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Organoids capture tissue-specific innate lymphoid cell development in mice and humans

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Article number111281
JournalCell Reports
Volume40
Issue number9
DOIs
Published30 Aug 2022

Bibliographical note

Funding Information: G.M.J. acknowledges a PhD studentship from the Wellcome Trust (108874/B/15/Z), a Biomedical Research Centre (BRC) Bright Sparks Precision Medicine Early Career Research Award, and a Schmidt Science Fellowship. E.R. acknowledges a PhD studentship from the Wellcome Trust (108874/B/15/Z). J.F.N. acknowledges a Marie Skłodowska-Curie Fellowship, a King's Prize fellowship, an RCUK/UKRI Rutherford Fund fellowship (MR/R024812/1), and a Seed Award in Science from the Wellcome Trust (204394/Z/16/Z). D.C. acknowledges a PhD studentship from the National Institute of Health and Care Research (NIHR) BRC based at Guy's and St. Thomas' (GSTT) NHS Foundation Trust and King's College London (KCL). L.B.R. was supported by NIHR BRC based at GSTT and KCL. T.-J.T. M.A.C. E.G. and J.F.N. are grateful to the Gut Human Organoid Platform (Gut-HOP) at King's College London, which is supported by a King's Together Strategic Award. G.M.L. was supported by the Wellcome Trust (091009) and the Medical Research Council (MR/M003493/1 and MR/K002996/1). We thank the BRC flow cytometry core team and acknowledge financial support from the Department of Health via the NIHR comprehensive BRC award to GSTT NHS Foundation Trust in partnership with KCL and King's College Hospital NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. D.D. is an employee of KCL and an employee of bit.bio. D.D. declares no other affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter or materials discussed in this manuscript. We are grateful to E. Slatery for producing the graphical abstract of this manuscript. We thank I. Heo, D. Dutta, and H. Clevers for providing raw data for meta-analysis. We thank A.N.J. McKenzie and J. Wells for fruitful discussion. We thank S. Joseph for murine GF animals, G. Eberl for RORCGFP animals, and J. Zhu for T-betAmCyan animals. We also thank I. Jackson, E. Timms, N. Almeida, and C. Martinez for technical assistance. J.F.N. initiated the project. G.M.J. and J.F.N. designed the experiments. G.M.J. E.R. L.B.R. and J.F.N. acquired and interpreted data. G.M.J. and U.N. performed bioinformatics analyses. G.M.J. E.R. T.Z. D.C. R.R. and J.F.N. performed murine experiments. G.M.J. T.-J.T. and M.V.G. produced hiPSC organoids. G.M.J. performed human experiments and prepared, wrote, and revised the manuscript. L.B.R. E.G. D.D. L.V. and M.A.C. provided resources and reagents. G.M.J. G.M.L. and J.F.N. acquired funding for the project. G.M.L. and J.F.N. supervised the project. All authors reviewed the manuscript. G.M.J. and J.F.N. are inventors on a patent application related to this work (UK Patent Application No. 2208963.5). The remaining authors declare no competing interests. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. Funding Information: G.M.J. acknowledges a PhD studentship from the Wellcome Trust (108874/B/15/Z), a Biomedical Research Centre (BRC) Bright Sparks Precision Medicine Early Career Research Award, and a Schmidt Science Fellowship. E.R. acknowledges a PhD studentship from the Wellcome Trust ( 108874/B/15/Z ). J.F.N. acknowledges a Marie Skłodowska-Curie Fellowship, a King’s Prize fellowship, an RCUK /UKRI Rutherford Fund fellowship ( MR/R024812/1 ), and a Seed Award in Science from the Wellcome Trust ( 204394/Z/16/Z ). D.C. acknowledges a PhD studentship from the National Institute of Health and Care Research ( NIHR ) BRC based at Guy's and St. Thomas' (GSTT) NHS Foundation Trust and King's College London ( KCL ). L.B.R. was supported by NIHR BRC based at GSTT and KCL. T.-J.T., M.A.C., E.G., and J.F.N. are grateful to the Gut Human Organoid Platform (Gut-HOP) at King’s College London, which is supported by a King’s Together Strategic Award. G.M.L. was supported by the Wellcome Trust ( 091009 ) and the Medical Research Council ( MR/M003493/1 and MR/K002996/1 ). We thank the BRC flow cytometry core team and acknowledge financial support from the Department of Health via the NIHR comprehensive BRC award to GSTT NHS Foundation Trust in partnership with KCL and King’s College Hospital NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. D.D. is an employee of KCL and an employee of bit.bio. D.D. declares no other affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter or materials discussed in this manuscript. We are grateful to E. Slatery for producing the graphical abstract of this manuscript. We thank I. Heo, D. Dutta, and H. Clevers for providing raw data for meta-analysis. We thank A.N.J. McKenzie and J. Wells for fruitful discussion. We thank S. Joseph for murine GF animals, G. Eberl for RORC GFP animals, and J. Zhu for T-bet AmCyan animals. We also thank I. Jackson, E. Timms, N. Almeida, and C. Martinez for technical assistance. Publisher Copyright: © 2022 The Author(s)

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Abstract

Organoid-based models of murine and human innate lymphoid cell precursor (ILCP) maturation are presented. First, murine intestinal and pulmonary organoids are harnessed to demonstrate that the epithelial niche is sufficient to drive tissue-specific maturation of all innate lymphoid cell (ILC) groups in parallel, without requiring subset-specific cytokine supplementation. Then, more complex human induced pluripotent stem cell (hiPSC)-based gut and lung organoid models are used to demonstrate that human epithelial cells recapitulate maturation of ILC from a stringent systemic human ILCP population, but only when the organoid-associated stromal cells are depleted. These systems offer versatile and reductionist models to dissect the impact of environmental and mucosal niche cues on ILC maturation. In the future, these could provide insight into how ILC activity and development might become dysregulated in chronic inflammatory diseases.

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