Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis

被引：0
作者：
Maximilian Strunz
Lukas M. Simon
Meshal Ansari
Jaymin J. Kathiriya
Ilias Angelidis
Christoph H. Mayr
George Tsidiridis
Marius Lange
Laura F. Mattner
Min Yee
Paulina Ogar
Arunima Sengupta
Igor Kukhtevich
Robert Schneider
Zhongming Zhao
Carola Voss
Tobias Stoeger
Jens H. L. Neumann
Anne Hilgendorff
Jürgen Behr
Michael O’Reilly
Mareike Lehmann
Gerald Burgstaller
Melanie Königshoff
Harold A. Chapman
Fabian J. Theis
Herbert B. Schiller
机构：
[1] Helmholtz Zentrum Muenchen,Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC
[2] Member of the German Center for Lung Research (DZL),M bioArchive
[3] Helmholtz Zentrum München,Institute of Computational Biology
[4] University of Texas Health Science Center,Center for Precision Health, School of Biomedical Informatics
[5] University of California San Francisco,Biomedical Center
[6] Technische Universität München,Department of Mathematics
[7] University of Rochester,Department of Pediatrics
[8] Institute of Functional Epigenetics,Member of the German Center for Lung Research (DZL), Center for Comprehensive Developmental Care (CDeCLMU), Department of Neonatology, Perinatal Center Grosshadern
[9] Helmholtz Zentrum München,Member of the German Center for Lung Research (DZL), Department of Internal Medicine V
[10] Institute of Pathology,Comprehensive Pneumology Center (CPC), Research Unit Lung Repair and Regeneration
[11] Ludwig Maximilians University Hospital Munich,undefined
[12] Hospital of the Ludwig-Maximilians University (LMU),undefined
[13] Ludwig Maximilians University Hospital (LMU) Munich,undefined
[14] Asklepios Fachkliniken in Munich-Gauting,undefined
[15] Helmholtz Zentrum München,undefined
[16] Member of the German Center for Lung Research (DZL),undefined
[17] University of Colorado,undefined
[18] Department of Pulmonary Sciences and Critical Care Medicine,undefined
来源：
Nature Communications | / 11卷
关键词：
D O I：
暂无
中图分类号：
学科分类号：
摘要：
The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8 + transitional stem cell state during alveolar regeneration. These cells have squamous morphology, feature p53 and NFkB activation and display transcriptional features of cellular senescence. The Krt8+ state appears in several independent models of lung injury and persists in human lung fibrosis, creating a distinct cell–cell communication network with mesenchyme and macrophages during repair. We generated a model of gene regulatory programs leading to Krt8+ transitional cells and their terminal differentiation to alveolar type-1 cells. We propose that in lung fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states.
引用
收藏
相关论文
共 116 条
  • [1] Hogan BLM(2014)Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function Cell Stem Cell 15 123-138
  • [2] Logan CY(2015)Keeping it together: pulmonary alveoli are maintained by a hierarchy of cellular programs Bioessays 37 1028-1037
  • [3] Desai TJ(2014)Lung development: orchestrating the generation and regeneration of a complex organ Development 141 502-513
  • [4] Herriges M(2018)Type 2 immunity in tissue repair and fibrosis Nat. Rev. Immunol. 18 62-76
  • [5] Morrisey EE(2017)Two-way conversion between lipogenic and myogenic fibroblastic phenotypes marks the progression and resolution of lung fibrosis Cell Stem Cell 20 571-2404
  • [6] Gieseck RL(2017)Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span J. Exp. Med. 214 2387-3036
  • [7] Wilson MS(2013)Type 2 alveolar cells are stem cells in adult lung J. Clin. Invest. 123 3025-625
  • [8] Wynn TA(2015)Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury Nature 517 621-620
  • [9] El Agha E(2015)p63(+)Krt5(+) distal airway stem cells are essential for lung regeneration Nature 517 616-255
  • [10] Misharin AV(2018)Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor Nature 555 251-738
12345678910