Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration

Yongyou Zhang; Amar Desai; Sung Yeun Yang; Ki Beom Bae; Monika I. Antczak; Stephen P. Fink; Shruti Tiwari; Joseph E. Willis; Noelle S. Williams; Dawn M. Dawson; David Wald; Wei Dong Chen; Zhenghe Wang; Lakshmi Kasturi; Gretchen A. Larusch; Lucy He; Fabio Cominelli; Luca Di Martino; Zora Djuric; Ginger L. Milne; Mark Chance; Juan Sanabria; Chris Dealwis; Debra Mikkola; Jacinth Naidoo; Shuguang Wei; Hsin Hsiung Tai; Stanton L. Gerson; Joseph M. Ready; Bruce Posner; James K V Willson; Sanford D. Markowitz

doi:10.1126/science.aaa2340

Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration

Yongyou Zhang, Amar Desai, Sung Yeun Yang, Ki Beom Bae, Monika I. Antczak, Stephen P. Fink, Shruti Tiwari, Joseph E. Willis, Noelle S. Williams, Dawn M. Dawson, David Wald, Wei Dong Chen, Zhenghe Wang, Lakshmi Kasturi, Gretchen A. Larusch, Lucy He, Fabio Cominelli, Luca Di Martino, Zora Djuric, Ginger L. MilneMark Chance, Juan Sanabria, Chris Dealwis, Debra Mikkola, Jacinth Naidoo, Shuguang Wei, Hsin Hsiung Tai, Stanton L. Gerson, Joseph M. Ready, Bruce Posner, James K V Willson, Sanford D. Markowitz

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	2340
Journal	Science
Volume	348
Issue number	6240
DOIs	https://doi.org/10.1126/science.aaa2340
State	Published - Jun 12 2015

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Zhang, Y., Desai, A., Yang, S. Y., Bae, K. B., Antczak, M. I., Fink, S. P., Tiwari, S., Willis, J. E., Williams, N. S., Dawson, D. M., Wald, D., Chen, W. D., Wang, Z., Kasturi, L., Larusch, G. A., He, L., Cominelli, F., Di Martino, L., Djuric, Z., ... Markowitz, S. D. (2015). Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science, 348(6240), Article 2340. https://doi.org/10.1126/science.aaa2340

Zhang, Y, Desai, A, Yang, SY, Bae, KB, Antczak, MI, Fink, SP, Tiwari, S, Willis, JE, Williams, NS, Dawson, DM, Wald, D, Chen, WD, Wang, Z, Kasturi, L, Larusch, GA, He, L, Cominelli, F, Di Martino, L, Djuric, Z, Milne, GL, Chance, M, Sanabria, J, Dealwis, C, Mikkola, D, Naidoo, J, Wei, S, Tai, HH, Gerson, SL, Ready, JM , Posner, B, Willson, JKV & Markowitz, SD 2015, 'Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration', Science, vol. 348, no. 6240, 2340. https://doi.org/10.1126/science.aaa2340

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title = "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.",

author = "Yongyou Zhang and Amar Desai and Yang, {Sung Yeun} and Bae, {Ki Beom} and Antczak, {Monika I.} and Fink, {Stephen P.} and Shruti Tiwari and Willis, {Joseph E.} and Williams, {Noelle S.} and Dawson, {Dawn M.} and David Wald and Chen, {Wei Dong} and Zhenghe Wang and Lakshmi Kasturi and Larusch, {Gretchen A.} and Lucy He and Fabio Cominelli and {Di Martino}, Luca and Zora Djuric and Milne, {Ginger L.} and Mark Chance and Juan Sanabria and Chris Dealwis and Debra Mikkola and Jacinth Naidoo and Shuguang Wei and Tai, {Hsin Hsiung} and Gerson, {Stanton L.} and Ready, {Joseph M.} and Bruce Posner and Willson, {James K V} and Markowitz, {Sanford D.}",

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AU - Antczak, Monika I.

AU - Fink, Stephen P.

AU - Tiwari, Shruti

AU - Willis, Joseph E.

AU - Williams, Noelle S.

AU - Dawson, Dawn M.

AU - Wald, David

AU - Chen, Wei Dong

AU - Wang, Zhenghe

AU - Kasturi, Lakshmi

AU - Larusch, Gretchen A.

AU - He, Lucy

AU - Cominelli, Fabio

AU - Di Martino, Luca

AU - Djuric, Zora

AU - Milne, Ginger L.

AU - Chance, Mark

AU - Sanabria, Juan

AU - Dealwis, Chris

AU - Mikkola, Debra

AU - Naidoo, Jacinth

AU - Wei, Shuguang

AU - Tai, Hsin Hsiung

AU - Gerson, Stanton L.

AU - Ready, Joseph M.

AU - Posner, Bruce

AU - Willson, James K V

AU - Markowitz, Sanford D.

PY - 2015/6/12

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N2 - 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.

AB - 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.

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Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration

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