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The University of Texas at Austin

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Nat. Cell Biol., Published: 02 September 2021 | https://doi.org/10.1038/s41556-021-00742-6 Release of Notch activity coordinated by IL-1β signalling confers differentiation plasticity of airway progenitors via Fosl2 during alveolar regeneration

Jinwook Choi^1,10, Yu Jin Jang^2,10, Catherine Dabrowska^1,3, Elhadi Iich¹, Kelly V. Evans^1,3, Helen Hall⁴, Sam M. Janes ⁴, Benjamin D. Simons ^1,5,6, Bon-Kyoung Koo⁷, Jonghwan Kim^2,8,9,* and Joo-Hyeon Lee ^1,3,*

¹Wellcome–MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. ²Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA. ³Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. ⁴Lungs for Living Centre, UCL Respiratory, Division of Medicine, University College London, London, UK. ⁵Wellcome–Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK. ⁶Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Science, University of Cambridge, Cambridge, UK. ⁷Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna Biocenter (VBC), Vienna, Austria. ⁸Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA. ⁹Center for Systems and Synthetic Biology, The University of Texas at Austin, Austin, TX, USA. ¹⁰These authors contributed equally: Jinwook Choi, Yu Jin Jang.

^*Correspondence to Jonghwan Kim or Joo-Hyeon Lee.

Abstract

While the acquisition of cellular plasticity in adult stem cells is essential for rapid regeneration after tissue injury, little is known about the underlying mechanisms governing this process. Our data reveal the coordination of airway progenitor differentiation plasticity by inflammatory signals during alveolar regeneration. Following damage, interleukin-1β (IL-1β) signalling-dependent modulation of Jag1 and Jag2 expression in ciliated cells results in the inhibition of Notch signalling in secretory cells, which drives the reprogramming and acquisition of differentiation plasticity. We identify the transcription factor Fosl2 (also known as Fra2) for secretory cell fate conversion to alveolar type 2 cells that retain the distinct genetic and epigenetic signatures of secretory lineages. We also reveal that human secretory cells positive for KDR (also known as FLK-1) display a conserved capacity to generate alveolar type 2 cells via Notch inhibition. Our results demonstrate the functional role of an IL-1β–Notch–Fosl2 axis in the fate decision of secretory cells during injury repair, proposing a potential therapeutic target for human lung alveolar regeneration.

논문정보

형식Research article
게재일2021년 09월 (BRIC 등록일 2021-09-10)
연구진국외 연구진
분야 생명과학 > 세포생물학

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