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The production of mature functioning thyroid follicular cells (TFCs) from human induced pluripotent stem cells (iPSCs) is critical for potential novel therapeutic approaches to post-surgical and congenital hypothyroidism. To accomplish this, we developed a novel human iPSC line that expresses fluorophores targeted to the NKX2-1 and PAX8 loci, allowing for the identification and purification of cells destined to become TFCs. Optimizing a sequence of defined, serum-free media to promote stepwise developmental directed differentiation, we found that bone morphogenic protein 4 (BMP4) and fibroblast growth factor 2 (FGF2) stimulated lineage specification into TFCs from multiple iPSC lines. Single-cell RNA sequencing demonstrated that BMP4 withdrawal after lineage specification promoted TFC maturation, with mature TFCs representing the majority of cells present within 1 month. After xenotransplantation into athyreotic immunodeficient mice, engrafted cells exhibited thyroid follicular organization with thyroglobulin protein detected in the lumens of NKX2-1-positive follicles. While our iPSC-derived TFCs presented durable expression of thyroid-specific proteins, they were unable to rescue hypothyroidism in vivo., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The rapid proliferation of businesses engaged in direct-to-consumer advertising of unproven stem cell interventions has raised troubling questions about whether government bodies can regulate this health market effectively. Recent developments in Australia and Canada suggest that such fears are unfounded and that targeted regulatory action can have meaningful effects., Competing Interests: Declaration of interests J.E.J.R. has advisory roles in the Gene Technology Technical Advisory Committee, Office of the Gene Technology Regulator, Australian Government; in the Human Research Ethics Committee, Genea; and as a member of the Data Safety Monitoring Board for a Fanconi anemia trial. He has shareholdings with Rarecyte and Woke and receives grant/research support from the NHMRC (GNT1177305), the NSWCC, the CINSW, the MRFF, Therapeutic Innovation Australia, and philanthropic foundations. J.E.J.R. receives supply of material (MTA), consultancy, or honoraria from Rarecyte; Novartis; bluebird bio; Spark Therapeutics, Inc.; Cynata Therapeutics; Pfizer; and CRISPRTx. He is a member of the board of directors or an advisory committee for these bodies: AAVec Bio, cofounder, and Kennerton Capital, non-executive director. He is employed by the Sydney Local Health District at Royal Prince Alfred Hospital. L.T. served as a compensated expert witness for the US government in a criminal case and as a pro bono expert witness in a class action lawsuit. He is a member of the International Society for Cell & Gene Therapy and its Ethics of Cell and Gene Therapy Committee. He is also a member of the International Society for Stem Cell Research and its Ethics Committee. L.T.’s research program has received funding from the Pew Charitable Trusts and the University of California, Irvine. L.I. served as a pro bono expert witness in a class action lawsuit. He is a member of the International Society for Cell & Gene Therapy and its Ethics of Cell and Gene Therapy Committee. He is also a member of the International Society for Stem Cell Research. L.I.’s research program has received funding from the US National Institutes of Health and the University at Buffalo. M.M. serves on the board of the International Society for Stem Cell Research and is a member of its Ethics and Public Policy Committees. She is the President of the Australasian Society for Stem Cell Research and a board member of the National Stem Cell Foundation of Australia. M.M.’s research program receives funding from reNEW, the Novo Nordisk Foundation Center for Stem Cell Medicine (NNF21CC0073729), and the Australian Government Medical Research Future Fund (APP2007623)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Repair and regeneration of a diseased lung using stem cells or bioengineered tissues is an exciting therapeutic approach for a variety of lung diseases and critical illnesses. Over the past decade, increasing evidence from preclinical models suggests that mesenchymal stromal cells, which are not normally resident in the lung, can be used to modulate immune responses after injury, but there have been challenges in translating these promising findings to the clinic. In parallel, there has been a surge in bioengineering studies investigating the use of artificial and acellular lung matrices as scaffolds for three-dimensional lung or airway regeneration, with some recent attempts of transplantation in large animal models. The combination of these studies with those involving stem cells, induced pluripotent stem cell derivatives, and/or cell therapies is a promising and rapidly developing research area. These studies have been further paralleled by significant increases in our understanding of the molecular and cellular events by which endogenous lung stem and/or progenitor cells arise during lung development and participate in normal and pathological remodeling after lung injury. For the 2023 Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference, scientific symposia were chosen to reflect the most cutting-edge advances in these fields. Sessions focused on the integration of "omics" technologies with function, the influence of immune cells on regeneration, and the role of the extracellular matrix in regeneration. The necessity for basic science studies to enhance fundamental understanding of lung regeneration and to design innovative translational studies was reinforced throughout the conference.

Advances in single-cell RNA sequencing provide an unprecedented window into cellular identity. The abundance of data requires new theoretical and computational frameworks to analyze the dynamics of differentiation and integrate knowledge from cell atlases. We present 'single-cell Type Order Parameters' (scTOP): a statistical, physics-inspired approach for quantifying cell identity given a reference basis of cell types. scTOP can accurately classify cells, visualize developmental trajectories and assess the fidelity of engineered cells. Importantly, scTOP does this without feature selection, statistical fitting or dimensional reduction (e.g. uniform manifold approximation and projection, principle components analysis, etc.). We illustrate the power of scTOP using human and mouse datasets. By reanalyzing mouse lung data, we characterize a transient hybrid alveolar type 1/alveolar type 2 cell population. Visualizations of lineage tracing hematopoiesis data using scTOP confirm that a single clone can give rise to multiple mature cell types. We assess the transcriptional similarity between endogenous and donor-derived cells in the context of murine pulmonary cell transplantation. Our results suggest that physics-inspired order parameters can be an important tool for understanding differentiation and characterizing engineered cells. scTOP is available as an easy-to-use Python package., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

The field of regenerative medicine, including cellular immunotherapies, is on a remarkable growth trajectory. Dozens of cell-, tissue- and gene-based products have received marketing authorization worldwide while hundreds-to-thousands are either in preclinical development or under clinical investigation in phased clinical trials. However, the promise of regenerative therapies has also given rise to a global industry of direct-to-consumer offerings of prematurely commercialized cell and cell-based products with unknown safety and efficacy profiles. Since its inception, the International Society for Cell & Gene Therapy Committee on the Ethics of Cell and Gene Therapy has opposed the premature commercialization of unproven cell- and gene-based interventions and supported the development of evidence-based advanced therapy products. In the present Guide, targeted at International Society for Cell & Gene Therapy members, we analyze this industry, focusing in particular on distinctive features of unproven cell and cell-based products and the use of tokens of scientific legitimacy as persuasive marketing devices. We also provide an overview of reporting mechanisms for patients who believe they have been harmed by administration of unapproved and unproven products and suggest practical strategies to address the direct-to-consumer marketing of such products. Development of this Guide epitomizes our continued support for the ethical and rigorous development of cell and cell-based products with patient safety and therapeutic benefit as guiding principles., Competing Interests: Declaration of Competing Interest Hamid R. Bidkhori is the chancellor of the Biomedical Research Ethics Committee of Academic Center for Education, Culture and Research (ACECR) - Mashhad. He is a member of the International Society for Cell & Gene Therapy (ISCT), the International Society for Extracellular Vesicles (ISEV) and the ISCT Committee on the Ethics of Cell and Gene Therapy. Rachele Ciccocioppo is a member of the Advisory Board of Takeda (Italy) for the use of mesenchymal stromal cells in fistulizing Crohn's disease. Natividad Cuende is a member of the Governing Council of the Agencia Española de Medicamentos y Productos Sanitarios (Spanish Medicine and Medical Device Agency). She is member of the ISCT Committee on the Ethics of Cell and Gene Therapy and the ISCT Legal and Regulatory Affairs Committee–Europe. She is also member of the Spanish Guarantee Committee for Donation and Use of Human Cells and Tissues of the Spanish Ministry of Science and Innovation. She is not paid for these roles. Bambi Grilley is affiliated with QBRegulatory Consulting LLC that has provided regulatory affairs and project management support to AlloVir, Marker Therapeutics, LOKON Pharma, Tessa Therapeutics and March Biosciences. She is a member of ISCT and its Ethics of Cell and Gene Therapy (ECGT) Committee and is the incoming Chief Regulatory Officer of ISCT. She is not paid for her roles in ISCT. Conflict of interest is managed in accordance with Baylor College of Medicine policy and oversight. Laertis Ikonomou has written an expert report in a class action lawsuit filed against a business selling unproven “stem cell”-based interventions, and wrote the report on a pro bono basis. He is a member of the ISCT and the International Society for Stem Cell Research (ISSCR) and the chair of the ISCT Committee on the Ethics of Cell and Gene Therapy. He is not paid for these roles. Conflict of interest is managed in accordance with University at Buffalo policy and oversight. Aaron D. Levine is a member of ISCT and its ECGT committee. He is not paid for these roles. Levine's research program is supported by the National Science Foundation (NSF) (Grant No. EEC-1648035). Bruce Levine has received compensation for serving on the scientific advisory boards of Akron Bio, Avectas, Immuneel, Immusoft, In8bio, Ori Biotech, Oxford Biomedica, UTC Therapeutics and Vycellix. He has received compensation for consulting for GSK. He has received compensation and equity from Capstan Therapeutics as a co-founder and member of the Scientific Advisory Board. As co-founder of Tmunity Therapeutics, he received equity. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight. Megan Munsie is a member of the International Society for Stem Cell Research and its Ethics Committee and Public Policy Committee. She is also the President of the Australasian Society for Stem Cell Research. Munsie's research program is supported by the Novo Nordisk Foundation Center for Stem Cell Medicine (NNF21CC0073729). John E. J. Rasko: employment: Royal Prince Alfred Hospital; consultancy and honoraria: Rarecyte, Gilead, Roche, Novartis, Bluebird Bio, Spark therapeutics, Cynata, Pfizer; equity: Genea; shareholder: Rarecyte, Woke; DSMB: Diamond Fanconi anemia trial; research funding: National Health and Medical Research Council (NHMRC), New South Wales Cancer Council, Cancer Institute NSW (CINSW), Therapeutic Innovation Australia, Philanthropic foundations; Chair, Gene Technology Technical Advisory Committee, Office of The Gene Technology Regulator, Australian Government. Leigh Turner served as a compensated expert witness for the US government in a criminal case and as a pro bono expert witness in a class action lawsuit. He is a member of ISCT and its ECGT committee. He is also a member of the International Society for Stem Cell Research and its Ethics Committee and Membership Committee. Turner's research program is supported by the Pew Charitable Trusts. Daniel J. Weiss served as a compensated expert witness for the US government in a criminal case and as a pro bono expert witness in a class action lawsuit. He is a member of ISCT and its ECGT committee and is former Chief Scientific Officer of the ISCT. He is not paid for his roles in the ISCT. Dr. Weiss has received compensation for consulting with Mesoblast Inc., NextCell Inc., United Therapeutics. Inc. and Vertex Inc. Conflict of interest is managed in accordance with University of Vermont policy and oversight. Patricia J. Zettler reports serving as a consultant to the US Food & Drug Administration. All the other authors have no commercial, proprietary, or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Alveolar type 2 epithelial cells (AT2s) derived from human induced pluripotent stem cells (iAT2s) have rapidly contributed to our understanding of AT2 function and disease. However, while iAT2s are primarily cultured in three-dimensional (3D) Matrigel, a matrix derived from cancerous mouse tissue, it is unclear how a physiologically relevant matrix will impact iAT2s phenotype. As extracellular matrix (ECM) is recognized as a vital component in directing cellular function and differentiation, we sought to derive hydrogels from decellularized human lung alveolar-enriched ECM (aECM) to provide an ex vivo model to characterize the role of physiologically relevant ECM on iAT2 phenotype. We demonstrate aECM hydrogels retain critical in situ ECM components, including structural and basement membrane proteins. While aECM hydrogels facilitate iAT2 proliferation and alveolosphere formation, a subset of iAT2s rapidly change morphology to thin and elongated ring-like cells. This morphological change correlates with upregulation of recently described iAT2-derived transitional cell state genetic markers. As such, we demonstrate a potentially underappreciated role of physiologically relevant aECM in iAT2 differentiation., (© 2023. The Author(s).)

Patient interest in non-trial access pathways to investigational cell-and gene-based interventions, such as expanded access in the USA, is increasing, while the regulatory and business environments for non-trial access in the cell and gene therapy field are shifting. Against this background, in 2022 the International Society for Cell & Gene Therapy (ISCT) established a Working Group on Expanded Access to identify practical, ethical, and regulatory issues emerging from the use (and possible misuse) of the expanded access pathway in the cell and gene therapy field. In this Short Report, the Working Group sets the stage for its future activities by analyzing the history of expanded access and identifying three examples of questions that we anticipate arising as uses of expanded access for investigational cell and gene-based interventions increase and evolve., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

While the generation of many lineages from pluripotent stem cells has resulted in basic discoveries and clinical trials, the derivation of tissue-specific mesenchyme via directed differentiation has markedly lagged. The derivation of lung-specific mesenchyme is particularly important since this tissue plays crucial roles in lung development and disease. Here we generate a mouse induced pluripotent stem cell (iPSC) line carrying a lung-specific mesenchymal reporter/lineage tracer. We identify the pathways (RA and Shh) necessary to specify lung mesenchyme and find that mouse iPSC-derived lung mesenchyme (iLM) expresses key molecular and functional features of primary developing lung mesenchyme. iLM recombined with engineered lung epithelial progenitors self-organizes into 3D organoids with juxtaposed layers of epithelium and mesenchyme. Co-culture increases yield of lung epithelial progenitors and impacts epithelial and mesenchymal differentiation programs, suggesting functional crosstalk. Our iPSC-derived population thus provides an inexhaustible source of cells for studying lung development, modeling diseases, and developing therapeutics., (© 2023. The Author(s).)

Neonatal lung and heart diseases, albeit rare, can result in poor quality of life, often require long-term management and/or organ transplantation. For example, Congenital Heart Disease (CHD) is one of the most common type of congenital disabilities, affecting nearly 1% of the newborns, and has complex and multifactorial causes, including genetic predisposition and environmental influences. To develop new strategies for heart and lung regeneration in CHD and neonatal lung disease, human induced pluripotent stem cells (hiPSCs) provide a unique and personalized platform for future cell replacement therapy and high-throughput drug screening. Additionally, given the differentiation potential of iPSCs, cardiac cell types such as cardiomyocytes, endothelial cells, and fibroblasts and lung cell types such Type II alveolar epithelial cells can be derived in a dish to study the fundamental pathology during disease progression. In this review, we discuss the applications of hiPSCs in understanding the molecular mechanisms and cellular phenotypes of CHD (e.g., structural heart defect, congenital valve disease, and congenital channelopathies) and congenital lung diseases, such as surfactant deficiencies and Brain-Lung-Thyroid syndrome. We also provide future directions for generating mature cell types from iPSCs, and more complex hiPSC-based systems using three-dimensional (3D) organoids and tissue-engineering. With these potential advancements, the promise that hiPSCs will deliver new CHD and neonatal lung disease treatments may soon be fulfilled., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Transient, tissue-specific, embryonic progenitors are important cell populations in vertebrate development. In the course of respiratory system development, multipotent mesenchymal and epithelial progenitors drive the diversification of fates that results to the plethora of cell types that compose the airways and alveolar space of the adult lungs. Use of mouse genetic models, including lineage tracing and loss-of-function studies, has elucidated signaling pathways that guide proliferation and differentiation of embryonic lung progenitors as well as transcription factors that underlie lung progenitor identity. Furthermore, pluripotent stem cell-derived and ex vivo expanded respiratory progenitors offer novel, tractable, high-fidelity systems that allow for mechanistic studies of cell fate decisions and developmental processes. As our understanding of embryonic progenitor biology deepens, we move closer to the goal of in vitro lung organogenesis and resulting applications in developmental biology and medicine., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The 9th biennial conference titled "Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases" was hosted virtually, due to the ongoing COVID-19 pandemic, in collaboration with the University of Vermont Larner College of Medicine, the National Heart, Lung, and Blood Institute, the Alpha-1 Foundation, the Cystic Fibrosis Foundation, and the International Society for Cell & Gene Therapy. The event was held from July 12th through 15th, 2021 with a pre-conference workshop held on July 9th. As in previous years, the objectives remained to review and discuss the status of active research areas involving stem cells (SCs), cellular therapeutics, and bioengineering as they relate to the human lung. Topics included 1 ) technological advancements in the in situ analysis of lung tissues, 2 ) new insights into stem cell signaling and plasticity in lung remodeling and regeneration, 3 ) the impact of extracellular matrix in stem cell regulation and airway engineering in lung regeneration, 4 ) differentiating and delivering stem cell therapeutics to the lung, 5 ) regeneration in response to viral infection, and 6 ) ethical development of cell-based treatments for lung diseases. This selection of topics represents some of the most dynamic and current research areas in lung biology. The virtual workshop included active discussion on state-of-the-art methods relating to the core features of the 2021 conference, including in situ proteomics, lung-on-chip, induced pluripotent stem cell (iPSC)-airway differentiation, and light sheet microscopy. The conference concluded with an open discussion to suggest funding priorities and recommendations for future research directions in basic and translational lung biology.

Hospital exemption (HE) is a regulated pathway that allows the use of advanced therapy medicinal products (ATMPs) within the European Union (EU) under restrictive conditions overseen by national medicine agencies. In some EU countries, HE is granted for ATMPs with no demonstrated safety and efficacy; therefore, they are equivalent to investigational drugs. In other countries, HE is granted for ATMPs with demonstrated quality, safety and efficacy and for which centralized marketing authorization has not been requested. The Committee on the Ethics of Cell and Gene Therapy of the International Society for Cell & Gene Therapy reflects here on the ethical issues concerning HE application from the perspective of the patient, including risk-benefit balance, accessibility and transparency, while providing evidence that HE must not be regarded as a conduit for unproven and unethical ATMP-based interventions. Indeed, HE represents a legal instrument under which a patient's need for access to novel ATMPs is reconciled with ethics. Moreover, for some unmet medical needs, HE is the only pathway for accessing innovative ATMPs. Nonetheless, HE harmonization across EU Member States and limitations of ATMP use under the HE rule when similar products have already been granted centralized marketing authorization to avoid a parallel regulatory pathway are controversial issues whose political and economic consequences are beyond the scope of this review. Finally, the institution of an EU registry of HE applications and outcomes represents a priority to improve transparency, reduce patient risks, increase efficiency of health systems, facilitate company awareness of business opportunities and boost progressive entry of ATMPs into the therapeutic repertoire of health systems., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

The significant morbidity and mortality of coronavirus disease 19 (COVID-19) prompted a global race to develop new therapies. These include interventions using cell- or cell-derived products, several of which are being tested in well-designed, properly controlled clinical trials. Yet, the search for cell-based COVID-19 treatments has also been fraught with hyperbolic claims; flouting of crucial regulatory, scientific, and ethical norms; and distorted communication of research findings. In this paper, we critically examine ethical issues and public communication challenges related to the development of cell-based therapeutics for COVID-19. Drawing on the lessons learned from this ongoing process, we argue against the rushed development of cell-based interventions. We conclude by outlining ways to improve the ethical conduct of cell-based clinical investigations and public communication of therapeutic claims., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Stem cell-based therapies to reconstitute in vivo organ function hold great promise for future clinical applications to a variety of diseases. Hypothyroidism resulting from congenital lack of functional thyrocytes, surgical tissue removal, or gland ablation, represents a particularly attractive endocrine disease target that may be conceivably cured by transplantation of long-lived functional thyroid progenitors or mature follicular epithelial cells, provided a source of autologous cells can be generated and a variety of technical and biological challenges can be surmounted. Here we review the emerging literature indicating that thyroid follicular epithelial cells can now be engineered in vitro from the pluripotent stem cells (PSCs) of mice, normal humans, or patients with congenital hypothyroidism. We review the in vivo embryonic development of the thyroid gland and explain how emerging discoveries in developmental biology have been utilized as a roadmap for driving PSCs, which resemble cells of the early embryo, into mature functional thyroid follicles in vitro . Finally, we discuss the bioengineering, biological, and clinical hurdles that now need to be addressed if the goals of life-long cure of hypothyroidism through cell- and/or gene-based therapies are to be attained., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Posabella, Alber, Undeutsch, Droeser, Hollenberg, Ikonomou and Kotton.)

The global COVID-19 pandemic has prompted urgent need for potential therapies for severe respiratory consequences resulting from coronavirus infection. New therapeutic agents that will attenuate ongoing inflammation and at the same time promote regeneration of injured lung epithelial cells are urgently needed. Cell-based therapies, primarily involving mesenchymal stromal cells (MSCs) and their derivatives, are currently investigated worldwide for SARS-CoV-2-induced lung diseases. A significant number of academic centers and companies globally have already initiated such trials. However, at a time of unprecedented need, it is also foreseen that families and caregivers will seek all available options, including access to cell-based and other investigational products, even before proven safety and efficacy as well as regulatory approval. This should not be an excuse for opportunists to sell or advertise unproven therapies of any kind. "Compassionate use" should be conducted in the context of a clinical investigation framed by strict ethical and regulatory permissions, with the goal of obtaining mechanistic information wherever possible.

A workshop entitled "Stem Cells, Cell Therapies and Bioengineering in Lung Biology and Diseases" was hosted by the University of Vermont Larner College of Medicine in collaboration with the National Heart, Lung and Blood Institute, the Alpha-1 Foundation, the Cystic Fibrosis Foundation, the International Society for Cell and Gene Therapy and the Pulmonary Fibrosis Foundation. The event was held from July 15 to 18, 2019 at the University of Vermont, Burlington, Vermont. The objectives of the conference were to review and discuss the current status of the following active areas of research: 1) technological advancements in the analysis and visualisation of lung stem and progenitor cells; 2) evaluation of lung stem and progenitor cells in the context of their interactions with the niche; 3) progress toward the application and delivery of stem and progenitor cells for the treatment of lung diseases such as cystic fibrosis; 4) progress in induced pluripotent stem cell models and application for disease modelling; and 5) the emerging roles of cell therapy and extracellular vesicles in immunomodulation of the lung. This selection of topics represents some of the most dynamic research areas in which incredible progress continues to be made. The workshop also included active discussion on the regulation and commercialisation of regenerative medicine products and concluded with an open discussion to set priorities and recommendations for future research directions in basic and translation lung biology., Competing Interests: Conflict of interest: D.E. Wagner reports a grant from the US NIH (R13 HL149436, conference grant), and grants for conference support from the Alpha-1 Foundation, the International Society for Cell and Gene Therapy, and the Pulmonary Fibrosis Foundation, during the conduct of the study; and honoraria from Boehringer Ingelheim outside the submitted work. In addition, D.E. Wagner has patent US20160067378A1 pending. Conflict of interest: L. Ikonomou has nothing to disclose. Conflict of interest: S.E. Gilpin has nothing to disclose. Conflict of interest: C.M. Magin reports consulting fees from Sharklet Technologies, Inc., outside the submitted work; and a patent, “3D in vitro models of lung tissue”, pending. Conflict of interest: F. Cruz has nothing to disclose. Conflict of interest: A. Greaney has nothing to disclose. Conflict of interest: M. Magnusson has nothing to disclose. Conflict of interest: Y-W. Chen has nothing to disclose. Conflict of interest: B. Davis has nothing to disclose. Conflict of interest: K. Vanuytsel has nothing to disclose. Conflict of interest: S. Rolandsson Enes has nothing to disclose. Conflict of interest: A. Krasnodembskaya reports grants from the Medical Research Council (MRC) UK during the writing of this article. She is funded by the MRC (national funder for medical and translational research) to conduct research in the area of stem cell-based therapies for lung diseases. Conflict of interest: M. Lehmann has nothing to disclose. Conflict of interest: G. Westergren-Thorsson has nothing to disclose. Conflict of interest: J. Stegmayr has nothing to disclose. Conflict of interest: H.N. Alsafadi has nothing to disclose. Conflict of interest: E.T. Hoffman has nothing to disclose. Conflict of interest: D.J. Weiss reports grants from the NIH during the conduct of the study. Conflict of interest: A.L. Ryan reports grants from the Cystic Fibrosis Foundation and the NIH, outside the submitted work., (Copyright ©ERS 2020.)

Multipotent Nkx2-1-positive lung epithelial primordial progenitors of the foregut endoderm are thought to be the developmental precursors to all adult lung epithelial lineages. However, little is known about the global transcriptomic programs or gene networks that regulate these gateway progenitors in vivo. Here we use bulk RNA-sequencing to describe the unique genetic program of in vivo murine lung primordial progenitors and computationally identify signaling pathways, such as Wnt and Tgf-β superfamily pathways, that are involved in their cell-fate determination from pre-specified embryonic foregut. We integrate this information in computational models to generate in vitro engineered lung primordial progenitors from mouse pluripotent stem cells, improving the fidelity of the resulting cells through unbiased, easy-to-interpret similarity scores and modulation of cell culture conditions, including substratum elastic modulus and extracellular matrix composition. The methodology proposed here can have wide applicability to the in vitro derivation of bona fide tissue progenitors of all germ layers.

Respiratory diseases, such as chronic obstructive pulmonary disease and pulmonary fibrosis, result in severely impaired quality of life and impose significant burdens on healthcare systems worldwide. Current disease management involves pharmacologic interventions, oxygen administration, reduction of infections, and lung transplantation in advanced disease stages. An increasing understanding of mechanisms of respiratory epithelial and pulmonary vascular endothelial maintenance and repair and the underlying stem/progenitor cell populations, including but not limited to airway basal cells and type II alveolar epithelial cells, has opened the possibility of cell replacement-based regenerative approaches for treatment of lung diseases. Further potential for personalized therapies, including in vitro drug screening, has been underscored by the recent derivation of various lung epithelial, endothelial, and immune cell types from human induced pluripotent stem cells. In parallel, immunomodulatory treatments using allogeneic or autologous mesenchymal stromal cells have shown a good safety profile in clinical investigations for acute inflammatory conditions, such as acute respiratory distress syndrome and septic shock. However, as yet, no cell-based therapy has been shown to be both safe and effective for any lung disease. Despite the investigational status of cell-based interventions for lung diseases, businesses that market unproven, unlicensed and potentially harmful cell-based interventions for respiratory diseases have proliferated in the United States and worldwide. The current status of various cell-based regenerative approaches for lung disease as well as the effect of the regulatory environment on clinical translation of such approaches are presented and critically discussed in this review.

Background: There is a plethora of treatment algorithms for managing patients with malignant pleural effusions (MPEs), sharing many common points and principles. Our study aims to compare hyperthermic intrapleural chemotherapy (HITHOC) and talc pleurodesis (TALC), as treatment options for patients with non-small cell lung cancer (NSCLC) and metastatic MPE., Methods: This prospective, randomized trial was conducted at a single thoracic surgery center, the "Theagenio" Cancer Institute, in Greece, under the identification code NCT01409551 and was completed. All 40 patients enrolled were adults with histologically proven metastatic, unilateral, MPE caused by NSCLC. Exclusion criteria included patients >80 years, trapped lung, and major comorbidities. Patients were randomly and equally assigned 1:1 to either HITHOC (group A) or TALC (group B) by video assisted thoracic surgery (VATS). The primary outcome was the median overall survival (OS) from trial intervention to death, while secondary outcome was the identification of clinical factors affecting the survival., Results: The patients were followed up for 45 months. The OS of the full group was 8 months (95% CI: 7.046-8.954). Participants who underwent HITHOC had an OS of 8 months (95% CI: 7.141-8.859), whereas the participants of TALC had an OS of 9 months (95% CI: 7.546-10.454), with no significant difference between groups. Among fifty-four factors that were tested for their effects on survival, only TNM stage and creatinine values both preoperatively and 7 days postoperatively could be regarded as risk-factors for survival. Other recorded parameters, which had significant variance between the two groups, were urea levels, C-reactive protein, white blood cells and total in hospital length of stay (LOS)., Conclusions: Both HITHOC and TALC are equally effective and safe therapeutic options in treating patients with MPE and NSCLC with acceptable survival. The study revealed independent clinical risk factors influencing survival, which could be utilized as starting points for larger clinical studies., Keywords: Pleurodesis; pleural effusion; malignant; carcinoma; non-small cell lung; hyperthermia., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

The introduction and widespread adoption of induced pluripotent stem cell (iPSC) technology has opened new avenues for craniofacial regenerative medicine. Neural crest cells (NCCs) are the precursor population to many craniofacial structures, including dental and periodontal structures, and iPSC-derived NCCs may, in the near future, offer an unlimited supply of patient-specific cells for craniofacial repair interventions. Here, we used an established protocol involving simultaneous Wnt signaling activation and TGF-β signaling inhibition to differentiate three human iPSC lines to cranial NCCs. We then derived a mesenchymal progenitor cell (NCC-MPCs) population with chondrogenic and osteogenic potential from cranial NCCs and investigated their similarity to widely studied human postnatal dental or periodontal stem/progenitor cells. NCC-MPCs were quite distinct from both their precursor cells (NCCs) and bone-marrow mesenchymal stromal cells, a stromal population of mesodermal origin. Despite their similarity with dental stem/progenitor cells, NCC-MPCs were clearly differentiated by a core set of 43 genes, including ACKR3 (CXCR7), whose expression (both at transcript and protein level) appear to be specific to NCC-MPCs. Altogether, our data demonstrate the feasibility of craniofacial mesenchymal progenitor derivation from human iPSCs through a neural crest-intermediate and set the foundation for future studies regarding their full differentiation repertoire and their in vivo existence., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Cell and gene therapies (CGTs) are progressively entering into clinical practice in different parts of the world. The International Society for Cell & Gene Therapy (ISCT), a global scientific society, has been committed since 1992 to supporting and developing knowledge on clinical applications of CGTs. Considering the number of products that have been progressively approved and, in some cases, withdrawn in recent years, the ISCT would like to present a brief annual report on CGTs with marketing authorization (MA) in different regions. This article reflects the dynamic momentum around authorized CGTs coinciding with the parallel increase of unproven approaches where cells are delivered without appropriate and rigorous scientific and regulatory assessment and authorization. This is intended to be a living document with a yearly update linked to a dedicated section of the ISCT website for faster adjustments. The aim is to ultimately inform, by periodic snapshots, the scientific community, healthcare stakeholders and patient associations on authorized CGT products as a way to increase communication around the approved therapeutic approaches charged with heightened expectations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Businesses marketing unproven stem cell interventions proliferate within the U.S. and in the larger global marketplace. There have been global efforts by scientists, patient advocacy groups, bioethicists, and public policy experts to counteract the uncontrolled and premature commercialization of stem cell interventions. In this commentary, we posit that medical societies and associations of health care professionals have a particular responsibility to be an active partner in such efforts. We review the role medical societies can and should play in this area through patient advocacy and awareness initiatives., (Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The in vitro -directed differentiation of pluripotent stem cells (PSCs) through stimulation of developmental signaling pathways can generate mature somatic cell types for basic laboratory studies or regenerative therapies. However, there has been significant uncertainty regarding a method to separately derive lung versus thyroid epithelial lineages, as these two cell types each originate from Nkx2-1 + foregut progenitors and the minimal pathways claimed to regulate their distinct lineage specification in vivo or in vitro have varied in previous reports. Here, we employ PSCs to identify the key minimal signaling pathways (Wnt+BMP versus BMP+FGF) that regulate distinct lung- versus thyroid-lineage specification, respectively, from foregut endoderm. In contrast to most previous reports, these minimal pathways appear to be evolutionarily conserved between mice and humans, and FGF signaling, although required for thyroid specification, unexpectedly appears to be dispensable for lung specification. Once specified, distinct Nkx2-1 + lung or thyroid progenitor pools can now be independently derived for functional 3D culture maturation, basic developmental studies or future regenerative therapies., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)