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

Abstract

Tissue regeneration is a medical challenge faced in injury from disease and during medical treatments such as bone marrow transplantation. Prostaglandin PGE2, which 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. SW033291 also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. These findings raise the possibility that inhibiting 15-PGDH could be a useful therapeutic strategy in several distinct clinical settings.

Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength

“…Indeed, a single injection of PGE2 alone (without MuSCs) directly into injured muscles led to a striking increase in endogenous MuSC numbers and myofiber sizes that was apparent within 2 wk. The beneficial effects of delivery of the inhibitor of the PGE2-degrading enzyme (15-PGDH) SW033291 on hematopoietic, liver, and colon regeneration are likely due to a similar augmentation of endogenous PGE2 levels (45). Notably, PGE2 and its analogs have safely been used in patients for more than a decade, for instance to induce labor (46) and to promote hematopoietic stem-cell transplantation (44).…”

Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer

“…Two of the top four genes overexpressed in CC are bona fide tumor suppressor genes-GALNT12 and HPGDwhereas the role of the other two-UBD and NUDT11-in CRC is uncertain (42)(43)(44). Because we previously showed EGFRinduced COX-2 expression and basolateral release of one of the COX-2 products, PGE 2 in HCA-7 cells, we decided to focus on HPGD because HPGD metabolizes PGE 2 to 13,14-dihydro-15-keto-PGE 2 (16,45,46). HPGD thus reduces the levels of PGE 2 , which is thought to be the major tumor-promoting eicosanoid (47).…”

Prostaglandin E2 Activates Yap and a Positive-Signaling Loop to Promote Colon Regeneration Following Colitis but also Carcinogenesis in Mice

“…YAP and PGE 2 are thought to be key mediators of colon regeneration following colitis 3,9,31 . Importantly, YAP and PGE 2 are both abruptly upregulated following tissue injury 3,9,32 . We therefore examined whether PGE 2 might promote colon regeneration by up-regulating YAP expression in mice.…”

“…Thus, PGE 2 is an important drug target for regenerative medicine and cancer prevention 1,2 . For example, recently, a 15-PGDH inhibitor (SW033291) was shown to promote tissue regeneration by increasing PGE 2 levels 3 . On the other hand, prolonged use of COX inhibitors, which decrease PGE 2 , lowers the risk of colorectal cancer development 2 but inhibits colon regeneration after colitis by reducing PGE 2 levels.…”

“…As To test whether PGE 2 also regulates YAP in vivo, we examined: 1) mice deficient in the PGE 2 -degrading enzyme 15-prostaglandin dehydrogenase (15-PGDH) 3,15,16 , and 2) both WT and 15-PGDH-KO mice that were treated with the COX inhibitor indomethacin to block PGE 2 synthesis ( Figure. 1E).…”