CXCR4-transgene expression significantly improves marrow engraftment of cultured hematopoietic stem cells
CXCR4-transgene expression significantly improves marrow engraftment of cultured hematopoietic stem cells
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DOI：
10.1634/stemcells.2003-0196
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发表时间：
2004-01-01
期刊：
影响因子：
5.2
通讯作者：
Malech, HL
中科院分区：
文献类型：
--
作者：
Brenner, S;Whiting-Theobald, N;Malech, HL
造血干细胞（HSC）在离体培养过程中丧失骨髓重建潜能。HSC向基质细胞衍生因子（SDF）-1（CXCL 12）的迁移与CXC趋化因子受体4（CXCR 4）表达和骨髓移植相关。我们证明，动员的人CD 34（+）外周血干细胞（CD 34（+）PBSC）在长期培养过程中失去CXCR 4表达。我们用编码人CXCR 4的逆转录病毒载体转导CD 34（+）PBSCs，在超过87%的CD 34（+）细胞中CXCR 4的表达增加了18倍，CXCR 4转导的细胞产生了增加的钙流和高达10倍的向SDF-1的迁移。培养6天的CXCR 4转导细胞在非肥胖糖尿病/严重联合免疫缺陷小鼠中表现出显著的植入，而对照转导细胞导致低植入或无植入。我们的结论是，转导介导的CXCR 4的过表达显着提高培养的PBSC的骨髓移植。
Hematopoietic stem cells (HSCs) lose marrow reconstitution potential during ex vivo culture. HSC migration to stromal cell-derived factor (SDF)-1 (CXCL12) correlates with CXC chemokine receptor 4 (CXCR4) expression and marrow engraftment. We demonstrate that mobilized human CD34(+) peripheral blood stem cells (CD34(+) PBSCs) lose CXCR4 expression during prolonged culture. We transduced CD34(+) PBSCs with retrovirus vector encoding human CXCR4 and achieved 18-fold more CXCR4 expression in over 87% of CD34(+) cells.CXCR4-transduced cells yielded increased calcium flux and up to a 10-fold increase in migration to SDF-1. Six-day cultured CXCR4-transduced cells demonstrated significant engraftment in nonobese diabetic/severe combined immunodeficient mice under conditions in which control transduced cells resulted in low or no engraftment. We conclude that transduction-mediated overexpression of CXCR4 significantly improves marrow engraftment of cultured PBSCs.