State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Medicine, University of California, San Francisco, CA 94143.
Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2180-2185. doi: 10.1073/pnas.1718446115. Epub 2018 Jan 31.
Derivation of human hematopoietic stem cells (HSCs) from induced pluripotent stem cells (iPSCs) offers considerable promise for cell therapy, disease modeling, and drug screening. However, efficient derivation of functional iPSC-derived HSCs with in vivo engraftability and multilineage potential remains challenging. Here, we demonstrate a tractable approach for respecifying iPSC-derived blood cells into highly engraftable hematopoietic stem and progenitor cells (HSPCs) through transient expression of a single transcription factor, These induced HSPCs (iHSPCs) derived from iPSCs are able to fully reconstitute the human hematopoietic system in the recipient mice without myeloid bias. iHSPCs are long-term engraftable, but they are also prone to leukemic transformation during the long-term engraftment period. On the contrary, primary HSPCs with the same induction sustain the long-term engraftment without leukemic transformation. These findings demonstrate the feasibility of activating the HSC network in human iPSC-derived blood cells through expression of a single factor and suggest iHSPCs are more genomically instable than primary HSPCs, which merits further attention.
从诱导多能干细胞（iPSCs）中衍生出血液干细胞（HSCs）为细胞治疗、疾病建模和药物筛选提供了很大的希望。然而，高效地从诱导多能干细胞中衍生出具有体内植入能力和多能性的功能性 HSCs 仍然具有挑战性。在这里，我们通过瞬时表达单个转录因子展示了一种可行的方法，将 iPSC 衍生的血细胞重编程为高度可植入的造血干细胞和祖细胞（HSPCs）。这些从 iPSCs 中诱导的 HSPC（iHSPCs）能够在受体小鼠中完全重建人类造血系统，而没有骨髓偏向。iHSPCs 具有长期植入能力，但在长期植入期间也容易发生白血病转化。相反，具有相同诱导的原代 HSPC 可以在没有白血病转化的情况下维持长期植入。这些发现表明，通过表达单个因子激活人 iPSC 衍生血细胞中的 HSC 网络是可行的，并表明 iHSPCs 比原代 HSPCs 具有更高的基因组不稳定性，这值得进一步关注。
