Abstract
Organ fibrosis involves a complex interplay between diverse cell types and signaling pathways that ultimately leads to the pathologic accumulation of excessive extracellular matrix, subsequently resulting in organ dysfunction. In recent years, the first drugs for the treatment of idiopathic pulmonary fibrosis have been approved; however, there is a major unmet need for effective antifibrotic therapies across organs. Despite the complexity of the fibrotic process in different tissues, certain features are shared and may form the basis for future therapeutic strategies. This Review will highlight these shared characteristics, cell states, and signaling pathways across organs with the goal of highlighting potential antifibrotic strategies.
Authors
Benjamin D. Humphreys
Abstract
Fibrosis is a major cause of mortality and morbidity worldwide with limited therapeutic options. Our understanding of fibrosis has significantly improved and led to the identification of “core” fibrogenic mechanisms that fuel a self-sustaining vicious cycle following the initial insult. The fibrotic niche is the result of complex cellular and molecular interactions that need to be disrupted to achieve transformational therapies. In this Review, we describe the current understanding of fibrogenic mechanisms, the progress and limitations of omics approaches in the identification of novel fibrotic pathways, and advances in therapeutic modalities that all together have the potential to unleash innovative cross-organ antifibrotic therapies.
Authors
Cynthia Lebeaupin, Katelyn L. Donahue, Ken Dower, Thomas A. Wynn, Kevin M. Hart, Thomas Fabre
Abstract
Fibrosis affects almost all organ systems, resulting in a dysfunctional extracellular matrix that impairs function and can lead to failure. Crosstalk between immune cells and the stromal environment exacerbates fibrosis in all organs and is an attractive therapeutic target. Here, we discuss recent findings regarding the cellular and molecular mechanisms that underlie inflammation and fibrosis across organs. We focus on how reciprocal immune/stromal signaling maintains fibrotic niches, outline strategies for therapeutic intervention beyond current antifibrotic agents, and highlight the bone marrow fibrotic disease myelofibrosis as a model for understanding, and ultimately reversing, fibrosis in human disease.
Authors
Lucas Greven, Stijn N.R. Fuchs, Hélène F.E. Gleitz, Rebekka K. Schneider
Abstract
The ECM is a dynamic component of the tumor microenvironment with a critical role in cancer progression, invasion, metastasis, immune exclusion, and response to therapy. Recent advances in proteomic analyses investigating the insoluble ECM fractions (termed “matrisome analysis”), along with single-cell RNA sequencing and spatial transcriptomics, have revealed cancer-specific patterns of ECM remodeling. These studies have identified a panel of recurrently upregulated ECM proteins, including annexin A1, fibrillin-1, fibronectin, periostin, and tenascin-C, actively contributing to tumor growth, invasion, angiogenesis, and immune exclusion. The expression of the cancer-associated ECM is largely driven by cancer-associated fibroblasts (CAFs), whose molecular diversity has been dissected through single-cell profiling and consolidated in emerging CAF atlases across cancers. By investigating the matrisome composition and CAF heterogeneity, these studies have unraveled the pivotal role of the stroma in shaping tumor biology. Based on these discoveries, ECM proteins and CAFs are now being explored as biomarkers and therapeutic targets. Future integration of multi-omics datasets with clinical outcomes will help to translate these insights into novel biomarkers for patient stratification and stroma-directed therapeutic interventions.
Authors
Romain Desert, Orlando Musso, Thomas F. Baumert
Abstract
As the principal ECM-producing cell type, fibroblasts are essential regulators of tissue architecture and function in development, homeostasis, and disease. While their disease-promoting functions in fibrosis have long been the center of attention, it is increasingly recognized that fibroblasts exert critical homeostatic roles across organs, acting as sentinels that regulate the function, proliferation, and recruitment of epithelial, endothelial and immune cells in health and disease. Here, we will review the roles of fibroblasts and fibroblast-like cells in tissue maintenance, physiological wound healing, regeneration, maladaptive fibrosis, and cancer across major organs, including the skin, lung, liver, intestine, and kidney, and highlight organ-specific and shared populations and functions. We will discuss the role of PI16+ and COL15A1+ universal fibroblasts, organ-specific fibroblasts, and pericyte and pericyte-like stellate cells as cellular sources for the majority of CTHRC1+ activated fibroblasts and αSMA+ or LRRC15+ myofibroblasts and highlight the functions of specialized subpopulations, such as inflammatory fibroblasts, antigen-presenting fibroblasts, and fibroblast-like cells, including mesothelial and smooth muscle cells. A refined understanding of fibroblast heterogeneity holds promise for novel therapeutic concepts, aimed at targeting pathogenic subpopulations while preserving or enhancing homeostatic functions.
Authors
Xiaochun Yang, Marcella Steffani, Sandeep Nadella, Dean Sheppard, Florian Rieder, Yuval Rinkevich, Rafael Kramann, David A. Tuveson, Robert F. Schwabe
Abstract
The oxygen-rich milieu of the lungs necessitates precise iron homeostasis and regulation, processes that are fundamental to pulmonary physiology but often receive limited attention. However, in recent years, dysregulation of iron homeostasis has been linked to numerous acute and chronic respiratory diseases. Here, we comprehensively evaluate the mechanisms governing iron homeostasis in the alveolar epithelium of the lung and examine how iron dysregulation contributes to impaired alveolar epithelial repair in respiratory disease. This Review focuses on the effects of iron on alveolar epithelial cell homeostasis and repair and disease pathogenesis. There will be a focus on emerging interventions designed to reestablish iron homeostasis and their potential therapeutic implications related to enhancing lung repair and limiting the progression of lung disease.
Authors
Ugonna Mbaekwe, Sarah Kenny, Suzanne M. Cloonan, Corrine R. Kliment
Abstract
Chronic obstructive pulmonary disease (COPD) was the third leading cause of global mortality in 2011 but receives limited attention and research funding. This Review describes the current knowledge on COPD risk factors, including genetic and epigenetic determinants and their interactions with the microbiome and environmental exposures. Preclinical models are being refined and single-cell transcriptomic, metabolomic, and proteomic technologies are being implemented to investigate the molecular mechanisms of disease progression. Patient cohorts to define biomarkers of early disease and the latest approaches to diagnose pre-COPD are essential to accelerate the development of novel and effective therapeutic interventions and translate new findings into clinical trials. This Review is a summary of topics covered by a symposium organized by the COPD-iNET consortium, an international network of researchers who have established a platform that facilitates collaboration of this multidisciplinary group of preclinical, translational, and clinical researchers.
Authors
Yohannes Tesfaigzi, Ali Önder Yildirim, Francesca Polverino, Thomas M. Conlon, Venkataramana Sidhaye, Maor Sauler, S. Vamsee Raju, Renata Z. Jurkowska, Divay Chandra, Michael H. Cho, Edwin K. Silverman, Ramon C. Sun, Peter Castaldi, Purushothama Rao Tata, Kambez H. Benam, Linto Antony, Mareike Lehmann, Beata Kosmider, Karim Bahmed, Zerihun H. Negasi, Kamakshi Bankoti, Carter Swaby, Dave A. Lagowala, Yeşim Vural, Hasan Bayram, Rosa Faner, George Washko, Dinh Son Bui, Bartolome Celli, Roxana Maria Wasnick, Enid Neptune
Abstract
Bronchopulmonary dysplasia (BPD) remains a debilitating disease in premature infants. The chronic pathogenesis of BPD with complex prenatal and postnatal programming challenges attempts at precisely defining or treating disease. While existing BPD definitions categorize disease severity, a lack of consideration of disease heterogeneity and endotypes has contributed to the failure of clinical trials to improve BPD outcomes. Recent studies have used advanced lung imaging techniques, echocardiography, and lung function tests to identify airway, parenchymal, and vascular BPD endotypes. These endotypes carry different prognoses and require endotype-specific treatment strategies to optimize infant outcomes. In this Review, we focus on the pathogenic mechanisms that specify individual BPD endotypes and discuss how combining biomarkers, functional studies, and artificial intelligence–based characterization of endotypes can inform precision therapies for BPD.
Authors
Megha Sharma, Gangaram Akangire, Noah H. Hillman, Winston M. Manimtim, Mark Ivan Attard, Venkatesh Sampath
Abstract
Long COVID is a debilitating condition that can develop after a SARS-CoV-2 infection and is characterized by a wide range of chronic symptoms, including weakness, neurocognitive impairment, malaise, fatigue, and many others, that affect multiple organ systems. At least 10% of individuals with a previous infection may develop long COVID, which affects their ability to perform daily functions and work. Despite its severity and widespread impact, this multisystemic condition remains poorly understood. Recent studies suggest that dysregulation of the complement system, a key component of the innate immune response, may contribute to the pathogenesis of long COVID, particularly in connection with coagulation, inflammation, and vascular injury. In this Review, we examine the evidence linking complement system dysregulation to long COVID and explore its potential role in driving disease pathology.
Authors
Rafael Bayarri-Olmos, William Bain, Akiko Iwasaki
Abstract
Transcription factors (TFs) play a pivotal role in the development and differentiation of T cells. Recent studies have highlighted unique transcriptional profiles in chimeric antigen receptor T (CAR-T) cells derived from patients with favorable clinical outcomes, suggesting a potential link between TF modulation and improved therapeutic efficacy. Although CAR-T cell therapies have shown some success in treating hematological malignancies, they are limited by challenges such as poor persistence, functional exhaustion, and tumor resistance. To overcome these limitations, researchers have attempted to enhance the efficacy of CAR-T cells through manipulation of TF expression. This Review provides a comprehensive overview of TF engineering in CAR-T cells and elucidates the complex regulatory network between TFs. Notably, modification of basic leucine zipper ATF-like transcription factor in CAR-T cells results in contradictory functional outcomes in different studies. We summarize the potential factors leading to such results and elucidate the importance of setting up a relevant in vitro model to evaluate the effect of TFs on CAR-T cells. In conclusion, this Review highlights the latest advances in TF modifications and proposes strategies for harnessing these insights to empower CAR-T cells with superior antitumor efficacy.
Authors
Ruoqi Chen, Lianqing Chen, Yu Tang, Xiaolin Shen, Yajie Wang, Peng Tang, Xingchao Shentu, Jie Sun
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