Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity.
Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity.
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设计的鼠类HSC重建了多轮型造血和适应性免疫。
DOI：
10.1016/j.celrep.2016.11.077
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发表时间：
2016-12-20
期刊：
影响因子：
8.8
通讯作者：
Daley GQ
中科院分区：
文献类型：
--
作者：
Lu YF;Cahan P;Ross S;Sahalie J;Sousa PM;Hadland BK;Cai W;Serrao E;Engelman AN;Bernstein ID;Daley GQ
造血干细胞（HSC）移植可治愈恶性和遗传性血液疾病，但受到捐赠者可用性和免疫不匹配的限制。从患者匹配的胚胎/诱导多能干细胞 (ESC/iPSC) 中衍生 HSC 可以解决这些局限性。先前在小鼠模型中的研究利用异位 HoxB4 表达来驱动自我更新并实现多谱系重建，但在提供强大的淋巴移植方面存在不足。在这里，通过滴定 HoxB4-ESC-HSC 与 Notch 配体的接触，我们报道了工程化 HSC 的衍生，这些 HSC 能够自我更新，在初级和次级移植小鼠中重新填充多谱系造血功能，并赋予免疫缺陷受体适应性免疫。单细胞分析表明，在移植到骨髓生态位后，这些工程造血干细胞进一步指定为一种混合细胞类型，其中造血干/祖细胞和分化的造血谱系的不同基因调控网络共表达。我们的工作展示了通过调节控制自我更新和谱系启动的基因程序来设计功能齐全的 HSC。胚胎/诱导多能干细胞 (ESC/iPSC) 代表了用于治疗血液疾病的造血干细胞 (HSC) 的无限来源。通过调节控制自我更新和谱系引导途径的遗传程序，Lu 等人。获得具有强大淋巴潜能的工程造血干细胞，并赋予体内适应性免疫。
Hematopoietic stem cell (HSC) transplantation is curative for malignant and genetic blood disorders, but is limited by donor availability and immune-mismatch. Deriving HSCs from patient-matched embryonic/induced-pluripotent stem cells (ESC/iPSCs) could address these limitations. Prior efforts in murine models exploited ectopic HoxB4 expression to drive self-renewal and enable multi-lineage reconstitution, yet fell short in delivering robust lymphoid engraftment. Here, by titrating exposure of HoxB4-ESC-HSC to Notch ligands, we report derivation of engineered HSCs that self-renew, repopulate multi-lineage hematopoiesis in primary and secondary engrafted mice, and endow adaptive immunity in immune-deficient recipients. Single-cell analysis shows that following engraftment in the bone marrow niche, these engineered HSCs further specify to a hybrid cell-type in which distinct gene regulatory networks of hematopoietic stem/progenitors and differentiated hematopoietic lineages are co-expressed. Our work demonstrates engineering of fully functional HSCs via modulation of genetic programs that govern self-renewal and lineage priming. Embryonic/induced pluripotent stem cells (ESC/iPSCs) represent an unlimited source of hematopoietic stem cells (HSCs) for treating blood diseases. By modulating genetic programs governing self-renewal and lineage-guiding pathways, Lu et al. derive engineered HSCs with robust lymphoid potential and endow adaptive immunity in vivo.