Kelly M Zullo1, Bonnie Douglas1, Nicole M Maloney1, Yingbiao Ji1, Yun Wei2, Karl Herbine1, Rachel Cohen1, Christopher Pastore1, Zvi Cramer3, Xin Wang3, Wenjie Wei4, Ma Somsouk5, Li Yin Hung1,2, Christopher Lengner3, Michael H Kohanski6,7, Noam A Cohen6,7,8, De'Broski R Herbert1,2. 1. Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA. 2. Department of Medicine, Division of Experimental Medicine, University of California, San Francisco, CA, USA. 3. Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA. 4. Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 5. Department of Pathology, University of California, San Francisco, CA, USA. 6. Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA, USA. 7. The Corporal Michael J. Crescenz VA Medical Center Surgical Service, Philadelphia, PA, USA. 8. Monell Chemical Senses Center, Philadelphia, PA, USA.
Abstract
Aim: Recovery of damaged mucosal surfaces following inflammatory insult requires diverse regenerative mechanisms that remain poorly defined. Previously, we demonstrated that the reparative actions of Trefoil Factor 3 (TFF3) depend upon the enigmatic receptor, leucine rich repeat and immunoglobulin-like domain containing nogo receptor 2 (LINGO2). This study examined the related orphan receptor LINGO3 in the context of intestinal tissue damage to determine whether LINGO family members are generally important for mucosal wound healing and maintenance of the intestinal stem cell (ISC) compartment needed for turnover of mucosal epithelium.Methods and Results: We find that LINGO3 is broadly expressed on human enterocytes and sparsely on discrete cells within the crypt niche, that contains ISCs. Loss of function studies indicate that LINGO3 is involved in recovery of normal intestinal architecture following dextran sodium sulfate (DSS)-induced colitis, and that LINGO3 is needed for therapeutic action of the long acting TFF2 fusion protein (TFF2-Fc), including a number of signaling pathways critical for cell proliferation and wound repair. LINGO3-TFF2 protein-protein interactions were relatively weak however and LINGO3 was only partially responsible for TFF2 induced MAPK signaling suggesting additional un-identified components of a receptor complex. However, deficiency in either TFF2 or LINGO3 abrogated budding/growth of intestinal organoids and reduced expression of the intestinal ISC gene leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), indicating homologous roles for these proteins in tissue regeneration, possibly via regulation of ISCs in the crypt niche. Conclusion: We propose that LINGO3 serves a previously unappreciated role in promoting mucosal wound healing.
Aim: Recovery of damaged mucosal surfaces following inflammatory insult requires diverse regenerative mechanisms that remain poorly defined. Previously, we demonstrated that the reparative actions of Trefoil Factor 3 (TFF3) depend upon the enigmatic receptor, leucine rich repeat and immunoglobulin-like domain containing nogo receptor 2 (LINGO2). This study examined the related orphan receptor LINGO3 in the context of intestinal tissue damage to determine whether LINGO family members are generally important for mucosal wound healing and maintenance of the intestinal stem cell (ISC) compartment needed for turnover of mucosal epithelium.Methods and Results: We find that LINGO3 is broadly expressed on human enterocytes and sparsely on discrete cells within the crypt niche, that contains ISCs. Loss of function studies indicate that LINGO3 is involved in recovery of normal intestinal architecture following dextran sodium sulfate (DSS)-induced colitis, and that LINGO3 is needed for therapeutic action of the long acting TFF2 fusion protein (TFF2-Fc), including a number of signaling pathways critical for cell proliferation and wound repair. LINGO3-TFF2 protein-protein interactions were relatively weak however and LINGO3 was only partially responsible for TFF2 induced MAPK signaling suggesting additional un-identified components of a receptor complex. However, deficiency in either TFF2 or LINGO3 abrogated budding/growth of intestinal organoids and reduced expression of the intestinal ISC gene leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), indicating homologous roles for these proteins in tissue regeneration, possibly via regulation of ISCs in the crypt niche. Conclusion: We propose that LINGO3 serves a previously unappreciated role in promoting mucosal wound healing.
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: Geethanjali Pickert; Clemens Neufert; Moritz Leppkes; Yan Zheng; Nadine Wittkopf; Moritz Warntjen; Hans-Anton Lehr; Sebastian Hirth; Benno Weigmann; Stefan Wirtz; Wenjun Ouyang; Markus F Neurath; Christoph Becker Journal: J Exp Med Date: 2009-06-29 Impact factor: 14.307
Authors: Heather L Rossi; Jorge F Ortiz-Carpena; Devon Tucker; Andrew E Vaughan; Nilam S Mangalmurti; Noam A Cohen; De'Broski R Herbert Journal: Am J Respir Cell Mol Biol Date: 2022-03 Impact factor: 6.914