Most organs in the adult human body are able to maintain themselves and undergo repair after injury; these processes are largely dependent on stem cells. In this Monograph, the Guest Editors bring together leading authors in the field to provide information about the different classes of stem cells present both in the developing and adult lung: where they are found, how they function in homeostasis and pathologic conditions, the mechanisms that regulate their behaviour, and how they may be harnessed for therapeutic purposes. The book focuses on stem cells in the mouse and human lung but also includes the ferret as an increasingly important new model organism. Chapters also discuss how lung tissue, including endogenous stem cells, can be generated in vitro from pluripotent stem cell lines. This state-of-the-art collection comprehensively covers one of the most exciting areas of respiratory science.
- Page 1AbstractMarko Z. Nikolić, UCL Respiratory, Division of Medicine, Rayne Institute, 5 University Street, London, WC1E 6JF, UK. E-mail: m.nikolic@ucl.ac.uk
The study of human fetal lung development presents many challenges, partly due to the nature of the tissue required. While great strides have been made in characterising the molecular events driving lung development in the mouse, the same processes in humans have, until recently, remained vastly unexplored. This chapter highlights key events throughout the five phases of lung development, including those in the conducting airways, alveoli, mesenchyme and pleura, presenting a comparative analysis between humans and mice. The study of lung development is essential to formulate better therapies for extremely premature neonates, as well as to inform regenerative medicine efforts for patients with end-stage lung disease.
Cite as: Allen-Hyttinen J, Yung H, Nikolić MZ. Lung development. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 1–16 [https://doi.org/10.1183/2312508X.10008720].
- Page 17AbstractNan Tang, National Institute of Biological Sciences, Beijing 102206, China. E-mail: tangnan@nibs.ac.cn
Alveoli contain two types of epithelial cells: AT1 and AT2 cells. AT1 cells are squamous and are in close contact with capillaries to perform gas exchange. AT2 cells are cuboid and secrete surfactant to reduce surface tension during alveolar expansion. During development, alveolar progenitor cells differentiate into AT1 and AT2 cells in a proximal-to-distal pattern. When a lung lobe is removed, AT2 cells function as alveolar stem cells to self-renew and differentiate into AT1 cells. Alveolar development and regrowth are coordinately regulated by mechanical force-mediated and growth factor-mediated signalling. In this chapter, we summarise the process of alveolar development and regrowth and the regulatory mechanisms involved.
Cite as: Li J, Tang N. Alveolar stem cells in lung development and regrowth. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 17–30 [https://doi.org/10.1183/2312508X.10009520].
- Page 31AbstractChristiana Ruhrberg, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK. E-mail c.ruhrberg@ucl.ac.uk. Tsvetana Stoilova, UCL Institute of Ophthalmology, 11–43 Bath Street, London, EC1V 9EL, UK. E-mail: tsvetana.stoilova.17@ucl.ac.uk.
Defective development of blood or lymphatic vasculature in the lungs causes congenital diseases, such as BPD and lymphangiectasia. Although much is known about the mechanisms regulating lung epithelial branching and differentiation, the molecular and cellular pathways that regulate lung vascular development are not well understood. In this chapter, we review current knowledge of the origin of the endothelial cells that give rise to blood and lymphatic vessels and provide an overview of key molecular and cellular mechanisms known to regulate vascular patterning and vascular–epithelial crosstalk in the lungs. Research that defines how lung blood and lymphatic vessels form and integrate with other lung structures improves our understanding of congenital lung diseases, and may identify confounding factors for adult-onset lung disorders.
Cite as: Stoilova T, Ruhrberg C. Lung blood and lymphatic vascular development. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 31–43 [https://doi.org/10.1183/2312508X.10008920].
- Page 44AbstractXin Sun, Dept of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA. E-mail: xinsun@ucsd.edu. Barbara Dash, Dept of Pediatrics, University of California, San Diego, CA 92093, USA. E-mail: bdash@ucsd.edu.
As a gas-exchange organ, the lung is constantly exposed to a diverse array of aerosol inputs such as pollutants, allergens, pathogens and varying levels of oxygen. How the lung senses and interprets these signals into distinct physiological outputs remains poorly understood. PNECs are rare airway epithelial cells that act as sensors in the lung. In response to signals such as allergens, hypoxia and nicotine, they secrete bioactive neuropeptides and neurotransmitters. They are innervated by both afferent and efferent nerves. While the full range of PNEC biological functions is still being elucidated, recent evidence demonstrates that PNECs are essential for amplifying allergen-induced immune responses and goblet cell metaplasia. As well as acting as sensors, PNECs possess both progenitor and progenitor niche capacities, and contribute to airway regeneration following injury. Interestingly, PNEC pathologies have been documented in a large number of lung diseases such as asthma, COPD, pulmonary hypertension and small cell lung carcinoma, making them an attractive target for therapy. This chapter will discuss PNEC development, regulation, function and pathogenesis. The summation of current findings demonstrates that, despite their rarity, PNECs play notable roles in multiple aspects of lung homeostasis, including sensing the environment, repairing damage, and coordinating the function of the lung with that of the immune and nervous systems.
Cite as: Dash B, Kim E, Sun X. Neuroendocrine cells in lung development and disease. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 44–55 [https://doi.org/10.1183/2312508X.10025020].
- Page 56AbstractHongmei Mou, The Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Jackson Building 1402, 55 Fruit Street, Boston, MA 02114, USA. E-mail: hmou@mgh.harvard.edu. Jayaraj Rajagopal, Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA. E-mail: JRAJAGOPAL@mgh.harvard.edu
The basal cells of the mouse and human airway serve as stem cells for the airway epithelium. Airway basal cells are additionally involved in many other aspects of epithelial biology, including intraepithelial signalling, barrier formation and immune regulation. There is increasing evidence of heterogeneity within the basal cell population. However, the significance of this heterogeneity is unknown. At the population level, basal cells can be sorted using either surface markers or genetic tags. Additionally, basal cell-specific murine driver lines have permitted the mechanistic dissection of basal cell-specific behaviours, including their differentiation, self-renewal and signalling. Together, these advances have led to improved methods for culturing and expanding primary mouse and human basal cells and the generation of basal cells from patient-specific iPSCs.
Cite as: Lin B, Sun J, Mou H, et al. Adult mouse and human airway epithelial basal stem cells. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 56–69 [https://doi.org/10.1183/2312508X.10009020].
- Page 70AbstractAleksandra Tata, Dept of Cell Biology, 307 Research Drive, Nanaline Research Building, Room No. 353, Durham, NC 27710, USA. E-mail: Aleksandra.Tata@duke.edu
In the human lung, SMGs are the main source of mucus, a key component of airway clearance and defence. They are tubuloacinar structures buried in the mesenchyme along the cartilaginous airways and are composed of ciliated ducts, collecting ducts, mucous tubules and many serous acini. The secretory units are surrounded by stellate-shaped cells called myoepithelial cells. The myoepithelial cells and basal cells in the ducts function as stem cells of the SMGs and also contribute to the surface epithelium of the airway after injury. The SMG thereby serves as a reservoir of multipotent stem cells for the lung. SMGs exhibit widespread histological changes including mucous cell hypertrophy and excess mucus production in many muco-obstructive airway diseases including asthma, COPD and CF. Although the molecular mechanisms underlying such changes remain unknown, emerging studies using scRNA-seq are providing insights into SMG-mediated airway injury/repair and disease mechanisms, and may offer therapeutic avenues to treat muco-obstructive diseases.
Cite as: Tata A. Stem cells of submucosal glands: their function as tissue stem cells and a reserve population for airway repair. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 70–83 [https://doi.org/10.1183/2312508X.10009220].
- Page 84AbstractBarry R. Stripp, Dept of Medicine, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd, Los Angeles, CA 90048, USA. E-mail: barry.stripp@cshs.org. Joo-Hyeon Lee, Wellcome – MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Puddicombe Way, Cambridge, CB2 0AW, UK. E-mail: jhl62@cam.ac.uk.
Epithelial cells in the bronchiolar airways of the adult mouse lung are quiescent and fulfil specialised functions in the steady state, with club cells undergoing stochastic activation to effect normal homeostatic maintenance. Repair following injury involves proliferation of remaining club cells or other recruited progenitor cell types, depending on the type and extent of injury, leading to regeneration or remodelling. In some cases, there is evidence that some distal airway epithelial progenitor cell types can contribute to either repair or remodelling of injured alveolar epithelium. In this chapter, we discuss what is known of epithelial progenitor cell types that contribute to homeostatic maintenance or repair/remodelling of the distal airway and alveolar zone, and signalling pathways that regulate the behaviour and fate of progenitor cells and their progeny.
Cite as: Dabrowska C, Li J, Mulay A, et al. Adult mouse intralobar airway stem cells. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 84–98 [https://doi.org/10.1183/2312508X.10009120].
- Page 99AbstractElie El Agha, Institute for Lung Health (ILH), 35392 Giessen, Germany. Email: elie.el-agha@innere.med.uni-giessen.de. Saverio Bellusci, Dept of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, Germany. E-mail: saverio.bellusci@innere.med.uni-giessen.de
Exploring fundamental mechanisms of lung organogenesis is critical for understanding complex signalling networks that underlie pulmonary disease development and resolution later in life. In this regard, mesenchymal cells have taken centre stage, as they contribute to the niche that supports epithelial stem cells and guides their behaviour along the proximal–distal axis in various biological and pathological settings. Disturbance of mesenchymal cell homeostasis can have detrimental consequences on lung structure and function, leading to chronic lung diseases such as lung fibrosis. In the proximal part of the lung, ASM cells constitute the niche for airway epithelial progenitors; in the distal counterpart, lipofibroblasts are involved in AT2 cell growth and maintenance. Here, we summarise our knowledge regarding the heterogeneity of mesenchymal cells in the developing and post-natal lung with special emphasis on mesenchymal cell transdifferentiation, as well as niche–stem cell interactions during both airway and alveolar regeneration.
Cite as: El Agha E, Bellusci S. Evidence for the involvement of lipofibroblasts, airway smooth muscle cells and FGF10 signalling in lung repair. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 99–113 [https://doi.org/10.1183/2312508X.10009720].
- Page 114AbstractEdward E. Morrisey, University of Pennsylvania, Smilow Translational Research Center, Room 11-124, 3400 Civic Center Boulevard, Building 421, Philadelphia, PA 19104-5129, USA. E-mail: emorrise@pennmedicine.upenn.edu
The human lung is distinct from its murine counterpart in terms of both its greater size and in several aspects of its anatomical and cellular composition. This chapter will focus on differences between the murine and human lung, in particular the most distal airways of the human lung, the respiratory airways. This region, which contains the respiratory bronchioles, is a distinct anatomical structure within the lungs of large mammals. Within the respiratory bronchioles, airway epithelium is interspersed with regions of alveoli, allowing this region to participate in both airway conduction and gas exchange. Mice lack respiratory airways, and this region remains one of the least understood compartments of the human lung. The respiratory bronchioles represent a site of injury in several human respiratory diseases such as COPD and bronchiolitis obliterans syndrome (BOS), which have proved difficult to model in mice. More advanced genetic approaches and human tissue-based culture systems will be needed to define the cellular composition and molecular functions of this region and to advance our knowledge of how this region contributes to human lung injury, repair and regeneration. This chapter explores these differences with a focus on the respiratory bronchioles and their role in diseases such as COPD and BOS.
Cite as: Basil MC, Morrisey EE. Respiratory bronchioles: a unique structure in the human lung. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 114–121 [https://doi.org/10.1183/2312508X.10009320].
- Page 122AbstractWilliam J. Zacharias, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7009, Cincinnati, OH 45229, USA. E-mail: william.zacharias@cchmc.org
Alveolar regeneration requires extensive differentiation of epithelial AT1 and AT2 cells. This chapter summarises the historical data regarding the presence and activity of alveolar progenitors and reviews the evidence of the AT2 cell as the primary alveolar progenitor cell. Evidence of the multiple signalling inputs required for full function of alveolar progenitor cells is discussed, with an emphasis on Wnt signalling, which defines an AT2 cell state or sublineage with enhanced regenerative capacity. We review recent evidence regarding the transitional state of AT2 cells during differentiation into AT1 cells and consider more proximal epithelial lineages that impact on alveolar regeneration. Finally, we summarise the current challenges facing the field and provide suggestions for operationalising our understanding of alveolar progenitors for future therapies.
Cite as: Toth A, Zhao B, Zacharias WJ. Alveolar epithelial stem cells in homeostasis and repair. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 122–133 [https://doi.org/10.1183/2312508X.10009420].
- Page 134AbstractJason R. Rock, Genentech, 1 DNA Way MS 34, South San Francisco, CA 94080, USA. E-mail: rock.jason@gene.com. Andrew J. Thorley, 1 DNA Way, Building 46, South San Francisco, CA 94080, USA. E-mail: thorley.andrew@gene.com.
Knowledge about the mechanisms that control the behaviours of epithelial stem and progenitor cells in the adult lung will inform efforts to harness regenerative potential as a therapeutic strategy for lung disease. Technical advances in recent years have ushered in a new era of cell discovery, along with deep phenotypic and functional characterisation. In this chapter, we will discuss “fibroblasts” and immune cells, particularly how they contribute to repair and regeneration of alveoli and airways as stem cell niches. We conclude by discussing several outstanding issues, including the need to adopt universal nomenclature and develop comprehensive models that incorporate multiple cell types and acellular features including mechanical forces.
Cite as: Thorley AJ, Rock JR. Mesenchymal cells, immune cells and the lung stem cell niche. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 134–143 [https://doi.org/10.1183/2312508X.10009620].
- Page 144AbstractJichao Chen, 6565 MD Anderson Blvd, Z9.5052 Houston, TX 77030, USA. E-mail: jchen16@mdanderson.org. Lisandra Vila Ellis, Dept of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd, Z9.5000.02, Houston, TX 77030, USA. E-mail: lvila@mdanderson.org.
Pulmonary endothelial cells, a key player in lung pathophysiology, have recently become better understood owing to advances in single-cell technology. The lung endothelium is heterogeneous, composed in mice mainly of two molecularly distinct capillary populations: Car4 endothelial cells expressing carbonic anhydrase 4 and Plvap endothelial cells expressing plasmalemma vesicle-associated protein. These cells engage in crosstalk with the other cell types in the lung, making them active members within their niche, and play an important role in developmental pathologies, as well as in the onset and progression of diseases of the adult lung. The recently described lung endothelial cell heterogeneity leads to new questions including the unique contribution of each endothelial cell type to development, homeostasis, disease and regeneration. This chapter will compare endothelial cells across organs, summarise their role as signalling and receiving cells in developing and adult lungs, and discuss the implications in lung diseases. A better understanding of the lung endothelium will not only further our knowledge about normal physiology but will also provide new therapeutic targets and interventions for prevalent lung pathologies.
Cite as: Vila Ellis L, Shuet Lin Kong C, Chen J. Endothelial cells in the lung. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 144–157 [https://doi.org/10.1183/2312508X.10009820].
- Page 158AbstractKerstin B. Meyer, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. E-mail: km16@sanger.ac.uk
To understand how the lung functions, is maintained in homeostasis and repairs itself after injury or infection, and to be able to interpret the pathological changes observed in disease, it is critical to gain a detailed understanding of all cell types of the lung and to map these into their spatial context, thus generating a human lung cell atlas. The ability to deliver such an atlas is driven by recent technological breakthroughs in single-cell profiling technologies, rapid advances in spatial profiling of gene expression, and the development of powerful computational tools to analyse this data and generate novel insights. Recent progress in mapping the cellular landscape of the lung has revealed a remarkable plasticity in some of the cellular lineages and the presence of a spectrum of transitional molecular phenotypes, indicating that cell-type identities might merely reflect intermediate phenotypes along a trajectory of possible cell states. To be able to generate the Human Lung Cell Atlas as a valuable reference map, we therefore need to examine cell populations and their precursors and progeny dynamically over time, in space and in health versus disease.
Cite as: Meyer KB, Wilbrey-Clark A, Nawijn M, et al. The Human Lung Cell Atlas: a transformational resource for cells of the respiratory system. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 158–174 [https://doi.org/10.1183/2312508X.10010920].
- Page 175AbstractHiroaki Katsura, Laboratory for Lung Development and Regeneration, Riken Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuou-ku, Kobe 650-0047, Japan. E-mail: hiroaki.katsura@riken.jp. Brigid L.M. Hogan, Duke University Dept of Cell Biology, Nanaline Duke Building, Room 388, 307 Research Drive, Durham, NC 27710, USA. Email: brigid.hogan@duke.edu
Organoids are self-organising, three-dimensional structures derived from stem/progenitor cells grown in culture. They maintain, at least in part, cellular and molecular properties and physiological functions of embryonic or adult tissues. Organoids are powerful tools for studying molecular mechanisms underlying the proliferation and differentiation of stem cells, the interactions between different cell populations, and disease development. In addition, because organoids more closely resemble primary tissue than cell lines, they provide reliable and scalable platforms for drug screening. In the respiratory tract, organoids have been derived from at least three distinct classes of stem/progenitor cells: basal cells, subsets of secretory cells and AEC2s. Here, we describe current procedures and the molecular and cellular characteristics of lung organoid cultures from mouse and human stem/progenitor cells. Furthermore, we exemplify how these organoids have been used to study lung stem cell biology and to model lung diseases for drug screening. Lastly, we discuss the current limitations and future directions of lung organoid cultures.
Cite as: Katsura H, Hogan BLM. Lung organoids: powerful tools for studying lung stem cells and diseases. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 175–189 [https://doi.org/10.1183/2312508X.10009920].
- Page 190AbstractAmy L. Ryan, Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Dept of Medicine, HMR 712, University of Southern California, Los Angeles, CA 90033, USA. E-mail: amy.firth@med.usc.edu. Finn Hawkins, Center for Regenerative Medicine (CReM), Boston University, Boston, MA 02118, USA. E-mail: hawk@bu.edu
iPSCs offer unique opportunities to study developmental programmes in human cells at time points that are typically inaccessible to researchers. iPSCs can be generated from any individual, expanded in large quantities while retaining pluripotency and, under appropriate conditions, can give rise to organ-specific cell types by recapitulating major developmental milestones in vitro through a process termed directed differentiation. In this chapter, we review the progress over the past decade in differentiating iPSCs into airway epithelial cells. We focus on airway basal cells, the primary stem cell of the airways, and the progress in generating these cells from iPSCs. Finally, we describe the current and future applications of this technology with a focus on disease modelling.
Cite as: Le Suer J, Sease R, Hawkins F, et al. Induced pluripotent stem cells for generating lung airway stem cells and modelling respiratory disease. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 190–204 [https://doi.org/10.1183/2312508X.10010120].
- Page 205AbstractDarrell N. Kotton, Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118, USA. E-mail: dkotton@bu.edu
An emerging literature now describes protocols for the directed differentiation of human iPSCs into functional iPSC-derived AT2 cells. These cells can be used to model human lung development, as well as a wide range of respiratory diseases. This chapter reviews this nascent field, beginning with past challenges in developing these protocols, as well as recent applications for disease modelling. Future work is needed to generate other alveolar cell types from iPSCs to reflect the complexity of the human lung alveoli.
Cite as: Huang J, Kotton DN. Induced pluripotent stem cells for generating lung alveolar epithelial cells and modelling respiratory disease. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 205–221 [https://doi.org/10.1183/2312508X.10010220].
- Page 222AbstractMelanie Königshoff, Division of Pulmonary, Allergy and Critical Care Medicine, UPMC Montefiore, NW628, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA. E-mail: koenigshoffm@upmc.edu. Charlotte Dean, National Heart and Lung Institute, Imperial College London, Sir Alexander Fleming Building, Exhibition Rd, South Kensington, London, SW7 2AZ, UK. E-mail: c.dean@imperial.ac.uk.
Precision-cut lung slices (PCLS) are 300–500 μm-thick sections of lung tissue. As such, they represent a small piece of lung that contains all of the resident cell populations. Moreover, the cells are present in the same ratios and with the same cell–cell and cell–matrix interactions as found in vivo. PCLS can be obtained from both healthy and diseased human lungs or from other animal species including mouse, rat and pig. In recent years, the growing use of PCLS for mechanistic investigations, studies of pathobiology and toxicological screening has highlighted the versatility of this tool, placing PCLS as one of the key ex vivo models for lung research.
Cite as: Dean C, Königshoff M. Three-dimensional tissue-based models for translational lung stem cell research: precision-cut lung slices. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 222–231 [https://doi.org/10.1183/2312508X.10011120].
- Page 232AbstractYair Reisner, Dept of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, 7435 Fannin Street, Houston, TX 77054, USA. E-mail: YReisner@mdanderson.org
The World Health Organization ranks lung diseases among the leading causes of morbidity and mortality worldwide. The definitive treatment for rapidly progressing and end-stage respiratory disease is lung transplantation, but due to the shortage of suitable donor lungs, this treatment is available only to a limited number of patients suffering from terminal lung disease. Advances in our understanding of lung biology suggest that this challenge could potentially be addressed by stem cell-based therapies. To this end, it is crucial to develop strategies for the use of allogeneic donors, as well as reliable animal assays for investigation of different lung progenitors, allowing us to determine their short- and long-term differentiation potential along different lung cell lineages, their self-renewal and the optimal administration route, as well as their morphological and functional curative capabilities in various disease models. In this chapter, we review a novel approach for attaining this goal, based on insights gained over a number of years from HSC transplantation, with special emphasis on the role of adequate pre-conditioning.
Cite as: Rosen C, Reisner Y. The use of pre-conditioning and novel assays in the development of protocols for transplantation of lung progenitors. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 232–247 [https://doi.org/10.1183/2312508X.10026620].
- Page 248AbstractDarcy E. Wagner, Dept of Experimental Medical Sciences, Lund University, B10 BMC, Lund, Sweden. E-mail: darcy.wagner@med.lu.se
The lung is a vital and dynamic organ that serves as a critical first barrier to environmental stimuli and facilitates gas exchange from birth until death. Developmental or genetic defects that impair lung function severely impact quality of life. Minor defects present in early life increase the likelihood that patients will develop chronic lung diseases in adulthood that have no cure. Current therapies aim to slow disease progression, with lung transplantation remaining the only option at end-stage disease. While a number of discoveries have been made using conventional cell culture and in vivo animal studies, new approaches are needed to develop effective therapies. Recent advances using bioengineering have created new models that more closely recapitulate human development and disease. In parallel, progress has been made towards generating lung tissue in the laboratory with the ultimate aim of transplantation. This chapter covers the progress and recent advances in applying bioengineering approaches towards improving our understanding of lung development, disease and regeneration.
Cite as: De Santis MM, Michielin F, Shibuya S, et al. Lung tissue bioengineering for transplantation and modelling of development, disease and regeneration. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 248–272 [https://doi.org/10.1183/2312508X.10011020].
- Page 273AbstractThomas J. Lynch, Dept of Surgery, University of Iowa, Iowa City, IA 52242, USA. E-mail: Thomas-lynch@uiowa.edu. John F. Engelhardt, Dept of Surgery, University of Iowa, Iowa City, IA 52242, USA. E-mail: john-engelhardt@uiowa.edu.
Ferrets (Mustela putorius furo) have had an extensive history in modelling respiratory diseases since the 1930s. Ferret and human lungs share conserved anatomical features and cellular compartments that differ from those of rodents. However, it is not yet known whether differences in stem cells or other aspects of anatomy explain why ferrets more accurately model certain airway diseases. In the same way that tissue structure is essential for proper function, tissue remodelling is intricately linked to pathogenesis. Thus, stem cells are vital to maintaining functional architecture and cellular composition. Recent advances in ferret genetic engineering have enabled stem cell fate-mapping, conditional genetics and the creation of disease models that parallel human pathology. Given their docile nature, short 42-day gestation and sexual maturation times (5–6 months), 10-year lifespan, tractability for longitudinal bronchoscopy and pulmonary function testing, and available genome, ferret models have expanded the opportunities to study stem cells in diseases such as CF, COPD, asthma and chronic allograft failure in lung transplantation.
Cite as: Pai AC, Parekh KR, Engelhardt JF, et al. Ferret respiratory disease models for the study of lung stem cells. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 273–289 [https://doi.org/10.1183/2312508X.10010320].
- Page 290AbstractPurushothama Rao Tata, 307 Research Drive, Nanaline Duke Building, Room 308, PO 3709, Durham, NC 27710, USA. E-mail: purushothamarao.tata@duke.edu. Rachel C. Chambers, 5 University Street, London WC1E 6JJ, UK. E-mail: r.chambers@ucl.ac.uk.
Stem cell proliferation and differentiation, carefully controlled re-activation of developmental pathways and finely regulated fibrogenesis all represent fundamental parts of the physiological regenerative processes following injury. When these overlapping processes are disrupted during the ensuing wound-healing response, this results in pathological fibrosis and organ dysfunction. IPF is the most progressive and fatal of all fibrotic conditions, and is hypothesised to be driven by epithelial stem cell dysfunction and a highly dysregulated epithelial–mesenchymal crosstalk in response to chronic epithelial injury in aged and genetically susceptible individuals. Dysregulated re-emergence of developmental pathways, genetic alterations, senescence and mechanical forces within the lung micro-environment drive transcriptional changes within existing stem cell populations, as well as the persistence of regenerative cell intermediates and the emergence of aberrant new cell populations. Dysfunctional epithelial stem cells and epithelial–mesenchymal crosstalk result in stem cell failure to effectively differentiate and repair, leading to fibrosis.
Cite as: Platé M, Kobayashi Y, Chambers RC, et al. Epithelial stem cells at the intersection of tissue regeneration and pulmonary fibrosis. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 290–305 [https://doi.org/10.1183/2312508X.10010420].
- Page 306AbstractTushar J. Desai, Room G3120b, Lokey Stem Cell Research Building, 265 Campus Drive, Stanford, CA 94305, USA. E-mail: tdesai@stanford.edu
CF is caused by mutations in the CFTR gene. Loss of airway CFTR ion-channel activity introduces a profound defect in mucus clearance and leads to inflammation, bacterial infection and irreversible structural damage starting as early as infancy. CF patients experience progressive lung function decline with infectious exacerbations, culminating in respiratory insufficiency and death. While pharmacological modulators that augment CFTR activity have tremendously improved the health of many CF patients, there is continued interest in developing durable and potentially curative cell-based therapies that can be deployed universally. Ongoing advances in viral vectors continue to motivate attempts at in vivo gene-therapy approaches. In parallel, the advent of iPSC lung differentiation protocols and efficient genome-editing technology have animated efforts for CFTR gene correction. Here, we discuss the prospects for gene therapy for CF lung disease in light of our current understanding of human airway cell lineages and how they are maintained, highlighting outstanding biological questions and logistical obstacles that will need to be overcome for clinical application in patients.
Cite as: Vaidyanathan S, McCarra M, Desai TJ. Lung stem cells and therapy for cystic fibrosis. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 306–321 [https://doi.org/10.1183/2312508X.10010520].
- Page 322AbstractPieter S. Hiemstra, Dept of Pulmonology, C2-P, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail: p.s.hiemstra@lumc.nl. Reinoud Gosens, Dept of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: r.gosens@rug.nl.
COPD is a progressive lung disease that becomes clinically manifest later in life and is a major cause of death worldwide. Airflow limitation, chronic bronchitis, small-airway remodelling and emphysema are characteristics of COPD. In most COPD patients, decades of smoking have resulted in repetitive micro-injuries to the epithelium with marked effects on stem cell populations in the lung. These insults underlie the defective epithelial repair underpinning airway remodelling and emphysema development. Here, we will review dysregulation of airway and alveolar epithelial stem cells in COPD and how an improved understanding of the contribution of this dysregulation to the pathogenesis can be used in disease treatment. In addition, we provide an overview of pharmacological and cell-therapy approaches for the treatment of COPD.
Cite as: Hiemstra PS, Wu X, Khedoe PPSJ, et al. The role of altered stem cell function in airway and alveolar repair and remodelling in COPD. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 322–339 [https://doi.org/10.1183/2312508X.10010620].
- Page 340AbstractSam M. Janes, Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, University College London, 5 University Street, London WC1E 6JF, UK. E-mail: s.janes@ucl.ac.uk
Lung cancers are a significant cause of cancer mortality so there is clinical need for a new understanding of lung cancer cell biology in the search for novel therapies to target these diseases. Here, we review the evidence that tissue-resident stem cells act as the cell of origin for lung cancers. Although significant evidence implicates tissue-resident somatic stem cells in the initiation of lung cancers, recent findings suggest that the lung epithelium is plastic; it therefore remains possible that some cancers arise through the de-differentiation of other epithelial cell types. Furthermore, we describe studies that assess the differentiation hierarchy of lung tumours and discuss the possible roles of lung cancer stem cells in tumour maintenance and therapy resistance.
Cite as: Lazarus KA, Pennycuick A, Hynds RE, et al. Stem cells and lung cancer. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 340–352 [https://doi.org/10.1183/2312508X.10010720].
- Page 353AbstractMichael A. Matthay, 505 Parnassus Avenue, M-917, University of California, San Francisco, CA 94143, USA. E-mail: michael.matthay@ucsf.edu
ARDS is a syndrome of acute respiratory failure that has a high mortality. Treatment remains supportive, as several clinical trials of various pharmaceutical interventions have failed. Recently, MSCs have shown considerable potential, with pre-clinical studies identifying homing, immunomodulatory, pathogen clearance and alveolocapillary barrier protective mechanisms, which synergistically enable MSCs to attenuate lung injury. Moreover, many of these functions are replicated by the MSC secretome and their isolated extracellular vesicles. Accumulation of a substantial body of research over the past decade has stimulated translation of MSC therapy to clinical trials for ARDS. These trials have demonstrated that administering MSCs is safe, and current trials are testing therapeutic efficacy in ARDS patients. Additional studies are necessary to fully understand the mechanisms that would enhance clinical applications of MSCs.
Cite as: Maishan M, Kuebler WM, Lim DL, et al. Progress and potential of mesenchymal stromal cell therapy in acute respiratory distress syndrome. In: Nikolić MZ, Hogan BLM, eds. Lung Stem Cells in Development, Health and Disease (ERS Monograph). Sheffield, European Respiratory Society, 2021; pp. 353–372 [https://doi.org/10.1183/2312508X.10010820].