characterized by irreversible lung tissue damage. We hypothesized that lung-derived mesenchymal stromal cells (LMSCs) reduce alveolar epithelial damage via paracrine processes, and may thus be suitable for cell-based strategies in COPD. We aimed to assess whether COPD-derived LMSCs display abnormalities. LMSCs [...] Read more.
COPD is characterized by irreversible lung tissue damage. We hypothesized that lung-derived mesenchymal stromal cells (LMSCs) reduce alveolar epithelial damage via paracrine processes, and may thus be suitable for cell-based strategies in COPD. We aimed to assess whether COPD-derived LMSCs display abnormalities. LMSCs were isolated from lung tissue of severe COPD patients and non-COPD controls. Effects of LMSC conditioned-medium (CM) on H2O2-induced, electric field- and scratch-injury were studied in A549 and NCI-H441 epithelial cells. In organoid models, LMSCs were co-cultured with NCI-H441 or primary lung cells. Organoid number, size and expression of alveolar type II markers were assessed. Pre-treatment with LMSC-CM significantly attenuated oxidative stress-induced necrosis and accelerated wound repair in A549. Co-culture with LMSCs supported organoid formation in NCI-H441 and primary epithelial cells, resulting in significantly larger organoids with lower type II-marker positivity in the presence of COPD-derived versus control LMSCs. Similar abnormalities developed in organoids from COPD compared to control-derived lung cells, with significantly larger organoids. Collectively, this indicates that LMSCs’ secretome attenuates alveolar epithelial injury and supports epithelial repair. Additionally, LMSCs promote generation of alveolar organoids, with abnormalities in the supportive effects of COPD-derived LMCS, reflective of impaired regenerative responses of COPD distal lung cells. Full article
(This article belongs to the Special Issue Cell Therapy for Lung Disease)
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Review

Jump to: Research

14 pages, 6072 KiB  
Review
Mesenchymal Stromal Cell-Derived Extracellular Vesicles for Neonatal Lung Disease: Tiny Particles, Major Promise, Rigorous Requirements for Clinical Translation
by Flore Lesage and Bernard Thébaud
Cells 2022, 11(7), 1176; https://doi.org/10.3390/cells11071176 - 31 Mar 2022
Cited by 12 | Viewed by 2392
Abstract
Extreme preterm birth disrupts late lung development and puts newborns at risk of developing chronic lung disease, known as bronchopulmonary dysplasia (BPD). BPD can be associated with life-long complications, and currently no effective treatment is available. Cell therapies are entering the clinics to [...] Read more.
Extreme preterm birth disrupts late lung development and puts newborns at risk of developing chronic lung disease, known as bronchopulmonary dysplasia (BPD). BPD can be associated with life-long complications, and currently no effective treatment is available. Cell therapies are entering the clinics to curb complications of extreme preterm birth with several clinical trials testing the feasibility, safety and efficacy of mesenchymal stromal cells (MSCs). The therapeutic effect of MSCs is contained in their secretome, and nanosized membranous structures released by the MSCs, known as extracellular vesicles (EVs), have been shown to be the therapeutic vectors. Driven by this discovery, the efficacy of EV-based therapy is currently being explored in models of BPD. EVs derived from MSCs, contain a rich cargo of anti-inflammatory and pro-angiogenic molecules, making them suitable candidates to treat multifactorial diseases such as BPD. Here, we review the state-of-the-art of preclinical studies involving MSC-derived EVs in models of BPD and highlight technical and regulatory challenges that need to be addressed before clinical translation. In addition, we aim at increasing awareness regarding the importance of rigorous reporting of experimental details of EV experiments and to increase the outreach of the current established guidelines amongst researchers in the BPD field. Full article
(This article belongs to the Special Issue Cell Therapy for Lung Disease)
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18 pages, 885 KiB  
Review
The Inflammatory Lung Microenvironment; a Key Mediator in MSC Licensing
by Hazel Dunbar, Daniel J Weiss, Sara Rolandsson Enes, John G Laffey and Karen English
Cells 2021, 10(11), 2982; https://doi.org/10.3390/cells10112982 - 2 Nov 2021
Cited by 12 | Viewed by 3334
Abstract
Recent clinical trials of mesenchymal stromal cell (MSC) therapy for various inflammatory conditions have highlighted the significant benefit to patients who respond to MSC administration. Thus, there is strong interest in investigating MSC therapy in acute inflammatory lung conditions, such as acute respiratory [...] Read more.
Recent clinical trials of mesenchymal stromal cell (MSC) therapy for various inflammatory conditions have highlighted the significant benefit to patients who respond to MSC administration. Thus, there is strong interest in investigating MSC therapy in acute inflammatory lung conditions, such as acute respiratory distress syndrome (ARDS). Unfortunately, not all patients respond, and evidence now suggests that the differential disease microenvironment present across patients and sub-phenotypes of disease or across disease severities influences MSC licensing, function and therapeutic efficacy. Here, we discuss the importance of licensing MSCs and the need to better understand how the disease microenvironment influences MSC activation and therapeutic actions, in addition to the need for a patient-stratification approach. Full article
(This article belongs to the Special Issue Cell Therapy for Lung Disease)
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27 pages, 4783 KiB  
Review
Evolution of Diploid Progenitor Lung Cell Applications: From Optimized Biotechnological Substrates to Potential Active Pharmaceutical Ingredients in Respiratory Tract Regenerative Medicine
by Alexis Laurent, Philippe Abdel-Sayed, Nathalie Hirt-Burri, Corinne Scaletta, Murielle Michetti, Anthony de Buys Roessingh, Wassim Raffoul and Lee Ann Applegate
Cells 2021, 10(10), 2526; https://doi.org/10.3390/cells10102526 - 24 Sep 2021
Cited by 3 | Viewed by 4649
Abstract
The objective of this review is to describe the evolution of lung tissue-derived diploid progenitor cell applications, ranging from historical biotechnological substrate functions for vaccine production and testing to current investigations around potential therapeutic use in respiratory tract regenerative medicine. Such cell types [...] Read more.
The objective of this review is to describe the evolution of lung tissue-derived diploid progenitor cell applications, ranging from historical biotechnological substrate functions for vaccine production and testing to current investigations around potential therapeutic use in respiratory tract regenerative medicine. Such cell types (e.g., MRC-5 or WI-38 sources) were extensively studied since the 1960s and have been continuously used over five decades as safe and sustainable industrial vaccine substrates. Recent research and development efforts around diploid progenitor lung cells (e.g., FE002-Lu or Walvax-2 sources) consist in qualification for potential use as optimal and renewed vaccine production substrates and, alternatively, for potential therapeutic applications in respiratory tract regenerative medicine. Potentially effective, safe, and sustainable cell therapy approaches for the management of inflammatory lung diseases or affections and related symptoms (e.g., COVID-19 patients and burn patient severe inhalation syndrome) using local homologous allogeneic cell-based or cell-derived product administrations are considered. Overall, lung tissue-derived progenitor cells isolated and produced under good manufacturing practices (GMP) may be used with high versatility. They can either act as key industrial platforms optimally conforming to specific pharmacopoeial requirements or as active pharmaceutical ingredients (API) for potentially effective promotion of lung tissue repair or regeneration. Full article
(This article belongs to the Special Issue Cell Therapy for Lung Disease)
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