Anatomically and Functionally Distinct Lung Mesenchymal Populations Marked by Lgr5 and Lgr6.,Cell

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Anatomically and Functionally Distinct Lung Mesenchymal Populations Marked by Lgr5 and Lgr6.
Cell ( IF 45.5 ) Pub Date : 2017-Sep-07 , DOI: 10.1016/j.cell.2017.07.028
Joo-Hyeon Lee ₁ , Tuomas Tammela ₂ , Matan Hofree ₃ , Jinwook Choi ₄ , Nemanja Despot Marjanovic ₂ , Seungmin Han ₅ , David Canner ₂ , Katherine Wu ₂ , Margherita Paschini ₆ , Dong Ha Bhang ₇ , Tyler Jacks ₈ , Aviv Regev ₉ , Carla F Kim ₆

Affiliation

Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary & Respiratory Diseases, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary & Respiratory Diseases, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

The diversity of mesenchymal cell types in the lung that influence epithelial homeostasis and regeneration is poorly defined. We used genetic lineage tracing, single-cell RNA sequencing, and organoid culture approaches to show that Lgr5 and Lgr6, well-known markers of stem cells in epithelial tissues, are markers of mesenchymal cells in the adult lung. Lgr6⁺ cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia and promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6⁺ cells impairs airway injury repair in vivo. Distinct Lgr5⁺ cells are located in alveolar compartments and are sufficient to promote alveolar differentiation of epithelial progenitors through Wnt activation. Modulating Wnt activity altered differentiation outcomes specified by mesenchymal cells. This identification of region- and lineage-specific crosstalk between epithelium and their neighboring mesenchymal partners provides new understanding of how different cell types are maintained in the adult lung.

中文翻译：

以 Lgr5 和 Lgr6 为标志的解剖学和功能上不同的肺间充质群。

肺中影响上皮稳态和再生的间充质细胞类型的多样性尚不清楚。我们使用遗传谱系追踪、单细胞 RNA 测序和类器官培养方法来证明 Lgr5 和 Lgr6（上皮组织中众所周知的干细胞标志物）是成人肺间充质细胞的标志物。Lgr6 ⁺细胞包含围绕气道上皮细胞的平滑肌细胞亚群，并通过 Wnt-Fgf10 合作促进上皮祖细胞的气道分化。^{Lgr6 +}细胞的基因消融会损害体内气道损伤修复。不同的 Lgr5 ⁺细胞位于肺泡区室中，足以通过 Wnt 激活促进上皮祖细胞的肺泡分化。调节 Wnt 活性改变了间充质细胞指定的分化结果。这种对上皮细胞与其相邻间充质伙伴之间区域和谱系特异性串扰的识别提供了对不同细胞类型如何在成人肺中维持的新理解。

更新日期：2017-09-07

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