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Science, 12 June 2015: Vol. 348 no. 6240 | DOI: 10.1126/science.aaa2340
Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration
Abstract
Yongyou Zhang1,*, Amar Desai1,*, Sung Yeun Yang1,2,*, Ki Beom Bae1,3,*, Monika I. Antczak4,*, Stephen P. Fink1,*, Shruti Tiwari1,5,*, Joseph E. Willis6,7,5, Noelle S. Williams4, Dawn M. Dawson6,7, David Wald6,7,5, Wei-Dong Chen1,†, Zhenghe Wang6,8, Lakshmi Kasturi1, Gretchen A. Larusch1, Lucy He1,‡, Fabio Cominelli1,5, Luca Di Martino1, Zora Djuric9, Ginger L. Milne10, Mark Chance11, Juan Sanabria12,5, Chris Dealwis13, Debra Mikkola1, Jacinth Naidoo4, Shuguang Wei4, Hsin-Hsiung Tai14,§, Stanton L. Gerson1,6,5,§||, Joseph M. Ready4,15,§||, Bruce Posner4,15,§||, James K. V. Willson15,§||, Sanford D. Markowitz1,6,5,§||
1Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
2Department of Gastroenterology, Haeundae Paik Hospital, Inje University, Busan 612896, South Korea.
3Department of Surgery, Busan Paik Hospital, and Paik Institute of Clinical Research and Ocular Neovascular Research Center, Inje University, Busan, South Korea.
4Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5Case Medical Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA.
6Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
7Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
8Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
9Department of Family Medicine, University of Michigan, Ann Arbor MI 48109, USA.
10Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
11Proteomics Center, Case Western Reserve University, Cleveland, OH 44106, USA.
12Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA.
13Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
14College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
15Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
† Present name and address: (Wei-Dong) David Chen, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
‡ Present address: Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
||Corresponding author.Sanford D. Markowitz, James K. V. Willson, Bruce Posner, Joseph M. Ready, Stanton L. Gerson
* These authors contributed equally to this work.
§ These authors contributed equally to this work.
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.
논문정보
- Research article
- 2015년 06월 (BRIC 등록일 2015-06-23)
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