Kawai Toshinao, Choi Uimook, Liu Po-Ching, Whiting-Theobald Narda L, Linton Gilda F, Malech Harry L
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1456, USA.
Stem Cells Dev. 2007 Jun;16(3):361-70. doi: 10.1089/scd.2007.9997.
Hematopoietic stem cell (HSC) graft cell dose impacts significantly on allogeneic transplant. Similarly, HSC gene therapy outcome is affected by loss of repopulating cells during culture required for ex vivo retrovirus transduction. Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 play a central role in marrow trafficking of HSCs, and maneuvers that enhance CXCR4 activation might positively impact outcome in settings of limiting graft dose. CD26/dipeptidyl peptidase IV (DPP-IV) is an ectoenzyme protease that cleaves SDF-1, thus reducing CXCR4 activation. We show that injection of irradiated nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with >or=2 micromol Diprotin A (a tripeptide specific inhibitor of CD26 protease activity) at the time of transplant of human granulocyte colony-stimulating factor (G-CSF) mobilized CD34(+) peripheral blood cells (CD34(+) PBCs) results in a >3.4-fold enhancement of engraftment of human cells. We also show that CD26 on residual stromal cells in the irradiated recipient marrow milieu, and not any CD26 activity in the human CD34(+) PBC graft itself, plays the critical role in regulating receptivity of this environment for the incoming graft. Human marrow stromal cells also express CD26, raising the possibility that Diprotin A treatment could significantly enhance engraftment of HSCs in humans in settings of limiting graft dose just as we observed in the NOD/SCID mouse human xenograft model.
造血干细胞（HSC）移植细胞剂量对异基因移植有显著影响。同样，HSC基因治疗的结果也会受到体外逆转录病毒转导所需培养过程中再增殖细胞损失的影响。基质细胞衍生因子-1（SDF-1）及其受体CXCR4在HSC的骨髓归巢中起核心作用，增强CXCR4激活的策略可能会对移植剂量有限的情况下的治疗结果产生积极影响。CD26/二肽基肽酶IV（DPP-IV）是一种外切酶蛋白酶，可裂解SDF-1，从而降低CXCR4激活。我们发现，在移植人粒细胞集落刺激因子（G-CSF）动员的CD34(+)外周血细胞（CD34(+) PBC）时，给经照射的非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）小鼠注射≥2微摩尔的二肽素A（一种CD26蛋白酶活性的三肽特异性抑制剂），可使人类细胞的植入增强>3.4倍。我们还发现，照射受体骨髓环境中残留基质细胞上的CD26，而非人CD34(+) PBC移植物本身的任何CD26活性，在调节该环境对植入移植物的接受性方面起关键作用。人骨髓基质细胞也表达CD26，这增加了一种可能性，即正如我们在NOD/SCID小鼠人异种移植模型中观察到的那样，在移植剂量有限的情况下，二肽素A治疗可能会显著增强人类HSC的植入。
