Lingampally Arun, Truchi Marin, Mauduit Olivier, Delcroix Vanessa, Vasquez-Pacheco Esmeralda, Gautier-Isola Marine, Chu Xuran, Khadim Ali, Chao Cho-Ming, Zabihi Mahsa, Taghizadeh Sara, Rivetti Stefano, Marega Manuela, Moiseenko Alena, Hadzic Stefan, Vazquez-Armendariz Ana Ivonne, Herold Susanne, Günther Stefan, Millar-Büchner Pamela, Koepke Janine, Samakovlis Christos, Wilhelm Jochen, Bartkuhn Marek, Braun Thomas, Weissmann Norbert, Zhang JinSan, Wygrecka Malgorzata, Makarenkova Helen P, Günther Andreas, Seeger Werner, Chen Chengshui, El Agha Elie, Mari Bernard, Bellusci Saverio
The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China.
Department of Medicine II, Internal Medicine, Pulmonary and Critical Care, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, Germany.
Eur Respir J. 2025 Feb 6;65(2). doi: 10.1183/13993003.00482-2023. Print 2025 Feb.
Fibrosis is often associated with aberrant repair mechanisms that ultimately lead to organ failure. In the lung, idiopathic pulmonary fibrosis (IPF) is a fatal form of interstitial lung disease for which there is currently no curative therapy. From the cell biology point of view, the cell of origin and eventual fate of activated myofibroblasts (aMYFs) have taken centre stage, as these cells are believed to drive structural remodelling and lung function impairment. While aMYFs are now widely believed to originate from alveolar fibroblasts, the heterogeneity and ultimate fate of aMYFs during fibrosis resolution remain elusive. We have shown previously that aMYF dedifferentiation and acquisition of a lipofibroblast (LIF)-like phenotype represent a route of fibrosis resolution.
In this study, we combined genetic lineage tracing and single-cell transcriptomics in mice, and data mining of human IPF datasets to decipher the heterogeneity of aMYFs and investigate differentiation trajectories during fibrosis resolution. Furthermore, organoid cultures were utilised as a functional readout for the alveolar mesenchymal niche activity during various phases of injury and repair in mice.
Our data demonstrate that aMYFs consist of four subclusters displaying unique pro-alveologenic pro-fibrotic profiles. Alveolar fibroblasts displaying a high LIF-like signature largely constitute both the origin and fate of aMYFs during fibrogenesis and resolution, respectively. The heterogeneity of aMYFs is conserved in humans and a significant proportion of human aMYFs displays a high LIF signature.
Our work identifies a subcluster of aMYFs that is potentially relevant for future management of IPF.
纤维化通常与异常的修复机制相关，最终导致器官衰竭。在肺部，特发性肺纤维化（IPF）是一种致命的间质性肺疾病，目前尚无治愈方法。从细胞生物学角度来看，活化肌成纤维细胞（aMYFs）的起源细胞和最终命运成为了核心问题，因为这些细胞被认为会驱动结构重塑和肺功能损害。虽然现在普遍认为aMYFs起源于肺泡成纤维细胞，但在纤维化消退过程中aMYFs的异质性和最终命运仍然不清楚。我们之前已经表明，aMYF去分化并获得脂成纤维细胞（LIF）样表型是纤维化消退的一条途径。
在本研究中，我们将基因谱系追踪和单细胞转录组学结合应用于小鼠，并对人类IPF数据集进行数据挖掘，以解读aMYFs的异质性，并研究纤维化消退过程中的分化轨迹。此外，利用类器官培养作为小鼠损伤和修复各阶段肺泡间充质微环境活性的功能读数。
我们的数据表明，aMYFs由四个亚群组成，呈现出独特的促肺泡生成和促纤维化特征。在纤维化形成和消退过程中，表现出高LIF样特征的肺泡成纤维细胞分别在很大程度上构成了aMYFs的起源和命运。aMYFs的异质性在人类中是保守的，并且相当一部分人类aMYFs表现出高LIF特征。
我们的工作确定了一个aMYFs亚群，其可能与IPF的未来治疗相关。
