Organ fibrosis is a common terminal pathway in many chronic diseases, such as idiopathic pulmonary fibrosis, cirrhosis, and heart failure, and there is currently a lack of effective treatments. The traditional view holds that fibrosis is primarily driven by fibroblasts within the organ. However, what role do mesothelial cells, which cover the surface of the organs, play in fibrosis—are they mere "bystanders" or "active participants"? If they are participants, how are they activated, how do they change, and how do they drive the disease process? These core questions have not been systematically addressed until now.
Answering these questions faces several challenges: Mesothelial cells are not a homogeneous population, yet there is a lack of a panoramic depiction of the different subtypes with distinct functions in both healthy and diseased states. Fibrosis is a dynamic and evolving process, making it difficult to capture the dynamic changes in mesothelial cells across different stages of the disease. Are the mechanisms discovered in mouse models applicable to humans? Do mesothelial cells in different organs (such as the lungs, liver, and heart) follow similar patterns in fibrosis? This requires large-scale, systematic comparative analysis.
This article presents the first cross-species "panoramic map" of mesothelial cells: The research team integrated single-cell RNA sequencing data from dozens of organs in both mice and humans to construct the world’s first comprehensive "mesothelial cell atlas." This map clearly reveals that, in a healthy state, mesothelial cells already exist as subpopulations with different functional tendencies; in disease states, they enter a completely new and highly specialized activated state.
Revealing the "Four-Step Dance" of Fibrosis: By conducting high temporal resolution analysis of a mouse pulmonary fibrosis model, the research team discovered for the first time that mesothelial cells are not simply "activated," but follow a clear four-stage differentiation pathway: First, they enter a metabolically active state; then, they differentiate into a proteolytic state with extracellular matrix degradation capabilities; next, they transition into an immune-regulatory state that recruits immune cells; and finally, they mature into a fibrogenic state that produces large amounts of collagen.
At the same time, the authors identified the "key switches" that regulate each step: The research successfully identified core genes that control the transition between each state. For instance, Ifi27l2a and Crip1 are the switches that initiate the "metabolically active state"; Dcn and Plac8 are the switches that guide the "proteolytic state"; and Mgp and Sparc are the switches that drive the "fibrogenic state."
Achieving "Directed Intervention" to Validate Therapeutic Potential: This is the most translationally valuable part of the study. The team developed a novel viral vector capable of precisely delivering genes to mesothelial cells in the mouse lungs. Excitingly, by "locking" the mesothelial cells in the metabolically active state (through overexpression of Ifi27l2a), they were able to effectively prevent the cells from differentiating into harmful states, thus significantly alleviating or even preventing the occurrence of pulmonary fibrosis. In contrast, forcing the cells into a proteolytic or fibrogenic state accelerated disease progression. This directly demonstrates that manipulating the state of mesothelial cells can decisively determine the progression of fibrosis.
This study fundamentally changes our understanding of the pathogenesis of fibrosis, elevating mesothelial cells from a peripheral role to a "core regulator" of the disease process. The cell atlas and differentiation pathway provided offer invaluable resources and a new theoretical framework for the entire field of fibrosis research.
The discovery of several key genes (especially the protective role of Ifi27l2a) offers unprecedented targets for the development of novel anti-fibrotic drugs. In the future, scientists may focus on finding drugs that can mimic the effects of Ifi27l2a, intervening at the level of this cell layer on the organ surface to prevent fibrosis from the "source," thus opening up a new direction for the treatment of currently almost incurable fibrotic diseases.
This study is a large-scale, systematic project that took approximately 5 to 6 years from the initial concept and data accumulation to the final publication of the paper. The collaborating institutions include Helmholtz Munich, the University of Munich, Capital Medical University, the Capital Medical Science and Innovation Center, among others, forming a multidisciplinary, multinational team.
The biggest challenge faced during the research was how to "precisely and specifically intervene in mesothelial cells located on the outer surface of organs in live animal models, and convincingly demonstrate that changes in their cellular state directly drive or inhibit fibrosis in deeper tissues." Traditional transgenic or gene knockout mouse models typically have systemic or broad organ-wide effects, making it impossible to specifically target the thin layer of mesothelial cells on the surface of the lungs, liver, or heart. This limitation makes it difficult to answer the core question of whether changes in mesothelial cells are a cause or a consequence of fibrosis. To overcome this bottleneck, the research team invested significant effort in designing and optimizing a novel adeno-associated virus (AAV) vector. They introduced an RGD peptide sequence on the viral coat, enabling efficient binding and infection of mesothelial cells. More importantly, they developed a minimally invasive surgical technique that allows precise injection of the virus into the pleural cavity (on the lung surface) or peritoneal cavity (on the liver and intestinal surfaces) of mice, enabling efficient and specific gene manipulation of mesothelial cells on the organ surfaces. The successful development of this technique was key to achieving a breakthrough in this project.
The authors proposed a disruptive new "outside-in" fibrosis model. The fibrosis process begins with the mesothelial cells on the organ surface. Once activated, these cells first degrade the existing matrix on the surface, and then "push" these degradation products, along with newly generated fibrotic signals, into the interior of the organ, thereby initiating and amplifying the fibrotic response in deeper tissues. This discovery opens a completely new "door" for understanding fibrosis. They identified a potential "fibrosis brake" — the metabolic state. By artificially "locking" mesothelial cells in a "metabolically active state" during the early stages of the disease, it is possible to prevent their progression to a more malignant state, thereby preventing fibrosis.
We will further validate the expression and function of key genes in human samples and develop intervention strategies targeting genes such as Crip1 and Ifi27l2a. At the same time, we will explore the mechanisms by which Crip1, Ifi27l2a, and other genes influence pulmonary fibrosis, and investigate their potential applications in other fibrotic diseases, such as liver and cardiac fibrosis.
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