Martijn A J Koppens1, Hayley Davis1, Gabriel N Valbuena1, Eoghan J Mulholland1, Nadia Nasreddin1, Mathilde Colombe2, Agne Antanaviciute3, Sujata Biswas1, Matthias Friedrich4, Lennard Lee5, Lai Mun Wang6, Viktor H Koelzer7, James E East8, Alison Simmons9, Douglas J Winton2, Simon J Leedham10. 1. Intestinal Stem Cell Biology Lab, Wellcome Centre Human Genetics, University of Oxford, Oxford, United Kingdom. 2. Li Ka Shing Centre, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom. 3. Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; Medical Research Council Weatherall Institute of Molecular Medicine Centre for Computational Biology, Medical Research Council Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom. 4. The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, United Kingdom. 5. Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. 6. Department of Laboratory Medicine, Changi General Hospital, SingHealth, Singapore, Singapore. 7. Department of Pathology and Molecular Pathology, University Hospital Zürich, Zürich, Switzerland; Department of Oncology and Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. 8. Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, and Oxford National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom. 9. Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, and Oxford National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom. 10. Intestinal Stem Cell Biology Lab, Wellcome Centre Human Genetics, University of Oxford, Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, and Oxford National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom. Electronic address: simon.leedham@well.ox.ac.uk.
Abstract
BACKGROUND & AIMS: In homeostasis, intestinal cell fate is controlled by balanced gradients of morphogen signaling. The bone morphogenetic protein (BMP) pathway has a physiological, prodifferentiation role, predominantly inferred through previous experimental pathway inactivation. Intestinal regeneration is underpinned by dedifferentiation and cell plasticity, but the signaling pathways that regulate this adaptive reprogramming are not well understood. We assessed the BMP signaling landscape and investigated the impact and therapeutic potential of pathway manipulation in homeostasis and regeneration. METHODS: A novel mouse model was generated to assess the effect of the autocrine Bmp4 ligand on individual secretory cell fate. We spatiotemporally mapped BMP signaling in mouse and human regenerating intestine. Transgenic models were used to explore the functional impact of pathway manipulation on stem cell fate and intestinal regeneration. RESULTS: In homeostasis, ligand exposure reduced proliferation, expedited terminal differentiation, abrogated secretory cell survival, and prevented dedifferentiation. After ulceration, physiological attenuation of BMP signaling arose through upregulation of the secreted antagonist Grem1 from topographically distinct populations of fibroblasts. Concomitant expression supported functional compensation after Grem1 deletion from tissue-resident cells. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory but functionally submaximal, because regeneration was impaired or enhanced by epithelial overexpression of Bmp4 or Grem1, respectively. Mechanistically, Bmp4 abrogated regenerative stem cell reprogramming despite a convergent impact of YAP/TAZ on cell fate in remodeled wounds. CONCLUSIONS: BMP signaling prevents epithelial dedifferentiation, and pathway attenuation through stromal Grem1 upregulation was required for adaptive reprogramming in intestinal regeneration. This intercompartmental antagonism was functionally submaximal, raising the possibility of therapeutic pathway manipulation in inflammatory bowel disease.
BACKGROUND & AIMS: In homeostasis, intestinal cell fate is controlled by balanced gradients of morphogen signaling. The bone morphogenetic protein (BMP) pathway has a physiological, prodifferentiation role, predominantly inferred through previous experimental pathway inactivation. Intestinal regeneration is underpinned by dedifferentiation and cell plasticity, but the signaling pathways that regulate this adaptive reprogramming are not well understood. We assessed the BMP signaling landscape and investigated the impact and therapeutic potential of pathway manipulation in homeostasis and regeneration. METHODS: A novel mouse model was generated to assess the effect of the autocrine Bmp4 ligand on individual secretory cell fate. We spatiotemporally mapped BMP signaling in mouse and human regenerating intestine. Transgenic models were used to explore the functional impact of pathway manipulation on stem cell fate and intestinal regeneration. RESULTS: In homeostasis, ligand exposure reduced proliferation, expedited terminal differentiation, abrogated secretory cell survival, and prevented dedifferentiation. After ulceration, physiological attenuation of BMP signaling arose through upregulation of the secreted antagonist Grem1 from topographically distinct populations of fibroblasts. Concomitant expression supported functional compensation after Grem1 deletion from tissue-resident cells. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory but functionally submaximal, because regeneration was impaired or enhanced by epithelial overexpression of Bmp4 or Grem1, respectively. Mechanistically, Bmp4 abrogated regenerative stem cell reprogramming despite a convergent impact of YAP/TAZ on cell fate in remodeled wounds. CONCLUSIONS: BMP signaling prevents epithelial dedifferentiation, and pathway attenuation through stromal Grem1 upregulation was required for adaptive reprogramming in intestinal regeneration. This intercompartmental antagonism was functionally submaximal, raising the possibility of therapeutic pathway manipulation in inflammatory bowel disease.
Authors: Toshiro Sato; Robert G Vries; Hugo J Snippert; Marc van de Wetering; Nick Barker; Daniel E Stange; Johan H van Es; Arie Abo; Pekka Kujala; Peter J Peters; Hans Clevers Journal: Nature Date: 2009-03-29 Impact factor: 49.962
Authors: Christopher J Lewis; Andrei N Mardaryev; Krzysztof Poterlowicz; Tatyana Y Sharova; Ahmar Aziz; David T Sharpe; Natalia V Botchkareva; Andrey A Sharov Journal: J Invest Dermatol Date: 2013-10-14 Impact factor: 8.551
Authors: Paige N Vega; Avlant Nilsson; Manu P Kumar; Hiroaki Niitsu; Alan J Simmons; James Ro; Jiawei Wang; Zhengyi Chen; Brian A Joughin; Wei Li; Eliot T McKinley; Qi Liu; Joseph T Roland; M Kay Washington; Robert J Coffey; Douglas A Lauffenburger; Ken S Lau Journal: Front Oncol Date: 2022-05-04 Impact factor: 5.738