药物增加 HIF1α 可增强造血干细胞和祖细胞归巢和植入。
Pharmacologic increase in HIF1α enhances hematopoietic stem and progenitor homing and engraftment.
机构信息
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN; and.
出版信息
Blood. 2014 Jan 9;123(2):203-7. doi: 10.1182/blood-2013-07-516336. Epub 2013 Oct 28.
Abstract
Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for a number of immunologic disorders. For effective transplant, HSCs must traffic from the peripheral blood to supportive bone marrow niches. We previously showed that HSC trafficking can be enhanced by ex vivo treatment of hematopoietic grafts with 16-16 dimethyl prostaglandin E2 (dmPGE2). While exploring regulatory molecules involved in dmPGE2 enhancement, we found that transiently increasing the transcription factor hypoxia-inducible factor 1-α (HIF1α) is required for dmPGE2-enhanced CXCR4 upregulation and enhanced migration and homing of stem and progenitor cells and that pharmacologic manipulation of HIF1α is also capable of enhancing homing and engraftment. We also now identify the specific hypoxia response element required for CXCR4 upregulation. These data define a precise mechanism through which ex vivo pulse treatment with dmPGE2 enhances the function of hematopoietic stem and progenitor cells; these data also define a role for hypoxia and HIF1α in enhancement of hematopoietic transplantation.
摘要
造血干细胞（HSC）移植是治疗多种免疫性疾病的救命疗法。为了进行有效的移植，HSCs 必须从外周血迁移到支持性的骨髓龛位。我们之前的研究表明，通过体外处理造血移植物用 16-16 二甲基前列腺素 E2（dmPGE2）可以增强 HSC 的迁移能力。在探索与 dmPGE2 增强相关的调节分子时，我们发现短暂增加转录因子缺氧诱导因子 1-α（HIF1α）是 dmPGE2 增强 CXCR4 上调以及增强干细胞和祖细胞迁移和归巢所必需的，并且药理学操纵 HIF1α 也能够增强归巢和植入。我们现在还确定了上调 CXCR4 所需的特定缺氧反应元件。这些数据定义了一个精确的机制，通过该机制，体外脉冲处理 dmPGE2 增强了造血干细胞和祖细胞的功能；这些数据还定义了缺氧和 HIF1α 在增强造血移植中的作用。
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