工程化小鼠造血干细胞可重建多谱系造血和适应性免疫。
Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity.
作者信息
Lu Yi-Fen, Cahan Patrick, Ross Samantha, Sahalie Julie, Sousa Patricia M, Hadland Brandon K, Cai Wenqing, Serrao Erik, Engelman Alan N, Bernstein Irwin D, Daley George Q
机构信息
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children's Hospital Boston, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Howard Hughes Medical Institute, Children's Hospital Boston, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Biomedical Engineering, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
出版信息
Cell Rep. 2016 Dec 20;17(12):3178-3192. doi: 10.1016/j.celrep.2016.11.077.
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.
造血干细胞（HSC）移植可治愈恶性和遗传性血液疾病，但受供体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）中获取造血干细胞可以解决这些限制。此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，但在实现强大的淋巴细胞植入方面仍有不足。在这里，通过滴定HoxB4-ESC-HSC对Notch配体的暴露，我们报告了工程化造血干细胞的衍生，这些细胞能够自我更新，在初次和二次移植小鼠中重新填充多谱系造血，并在免疫缺陷受体中赋予适应性免疫。单细胞分析表明，在植入骨髓微环境后，这些工程化造血干细胞进一步分化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同表达。我们的工作证明了通过调节控制自我更新和谱系启动的遗传程序来工程化全功能造血干细胞。
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