First Department of Pathology, Kansai Medical University, Moriguchi City, Osaka, Japan.
Stem Cells Dev. 2010 Apr;19(4):461-8. doi: 10.1089/scd.2009.0251.
When bone marrow transplantation (BMT) is carried out, survival of the donor hematopoietic stem cells is crucial to maintain donor hematopoiesis in the recipients. We have shown that intra-bone marrow-bone marrow transplantation (IBM-BMT) can induce the rapid recovery of donor hematopoiesis and allow a reduction in radiation doses as a pretreatment for BMT. If IBM-BMT methodology can be further improved, BMT could be carried out more safely and more easily. In this experiment, we attempted to suppress apoptosis of donor hematopoietic cells using a caspase inhibitor, ZVAD-fmk, upon IBM-BMT in mouse allogeneic IBM-BMT. IBM-BMT with ZVAD-fmk induced superior engraftment of donor hematopoietic cells and greater numbers of day-12 colony-forming units of spleen (CFU-S) than IBM-BMT without ZVAD-fmk upon allogeneic BMT (C57BL/6 into BALB/c mice). ZVAD-fmk slightly suppressed apoptosis of whole BMCs, whereas it significantly suppressed apoptosis of c-kit+/Sca-1+/lineage(-) cells (KSL cells) in vitro. These results suggest that ZVAD-fmk can suppress apoptosis of hematopoietic stem cells and/or immature progenitor cells of the donor bone marrow cells, thereby accelerating the donor hematopoiesis.
当进行骨髓移植（BMT）时，供体造血干细胞的存活对于维持受者供体造血至关重要。我们已经表明，骨髓内-骨髓内移植（IBM-BMT）可以诱导供体造血的快速恢复，并允许减少 BMT 前的辐射剂量。如果 IBM-BMT 方法能够进一步改进，BMT 可以更安全、更容易地进行。在这项实验中，我们试图在小鼠同种异体 IBM-BMT 中使用半胱氨酸天冬氨酸蛋白酶抑制剂 ZVAD-fmk 抑制供体造血细胞的凋亡。与未用 ZVAD-fmk 的 IBM-BMT 相比，ZVAD-fmk 诱导的同种异体 BMT（C57BL/6 进入 BALB/c 小鼠）中供体造血细胞的植入和第 12 天脾集落形成单位（CFU-S）的数量更多。ZVAD-fmk 轻度抑制了整个 BMC 的凋亡，而在体外则显著抑制了 c-kit+/Sca-1+/谱系(-)细胞（KSL 细胞）的凋亡。这些结果表明，ZVAD-fmk 可以抑制供体骨髓细胞的造血干细胞和/或不成熟祖细胞的凋亡，从而加速供体造血。
