YAP Regulates Hematopoietic Stem Cell Formation in Response to the Biomechanical Forces of Blood Flow.,Developmental Cell

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YAP Regulates Hematopoietic Stem Cell Formation in Response to the Biomechanical Forces of Blood Flow.
Developmental Cell ( IF 10.7 ) Pub Date : 2020-02-06 , DOI: 10.1016/j.devcel.2020.01.006
Vanessa Lundin ₁ , Wade W Sugden ₂ , Lindsay N Theodore ₂ , Patricia M Sousa ₃ , Areum Han ₃ , Stephanie Chou ₃ , Paul J Wrighton ₄ , Andrew G Cox ₄ , Donald E Ingber ₅ , Wolfram Goessling ₆ , George Q Daley ₇ , Trista E North ₂

Affiliation

Stem Cell Program, Division of Pediatric Hematology and Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
Stem Cell Program, Division of Pediatric Hematology and Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Stem Cell Program, Division of Pediatric Hematology and Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.
Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA.
Stem Cell Program, Division of Pediatric Hematology and Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Hematopoietic stem and progenitor cells (HSPCs), first specified from hemogenic endothelium (HE) in the ventral dorsal aorta (VDA), support lifelong hematopoiesis. Their de novo production promises significant therapeutic value; however, current in vitro approaches cannot efficiently generate multipotent long-lived HSPCs. Presuming this reflects a lack of extrinsic cues normally impacting the VDA, we devised a human dorsal aorta-on-a-chip platform that identified Yes-activated protein (YAP) as a cyclic stretch-induced regulator of HSPC formation. In the zebrafish VDA, inducible Yap overexpression significantly increased runx1 expression in vivo and the number of CD41+ HSPCs downstream of HE specification. Endogenous Yap activation by lats1/2 knockdown or Rho-GTPase stimulation mimicked Yap overexpression and induced HSPCs in embryos lacking blood flow. Notably, in static human induced pluripotent stem cell (iPSC)-derived HE culture, compound-mediated YAP activation enhanced RUNX1 levels and hematopoietic colony-forming potential. Together, our findings reveal a potent impact of hemodynamic Rho-YAP mechanotransduction on HE fate, relevant to de novo human HSPC production.

中文翻译：

YAP 响应血流的生物力学力调节造血干细胞的形成。

造血干细胞和祖细胞 (HSPCs) 最初由腹背主动脉 (VDA) 中的造血内皮 (HE) 指定，支持终生造血。它们的从头生产有望带来显着的治疗价值；然而，目前的体外方法不能有效地产生多能长寿命 HSPC。假设这反映了缺乏通常影响 VDA 的外在线索，我们设计了一个人类背主动脉芯片平台，该平台将 Yes 激活蛋白 (YAP) 确定为循环拉伸诱导的 HSPC 形成调节剂。在斑马鱼 VDA 中，诱导型 Yap 过表达显着增加体内 runx1 表达和 HE 规范下游 CD41+ HSPC 的数量。通过 lats1/2 敲低或 Rho-GTPase 刺激激活内源性 Yap 模拟了 Yap 过表达并在缺乏血流的胚胎中诱导 HSPC。值得注意的是，在静态人类诱导多能干细胞 (iPSC) 衍生的 HE 培养物中，化合物介导的 YAP 激活增强了 RUNX1 水平和造血集落形成潜力。总之，我们的研究结果揭示了血流动力学 Rho-YAP 机械转导对 HE 命运的强大影响，与从头人类 HSPC 生产相关。

更新日期：2020-02-07

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