Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America.
Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America.
PLoS One. 2022 May 19;17(5):e0268787. doi: 10.1371/journal.pone.0268787. eCollection 2022.
Emerging evidence implicates the eicosanoid molecule prostaglandin E2 (PGE2) in conferring a regenerative phenotype to multiple organ systems following tissue injury. As aging is in part characterized by loss of tissue stem cells' regenerative capacity, we tested the hypothesis that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) contributes to the diminished organ fitness of aged mice. Here we demonstrate that genetic loss of 15-PGDH (Hpgd) confers a protective effect on aging of murine hematopoietic and gastrointestinal (GI) tissues. Aged mice lacking 15-PGDH display increased hematopoietic output as assessed by peripheral blood cell counts, bone marrow and splenic stem cell compartments, and accelerated post-transplantation recovery compared to their WT counterparts. Loss of Hpgd expression also resulted in enhanced GI fitness and reduced local inflammation in response to colitis. Together these results suggest that 15-PGDH negatively regulates aged tissue regeneration, and that 15-PGDH inhibition may be a viable therapeutic strategy to ameliorate age-associated loss of organ fitness.
新出现的证据表明，类二十烷酸分子前列腺素 E2（PGE2）在组织损伤后赋予多种器官系统再生表型。由于衰老的部分特征是组织干细胞再生能力的丧失，我们检验了这样一个假设，即前列腺素降解酶 15-羟基前列腺素脱氢酶（15-PGDH）有助于减少老年小鼠的器官适应性。在这里，我们证明了 15-PGDH（Hpgd）的遗传缺失赋予了衰老的造血和胃肠道（GI）组织以保护作用。与 WT 相比，缺乏 15-PGDH 的老年小鼠外周血细胞计数、骨髓和脾脏干细胞区室的造血输出增加，移植后恢复速度加快。Hpgd 表达的缺失还导致对结肠炎的 GI 适应性增强和局部炎症减少。这些结果表明，15-PGDH 负调节衰老组织的再生，并且 15-PGDH 抑制可能是改善与年龄相关的器官适应性丧失的可行治疗策略。
