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首页> 外文期刊>Cell Reports >Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity
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Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity

机译：工程化的鼠类造血干细胞重建多谱系造血和适应性免疫

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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 (ESCs/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.
机译：造血干细胞（HSC）移植可治愈恶性和遗传性血液疾病，但受到供体可用性和免疫失配的限制。从患者匹配的胚胎/诱导多能干细胞（ESC / iPSC）衍生HSC可以解决这些限制。先前在鼠模型中所做的努力利用了异位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样植入方面却不足。在这里，通过滴定HoxB4-ESC-HSC与Notch配体的接触滴定，我们报道了工程HSC的衍生，该HSC在原代和继代移植小鼠中自我更新，重新填充多谱系造血，并赋予免疫缺陷受体以适应性免疫。单细胞分析表明，植入骨髓小生境后，这些经过工程改造的HSC进一步指明了一种杂合细胞类型，其中共表达了造血干/祖细胞和分化的造血谱系的独特基因调控网络。我们的工作通过调节控制自我更新和谱系启动的遗传程序，展示了功能齐全的HSC的工程设计。

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