Li Pulin, Lahvic Jamie L, Binder Vera, Pugach Emily K, Riley Elizabeth B, Tamplin Owen J, Panigrahy Dipak, Bowman Teresa V, Barrett Francesca G, Heffner Garrett C, McKinney-Freeman Shannon, Schlaeger Thorsten M, Daley George Q, Zeldin Darryl C, Zon Leonard I
1] Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA [2] Chemical Biology Program, Harvard University, Cambridge, Massachusetts 02138, USA.
Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachuestts 02115, USA.
Nature. 2015 Jul 23;523(7561):468-71. doi: 10.1038/nature14569.
Haematopoietic stem and progenitor cell (HSPC) transplant is a widely used treatment for life-threatening conditions such as leukaemia; however, the molecular mechanisms regulating HSPC engraftment of the recipient niche remain incompletely understood. Here we develop a competitive HSPC transplant method in adult zebrafish, using in vivo imaging as a non-invasive readout. We use this system to conduct a chemical screen, and identify epoxyeicosatrienoic acids (EETs) as a family of lipids that enhance HSPC engraftment. The pro-haematopoietic effects of EETs were conserved in the developing zebrafish embryo, where 11,12-EET promoted HSPC specification by activating a unique activator protein 1 (AP-1) and runx1 transcription program autonomous to the haemogenic endothelium. This effect required the activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway, specifically PI(3)Kγ. In adult HSPCs, 11,12-EET induced transcriptional programs, including AP-1 activation, which modulate several cellular processes, such as migration, to promote engraftment. Furthermore, we demonstrate that the EET effects on enhancing HSPC homing and engraftment are conserved in mammals. Our study establishes a new method to explore the molecular mechanisms of HSPC engraftment, and discovers a previously unrecognized, evolutionarily conserved pathway regulating multiple haematopoietic generation and regeneration processes. EETs may have clinical application in marrow or cord blood transplantation.
造血干细胞和祖细胞（HSPC）移植是治疗白血病等危及生命疾病的一种广泛应用的疗法；然而，调节受体微环境中HSPC植入的分子机制仍未完全了解。在此，我们利用体内成像作为一种非侵入性读数，在成年斑马鱼中开发了一种竞争性HSPC移植方法。我们使用该系统进行化学筛选，并确定环氧二十碳三烯酸（EETs）是一类能增强HSPC植入的脂质。EETs的促造血作用在发育中的斑马鱼胚胎中是保守的，其中11,12-EET通过激活一种独特的激活蛋白1（AP-1）和runx1转录程序促进HSPC特化，该程序对造血内皮具有自主性。这种作用需要磷脂酰肌醇-3-羟基激酶（PI(3)K）途径，特别是PI(3)Kγ的激活。在成年HSPC中，11,12-EET诱导转录程序，包括AP-1激活，从而调节迁移等多种细胞过程以促进植入。此外，我们证明EETs增强HSPC归巢和植入的作用在哺乳动物中是保守的。我们的研究建立了一种探索HSPC植入分子机制的新方法，并发现了一条先前未被认识的、进化上保守的调节多个造血生成和再生过程的途径。EETs可能在骨髓或脐血移植中有临床应用。
