Endothelium-targeted Delta-like 1 promotes hematopoietic stem cell expansion ex vivo and engraftment in hematopoietic tissues in vivo.
Endothelium-targeted Delta-like 1 promotes hematopoietic stem cell expansion ex vivo and engraftment in hematopoietic tissues in vivo.
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DOI：
10.1016/j.scr.2013.04.008
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发表时间：
2013-09
影响因子：
1.2
通讯作者：
D. Tian;Liang Liang-Liang;Xingcheng Zhao;M. Zheng;Xiu-li Cao;Hongyan Qin;Chun-mei Wang;Ying-min Liang;Hua Han
中科院分区：
文献类型：
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作者：
D. Tian;Liang Liang-Liang;Xingcheng Zhao;M. Zheng;Xiu-li Cao;Hongyan Qin;Chun-mei Wang;Ying-min Liang;Hua Han
缺口配体增强造血干细胞（hsc）的体外扩增。但要将Notch配体用于人类疾病的HSC治疗，还需要努力提高体外扩增效率和体内移植植入。设计与方法我们设计并制备了一种内皮靶向的可溶性Notch配体，即delta -样1的DSL结构域与RGD基序（D1R）融合，并研究了该蛋白在体内和体外对hsc的影响。结果d1r能有效促进小鼠骨髓和人脐带血造血干细胞的体外扩增。经D1R扩增的造血干细胞上调了许多与干细胞相关的基因，并表现出较高的骨髓移植效率和移植后的长期再生能力。此外，体内给药D1R增加了小鼠骨髓造血干细胞的数量，促进了照射后小鼠骨髓的恢复。注射D1R可显著改善放射小鼠骨髓移植后的HSC植入和髓系恢复。D1R不仅能促进小鼠骨髓内HSC的植入，还能促进小鼠骨髓移植后肝脏和脾脏内HSC的植入。D1R诱导移植的造血干细胞与内皮细胞紧密接触形成致密细胞团，使人联想到肝和脾的造血干细胞壁龛。结论sd1r可促进造血干细胞体外扩增和体内移植。
BackgroundNotch ligands enhance ex vivo expansion of hematopoietic stem cells (HSCs). But to use Notch ligands in HSC therapies of human diseases, efforts are required to improve ex vivo expansion efficiency and in vivo transplant engraftment.Design and methodsWe designed and produced an endothelium-targeted soluble Notch ligand, the DSL domain of Delta-like 1 fused with a RGD motif (D1R), and examined the effects of this protein on HSCs ex vivo and in vivo.ResultsD1R efficiently promoted ex vivo expansion of both mouse bone marrow (BM) and human umbilical cord blood HSCs. HSCs expanded with D1R up-regulated many of the stemness-related genes, and showed high BM engraftment efficacy with long-term repopulation capacity after transplantation. Moreover, in vivo administration of D1R increased the number of BM HSCs in mice, and facilitated BM recovery of mice after irradiation. Injection of D1R significantly improved HSC engraftment and myeloid recovery after BM transplantation in irradiated mice. D1R enhanced HSC engraftment not only in BM, but also in the liver and spleen after BM transplantation in mice. D1R induced the formation of compact cell clusters containing the transplanted HSCs in close contact with endothelial cells, reminiscent of HSC niches, in the liver and spleen.ConclusionsD1R might be applied in improving both HSC expansion ex vivo and HSC engraftment in vivo in transplantation.