Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Mol Ther. 2013 Jul;21(7):1424-31. doi: 10.1038/mt.2013.71. Epub 2013 May 14.
In vitro generation of hematopoietic stem cells (HSCs) from induced pluripotent stem cells (iPSCs) has the potential to provide novel therapeutic approaches for replacing bone marrow (BM) transplantation without rejection or graft versus host disease. Hitherto, however, it has proved difficult to generate truly functional HSCs transplantable to adult host mice. Here, we demonstrate a unique in vivo differentiation system yielding engraftable HSCs from mouse and human iPSCs in teratoma-bearing animals in combination with a maneuver to facilitate hematopoiesis. In mice, we found that iPSC-derived HSCs migrate from teratomas into the BM and their intravenous injection into irradiated recipients resulted in multilineage and long-term reconstitution of the hematolymphopoietic system in serial transfers. Using this in vivo generation system, we could demonstrate that X-linked severe combined immunodeficiency (X-SCID) mice can be treated by HSCs derived from gene-corrected clonal iPSCs. It should also be noted that neither leukemia nor tumors were observed in recipients after transplantation of iPSC-derived HSCs. Taken our findings together, our system presented in this report should provide a useful tool not only for the study of HSCs, but also for practical application of iPSCs in the treatment of hematologic and immunologic diseases.
体外诱导多能干细胞（iPSCs）生成造血干细胞（HSCs）有可能提供新的治疗方法，替代骨髓（BM）移植而不产生排斥反应或移植物抗宿主病。然而，迄今为止，很难从 iPSCs 中真正生成可移植到成年宿主小鼠的功能性 HSCs。在这里，我们展示了一种独特的体内分化系统，该系统可与促进造血的操作相结合，从鼠和人 iPSCs 中生成可植入的 HSCs。在小鼠中，我们发现 iPSC 衍生的 HSCs 从畸胎瘤迁移到 BM 中，将其静脉注射到辐照受体中，可导致血液和淋巴造血系统在连续转移中多谱系和长期重建。使用这种体内生成系统，我们可以证明可以通过来自基因校正的克隆 iPSCs 衍生的 HSCs 来治疗 X 连锁严重联合免疫缺陷（X-SCID）小鼠。还应注意的是，在移植 iPSC 衍生的 HSCs 后，受者中既没有观察到白血病也没有观察到肿瘤。综上所述，本报告中提出的系统不仅为 HSCs 的研究提供了有用的工具，也为 iPSCs 在血液和免疫疾病治疗中的实际应用提供了有用的工具。
