Reprogramming human endothelial cells to haematopoietic cells requires vascular induction.
Reprogramming human endothelial cells to haematopoietic cells requires vascular induction.
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DOI：
10.1038/nature13547
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发表时间：
2014-07-17
期刊：
影响因子：
64.8
通讯作者：
Rafii, Shahin
中科院分区：
文献类型：
--
作者：
Sandler, Vladislav M.;Lis, Raphael;Liu, Ying;Kedem, Alon;James, Daylon;Elemento, Olivier;Butler, Jason M.;Scandura, Joseph M.;Rafii, Shahin
从自体组织中产生可移植的人类造血细胞有望成为血液疾病的新疗法。多能干细胞的定向分化产生的造血细胞移植能力差。在这里，我们设计了一种方法来表型造血细胞的血管生态位微环境，从而使人内皮细胞（ECs）重编程为可移植的造血细胞，而无需通过多能中间体过渡。用转录因子（tf）、FOSB、GFI1、RUNX1和SPI1 （FGRS）介导高度纯化的非造血人脐静脉内皮细胞（HUVECs）或成人真皮微血管内皮细胞（hDMECs），在无血清的指导性血管生态位单层上增殖，诱导含有具有多能祖细胞（MPP）功能和免疫表型特征的造血集落的生长。这些重编程的ec -转化为人类mpp （rec - hmpp）获得集落形成细胞（CFC）的潜力，并在一次和二次移植后持久地植入免疫缺陷小鼠，产生长期的rec - hmpp衍生的髓系（粒细胞/单核细胞、红细胞、巨核细胞）和淋巴系（NK、B）后代。FGRS转基因的条件表达，结合血管诱导，激活内源性FGRS基因，使rEC-hMPPs具有类似于自我更新mpp的转录和功能谱。我们的方法强调了来自血管生态位的诱导线索在协调和维持造血规范中的作用，并可能证明对工程自体造血移植物治疗遗传性和获得性血液疾病有用。
Generating engraftable human hematopoietic cells from autologous tissues promises new therapies for blood diseases. Directed differentiation of pluripotent stem cells yields hematopoietic cells that poorly engraft. Here, we devised a method to phenocopy the vascular-niche microenvironment of hemogenic cells, thereby enabling reprogramming of human endothelial cells (ECs) into engraftable hematopoietic cells without transition through a pluripotent intermediate. Highly purified non-hemogenic human umbilical vein-ECs (HUVECs) or adult dermal microvascular ECs (hDMECs) were transduced with transcription factors (TFs), FOSB, GFI1, RUNX1, and SPI1 (FGRS), and then propagated on serum-free instructive vascular niche monolayers to induce outgrowth of hematopoietic colonies containing cells with functional and immunophenotypic features of multipotent progenitor cells (MPP). These reprogrammed ECs- into human-MPPs (rEC-hMPPs) acquire colony-forming cell (CFC) potential and durably engraft in immune-deficient mice after primary and secondary transplantation, producing long-term rEC-hMPP-derived myeloid (granulocytic/monocytic, erythroid, megakaryocytic) and lymphoid (NK, B) progeny. Conditional expression of FGRS transgenes, combined with vascular-induction, activates endogenous FGRS genes endowing rEC-hMPPs with a transcriptional and functional profile similar to self-renewing MPPs. Our approach underscores the role of inductive cues from vascular-niche in orchestrating and sustaining hematopoietic specification and may prove useful for engineering autologous hematopoietic grafts to treat inherited and acquired blood disorders.
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影响因子：
23.9
作者：
Butler JM;Nolan DJ;Vertes EL;Varnum-Finney B;Kobayashi H;Hooper AT;Seandel M;Shido K;White IA;Kobayashi M;Witte L;May C;Shawber C;Kimura Y;Kitajewski J;Rosenwaks Z;Bernstein ID;Rafii S
通讯作者：
Rafii S
影响因子：
23.9
作者：
Doulatov, Sergei;Vo, Linda T.;Chou, Stephanie S.;Kim, Peter G.;Arora, Natasha;Li, Hu;Hadland, Brandon K.;Bernstein, Irwin D.;Collins, James J.;Zon, Leonard I.;Daley, George Q.
通讯作者：
Daley, George Q.
影响因子：
64.5
作者：
Ginsberg M;James D;Ding BS;Nolan D;Geng F;Butler JM;Schachterle W;Pulijaal VR;Mathew S;Chasen ST;Xiang J;Rosenwaks Z;Shido K;Elemento O;Rabbany SY;Rafii S
通讯作者：
Rafii S
影响因子：
30.5
作者：
Pongubala, Jagan M. R.;Northrup, Daniel L.;Singh, Harinder
通讯作者：
Singh, Harinder
影响因子：
64.8
作者：
Hock, H;Hamblen, MJ;Orkin, SH
通讯作者：
Orkin, SH