title: TISSUE REGENERATION. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration.
abstract: Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Yongyou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Amar
authors.initials: A
authors.lastname: Desai
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Department of Gastroenterology, Haeundae Paik Hospital, Inje University, Busan 612896, South Korea.
authors.forename: Sung Yeun
authors.initials: SY
authors.lastname: Yang
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Department of Surgery, Busan Paik Hospital, and Paik Institute of Clinical Research and Ocular Neovascular Research Center, Inje University, Busan, South Korea.
authors.forename: Ki Beom
authors.initials: KB
authors.lastname: Bae
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Monika I
authors.initials: MI
authors.lastname: Antczak
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Fink
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Willis
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Dawson
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wald
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Chen
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Zhenghe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Kasturi
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Gretchen A
authors.initials: GA
authors.lastname: Larusch
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Cominelli
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Di Martino
authors.affiliation: Department of Family Medicine, University of Michigan, Ann Arbor MI 48109, USA.
authors.forename: Zora
authors.initials: Z
authors.lastname: Djuric
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.affiliation: Proteomics Center, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Chance
authors.affiliation: Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Sanabria
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Dealwis
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Mikkola
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jacinth
authors.initials: J
authors.lastname: Naidoo
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Wei
authors.affiliation: College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Hsin-Hsiung
authors.initials: HH
authors.lastname: Tai
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA. sxm10@cwru.edu james.willson@utsouthwestern.edu slg5@cwru.edu joseph.ready@utsouthwestern.edu bruce.posner@utsouthwestern.edu.
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. sxm10@cwru.edu james.willson@utsouthwestern.edu slg5@cwru.edu joseph.ready@utsouthwestern.edu bruce.posner@utsouthwestern.edu.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Ready
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. sxm10@cwru.edu james.willson@utsouthwestern.edu slg5@cwru.edu joseph.ready@utsouthwestern.edu bruce.posner@utsouthwestern.edu.
authors.forename: Bruce
authors.initials: B
authors.lastname: Posner
authors.affiliation: Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. sxm10@cwru.edu james.willson@utsouthwestern.edu slg5@cwru.edu joseph.ready@utsouthwestern.edu bruce.posner@utsouthwestern.edu.
authors.forename: James K V
authors.initials: JK
authors.lastname: Willson
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA. sxm10@cwru.edu james.willson@utsouthwestern.edu slg5@cwru.edu joseph.ready@utsouthwestern.edu bruce.posner@utsouthwestern.edu.
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D003092:Colitis / Q000201:enzymology / Q000517:prevention & control; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008115:Liver Regeneration / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D011453:Prostaglandins / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D011453:Prostaglandins; D011725:Pyridines; C000599192:SW033291; D013876:Thiophenes; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D015232:Dinoprostone