Cellular Plasticity of Defa4 Cre -Expressing Paneth Cells in Response to Notch Activation and Intestinal Injury.

Autor:	Jones JC; Cell Biology, Stem Cells and Development Graduate Program, University of Colorado Medical School, Aurora, Colorado., Brindley CD; Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado Medical School, Aurora, Colorado., Elder NH; Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado Medical School, Aurora, Colorado., Myers MG Jr; Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan., Rajala MW; Division of Gastroenterology, Department of Digestive Disease and Transplantation, Einstein Health Network, Philadelphia, Pennsylvania., Dekaney CM; Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina., McNamee EN; Mucosal Immunology Program, University of Colorado Medical School, Aurora, Colorado., Frey MR; Saban Research Institute, Children's Hospital Los Angeles, Department of Pediatrics, Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California., Shroyer NF; Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas., Dempsey PJ; Cell Biology, Stem Cells and Development Graduate Program, University of Colorado Medical School, Aurora, Colorado; Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado Medical School, Aurora, Colorado. Electronic address: Peter.Dempsey@ucdenver.edu.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2019; Vol. 7 (3), pp. 533-554. Date of Electronic Publication: 2018 Nov 27.
DOI:	10.1016/j.jcmgh.2018.11.004
Abstrakt:	Background & Aims: Loss of leucine-rich repeat-containing G-protein-coupled receptor 5-positive crypt base columnar cells provides permissive conditions for different facultative stem cell populations to dedifferentiate and repopulate the stem cell compartment. In this study, we used a defensin α4-Cre recombinase (Defa4Cre) line to define the potential of Paneth cells to dedifferentiate and contribute to intestinal stem cell (ISC) maintenance during normal homeostasis and after intestinal injury. Methods: Small intestine and enteroids from Defa4 Cre ;Rosa26 tandem dimer Tomato (tdTomato), a red fluoresent protein, (or Rosa26 Enhanced Yellow Fluorescent Protein (EYFP)) reporter, Notch gain-of-function (Defa4 Cre ;Rosa26 Notch Intracellular Domain (NICD)-ires-nuclear Green Fluorescent Protein (nGFP) and Defa4 Cre ;Rosa26 reverse tetracycline transactivator-ires Enhanced Green Fluorescent Protein (EGFP);TetO NICD ), A Disintegrin and Metalloproteinase domain-containing protein 10 (ADAM10) loss-of-function (Defa4 Cre ;ADAM10 flox/flox ), and Adenomatous polyposis coli (APC) inactivation (Defa4 Cre ;APC flox/flox ) mice were analyzed. Doxorubicin treatment was used as an acute intestinal injury model. Lineage tracing, proliferation, and differentiation were assessed in vitro and in vivo. Results: Defa4 Cre -expressing cells are fated to become mature Paneth cells and do not contribute to ISC maintenance during normal homeostasis in vivo. However, spontaneous lineage tracing was observed in enteroids, and fluorescent-activated cell sorter-sorted Defa4 Cre -marked cells showed clonogenic enteroid growth. Notch activation in Defa4 Cre -expressing cells caused dedifferentiation to multipotent ISCs in vivo and was required for adenoma formation. ADAM10 deletion had no significant effect on crypt homeostasis. However, after acute doxorubicin-induced injury, Defa4 Cre -expressing cells contributed to regeneration in an ADAM10-Notch-dependent manner. Conclusions: Our studies have shown that Defa4 Cre -expressing Paneth cells possess cellular plasticity, can dedifferentiate into multipotent stem cells upon Notch activation, and can contribute to intestinal regeneration in an acute injury model. (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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