Progenitor Resilience and the Early Onset of Chronic Lung Diseases

The Division of Lung Diseases at the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) recently convened a virtual workshop titled “Progenitor Resilience and the Early Onset of Chronic Lung Diseases” on November 7-8th, 2024. More than 400 participants logged in for the 2-day workshop from the U.S. and around the world.

The goal of this workshop was to bring together pulmonary medicine researchers and stem/progenitor cell biologists to understand the current state of science and to identify critical research gaps, challenges, opportunities, and key research questions in the area of resilience in chronic lung diseases, particularly focusing on lung progenitor cells resilience and their applications in early diagnosis, prevention, and treatment of chronic lung diseases. This workshop also aimed to foster collaborations among diverse stakeholders in the focused area. 

Background

The concept of lung resilience, which includes the ability to maintain or recover function after injury, has emerged as essential for proactive lung health strategies, particularly in vulnerable populations exposed to environmental stressors. Pulmonary progenitor cells, including but not limited to airway basal progenitor cells, alveolar epithelial type 2 (AT2) progenitor cells, and endothelial progenitor cells, are essential for lung health and resilience due to their regenerative potential (e.g., self-renewal, multipotent terminal differentiation) to repair injured airways and alveolar-capillary respiratory units. Emerging evidence implicates the critical contribution of pulmonary progenitor cell exhaustion and dysfunction, and resultant abnormal/inadequate repair, to the early onset and progression of chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). For example, circulating endothelial progenitor cells are reduced in patients with COPD and correlate with disease severity, and endothelial progenitor cells from COPD smokers also had lower colony-forming and migratory capacities than those from resilient smokers. Small airway basal progenitor exhaustion and dysfunction have been shown in early COPD with preserved lung function. In healthy lungs, epithelial progenitor cells are responsible for the repair and regeneration of alveolar tissue following injury. However, in IPF lungs, these cells exhibit diminished regenerative capacity and undergo premature senescence or apoptosis, leading to inadequate repair of lung tissue. This exhaustion and dysfunction of progenitors likely results from chronic environmental insults, genetic predispositions, and altered cellular microenvironments, known risk factors for COPD and pulmonary fibrosis which collectively impair the cells' ability to respond effectively to lung injury. As a result, the normal repair processes are replaced by aberrant inflammatory and fibrotic remodeling, characterized by excessive extracellular matrix deposition and scar formation. 

Understanding the mechanisms underlying progenitor cell exhaustion could pave the way for novel therapeutic strategies aimed at enhancing lung repair and mitigating the progression of chronic lung disease, however, many key questions remain. For example, are pulmonary epithelial and endothelial progenitor pool exhaustion and dysfunction the "canary in the coal mine" or the tipping point for onset of chronic lung diseases? What are the mechanisms (e.g., metabolic alteration, mitochondrial dysfunction, aging, epigenetics, post-transcriptional, microenvironment, etc.) causing progenitor exhaustion and dysfunction? Do pool size and proportion of pulmonary progenitor dysfunction within the pool matter? Can nasal/ bronchial basal progenitor cells or circulating endothelial progenitor cells number and dysfunction serve as biomarkers to predict early signs of chronic lung disease? Can early intervention aiming to preserve pulmonary progenitor pool and function prevent diseases?

To attain transformative and groundbreaking new discoveries, research is urgently needed to address whether lung/airway progenitor exhaustion and dysfunction drives early onset and progression of chronic lung diseases. Pulmonary progenitor cells are rare cell populations and hard to study. However, recent technology advancement in single cell multi-omics, spatial omics, imaging, and 3D in vitro model systems provide us emerging opportunities to address the roles of these cells in early onset, pathogenesis, detection, and early intervention of chronic lung diseases.
 

Summary of Discussions 

• Understanding Lung Resilience: A Critical Step to Promote Respiratory Health

  A population-based approach emphasized the impact of neighborhood disadvantage on respiratory health, highlighting increased exposure to pollutants and higher incidence of chronic lung disease. It challenged the traditional view of inevitable age-related decline in lung function by presenting research linking sustained cardiovascular fitness to lung resilience and stressing the need to identify other factors to predict and/or improve lung resilience. The need for reliable biomarkers to identify at-risk individuals and for functional characterization of genetic factors that  determine resilience and susceptibility was underscored, which could help identify and target those at higher risk for chronic lung diseases for early intervention and effective treatment. The discussion advocated for leveraging imaging and proteomics to map lung health and track early injury indicators, calling for a shift in research focus toward promoting respiratory health and understanding mechanisms of lung resilience. 

• Role of Progenitor Cells in Lung Repair

  Experts examined the critical role and underlying mechanisms of progenitor and stem cell resilience in chronic lung diseases. Discussions highlighted the remarkable regenerative capacity of the lung epithelium despite its vulnerability to injuries from viruses, bacteria, and toxins. Key insights were shared on the differentiation of alveolar AT2 cells into Type 1 (AT1) cells, which has been suggested to be regulated by signaling pathways such as Wnt, FGF, TGF-beta, and Notch. Advanced single-cell sequencing revealed a transitional state of alveolar epithelial cells that expands in response to lung injury and is linked to the integrated stress response (ISR) activation. The role of mitochondrial metabolism in lung epithelial stem cell fate was explored, highlighting the importance of NAD+ regeneration in preventing pathologic activation of the ISR to maintain lung health. Insights into human respiratory airway progenitor cells underscored their potential role in COPD and other degenerative lung diseases. Additionally, newly identified airway hillocks were presented as injury-resistant reservoirs of plastic stem cells, with significant implications for disease resilience and pathology. The session underscored the need for further research into these cellular mechanisms to develop targeted therapeutic interventions that enhance lung health and resilience.

• Advances in Model Systems and Technologies

  Cutting-edge technologies and model systems advancing the study of lung progenitor and stem cell resilience in chronic lung disease were explored. Highlights included the development of induced pluripotent stem cell (iPSC)-derived organoid models that recapitulate complex lung environments and address gaps in traditional models. Discussions emphasized multi-lineage vascularized lung organoids, which incorporate mesenchymal and endothelial cells to study epithelial-endothelial interactions in disease pathology. Additionally, dual recombinase systems for precise lineage tracing of lung epithelial cells were introduced as a valuable tool for understanding the origins of various stem cell populations in regeneration and repair. Transgenic ferret models were also discussed for their similarity to the human lung, crucial for translational research. These emerging technologies fill critical research gaps and enhance our understanding of lung progenitor resilience, paving the way for innovative therapeutic strategies.

• Potential progenitor-based biomarkers predicting early chronic lung diseases 

  To highlight the potential of progenitor-based markers for predicting the early onset of chronic lung diseases, discussants focused on airway basal progenitor dysfunction in younger smokers. It is characterized by altered bioenergetics and mitochondrial dynamics, which may be an early marker of COPD risk. Advanced single-cell genomics and proteomics approaches have identified a marker that correlates with lung function and disease progression in patients with pulmonary fibrosis. The development of non-invasive biomarkers detectable in peripheral fluids and the integration of large-scale data to enhance predictive modeling of lung disease were encouraged. These insights emphasize the need for continued research into progenitor-based biomarkers to enable early intervention and improve lung disease outcomes.

• Therapeutic approaches in early stage of chronic lung disease

  Participants delved into potentially groundbreaking therapeutic strategies targeting progenitor and stem cells to combat early-stage chronic lung diseases. They showcased the innovative use of induced pluripotent stem cells (iPSCs) to model COPD and emphysema, bridging critical gaps where animal models fall short. The transformative potential of mesenchymal stem cells (MSCs) was highlighted, particularly their ability to modulate immune responses, paving the way for personalized treatments. The session also unveiled new insights into the role of zinc metabolism regulating NAD+ synthesis in alveolar epithelial stem cell function, suggesting new avenues for tackling IPF.

• Lessons from other organ systems to improve our understanding of mechanisms of lung progenitor resilience

  The workshop also drew valuable lessons from other fields, leveraging insights from neuroscience, computational biology, and spatial metabolomics to enhance understanding of lung progenitor resilience. Discussions included the role of ISR in amyotrophic lateral sclerosis (ALS) and ISR inhibitors as a therapeutic strategy, computational methods for studying cell-cell interactions, insights from application of spatial metabolomics analysis in lung cancer models, and the potential role of neurons in lung regeneration. These interdisciplinary insights are expected to inform future research and therapeutic strategies, emphasizing the urgent need for continued exploration of progenitor-based therapies, leveraging genetic insights, and pioneering novel approaches to revolutionize lung disease treatment and improve overall lung health and resilience.

Critical research gaps, challenges, opportunities, and key research questions 

The workshop concluded with strategic discussions on fostering interdisciplinary collaborations and integrating knowledge from diverse fields, such as computational biology, immunology, and regenerative medicine, to enhance resilience in lung progenitors, eventually improving lung health. Investigators proposed forming a collaborative research network dedicated to facilitating data sharing and standardizing methodologies that specifically address the mechanisms of lung progenitor cell resilience. Priority areas for future research were identified, including the development of innovative therapeutic interventions that bolster progenitor cell resilience and promote lung health. The session underscored the need for sustained funding and support to drive these initiatives and enhance the translation of scientific discoveries into clinical applications, ultimately aiming to improve resilience against chronic lung diseases. The following are key knowledge gaps and recommendations:

• Need for standardized metrics to measure progenitor cell resilience and lung health.
• Need for understanding of the genetic and environmental factors especially their interactions that determine the progenitor cell resilience in various ethnic groups.
• Gaps in knowledge regarding the long-term effects of environmental exposures on lung progenitor cells.
• Insufficient data on the role of immune system interactions in maintaining epithelial progenitor resilience.
• Insufficient integration of multi-system models to comprehensively study life course lung function.
• Need to connect discretely defined progenitor cell populations with functional outcomes in the context of injury, infection, and repair.
• Opportunities to leverage advanced organoid models and iPSC technologies for disease modeling and therapeutic development, especially targeting the genetic susceptible factors identified from human populations.
• Need for novel imaging techniques to visualize progenitor cell dynamics and resilience in vivo.
• Need to bridge model gaps with human diseases.
• Opportunities to apply machine learning and AI in analyzing complex datasets for insights into progenitor cell behavior.
• Lack of comprehensive biomarker panels linking progenitor cell health to early disease risk and lung health.
• Potential to develop pharmacological agents or biologics specifically targeting the pathways that regulate progenitor cells to enhance lung resilience.
• Potential for interdisciplinary collaboration to enrich lung disease research and resilience studies.
• Lack of public awareness and educational resources on the importance of lung health resilience and prevention strategies.

Organizers and Speakers

Workshop Co-Chairs:    

• Ravi Kalhan, M.D., M.S., Northwestern University
• Jose Ordovas-Montanes, Ph.D., Boston Children's Hospital and Harvard Medical School

Workshop Co-Organizers: 

• Anny Xiaobo Zhou, Ph.D., Harvard Medical School
• SeungHye Han, M.D., M.P.H., Northwestern University

Workshop Moderators and Speakers:

• Amanda M. Jamieson, Ph.D., Brown University
• Andrew A. Wilson, M.D., Boston University
• Bin Zhou, M.D., Ph.D. Chinese Academy of Sciences
• Daniel J. Weiss, M.D., Ph.D., University of Vermont
• Dianhua Jiang, M.D., Ph.D., Cedars-Sinai Medical Center
• Frank McKeon, Ph.D., University of Houston
• Harold Chapman, M.D., University of California, San Francisco
• Helen Miranda, Ph.D., Case Western Reserve University
• Herbert Schiller, Ph.D., Helmholtz Munich
• Jayaraj Rajagopal, M.D., Harvard Medical School, Massachusetts General Hospital
• Jeong H. Yun, M.D., M.P.H., Brigham and Women’s Hospital and Harvard Medical School
• Jianwen Que, M.D., Ph.D., Columbia University
• John F. Engelhardt, Ph.D., University of Iowa
• Maria C. Basil, M.D., Ph.D., University of Pennsylvania
• Micha Sam Brickman Raredon, M.D., Ph.D., Yale School of Medicine
• Mingxia Gu, M.D., Ph.D., FAHA, Cincinnati Children's Hospital Medical Center
• Moumita Ghosh, Ph.D., University of Colorado
• Preetish Kadur Lakshminarasimha Murthy, Ph.D., University of Illinois, Chicago
• Purushothama Rao Tata, Ph.D., Duke University
• Ruobing Wang, M.D., Harvard Medical School
• Shawn Davidson, Ph.D., Northwestern University
• Susan M. Majka, Ph.D., National Jewish Health/University of Colorado AMC
• Yohannes Tesfaigzi, Ph.D., Massachusetts General Hospital, Harvard Medical School

NHLBI Planning Committee Members:

• Qing Lu, D.V.M., Ph.D., Division of Lung Diseases (Co-Chair)
• Christian Gomez, Ph.D., Division of Lung Diseases (Co-Chair)
• Gustavo Matute-Bello, M.D., Division of Lung Diseases
• Marrah Lackowicz-Scroggins, Ph.D., Division of Lung Diseases
• Jining Lu, Ph.D., Division of Lung Diseases
• Emmanuel Mongodin, Ph.D., Division of Lung Diseases
• Sara Lin, Ph.D., Division of Lung Diseases