Rapid and efficient reprogramming of human fetal and adult blood CD34+ cells into mesenchymal stem cells with a single factor
Rapid and efficient reprogramming of human fetal and adult blood CD34+ cells into mesenchymal stem cells with a single factor
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DOI：
10.1038/cr.2013.40
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发表时间：
2013-05-01
期刊：
影响因子：
44.1
通讯作者：
Zhang, Xiao-Bing
中科院分区：
文献类型：
--
作者：
Meng, Xianmei;Su, Rui-Jun;Zhang, Xiao-Bing
将皮肤细胞直接转化为成体干细胞，为再生医学开辟了新的治疗可能性。在这里，我们表明，通过使用单因子 OCT4 直接重编程，可以从脐带血（CB）或成人外周血（PB）-CD34（+）细胞有效地产生人诱导间充质干细胞（iMSC）。在 GSK3 抑制剂存在的情况下，16% 的 OCT4 转导的 CD34(+) 细胞在 2 周内转化为 iMSC。通过附加型载体介导的瞬时 OCT4 表达和慢病毒载体介导的 OCT4 转导可实现有效的直接重编程。 iMSCs表达MSC标志物，形态类似于骨髓(BM)-MSCs，具有体外多向分化能力，但与BM-MSCs相比具有更强的增殖能力。与 BM-MSC 类似，植入的 iMSC 形成骨和结缔组织，并且在小鼠中不致瘤。然而，BM-MSC 不会形成肌纤维，而 iMSC 确实会形成肌纤维，这表明 iMSC 具有潜在的功能优势。此外，我们观察到初始重编程和最佳 iMSC 自我更新需要高水平的 OCT4 表达，而多谱系分化需要 OCT4 表达的减少。我们的方法将有助于生成患者特异性 iMSC，这可能在再生医学中得到应用。这一发现还可能有助于开发将血细胞直接转化为具有临床重要性的其他类型细胞的策略。
The direct conversion of skin cells into somatic stem cells has opened new therapeutic possibilities in regenerative medicine. Here, we show that human induced mesenchymal stem cells (iMSCs) can be efficiently generated from cord blood (CB)- or adult peripheral blood (PB)-CD34(+) cells by direct reprogramming with a single factor, OCT4. In the presence of a GSK3 inhibitor, 16% of the OCT4-transduced CD34(+) cells are converted into iMSCs within 2 weeks. Efficient direct reprogramming is achieved with both episomal vector-mediated transient OCT4 expression and lentiviral vector-mediated OCT4 transduction. The iMSCs express MSC markers, resemble bone marrow (BM)-MSCs in morphology, and possess in vitro multilineage differentiation capacity, yet have a greater proliferative capacity compared with BM-MSCs. Similar to BM-MSCs, the implanted iMSCs form bone and connective tissues, and are non-tumorigenic in mice. However, BM-MSCs do not, whereas iMSCs do form muscle fibers, indicating a potential functional advantage of iMSCs. In addition, we observed that a high level of OCT4 expression is required for the initial reprogramming and the optimal iMSC self-renewal, while a reduction of OCT4 expression is required for multilineage differentiation. Our method will contribute to the generation of patient-specific iMSCs, which could have applications in regenerative medicine. This discovery may also facilitate the development of strategies for direct conversion of blood cells into other types of cells of clinical importance.