Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression.
Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression.
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DOI：
10.1016/j.cell.2012.09.032
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发表时间：
2012-10-26
期刊：
影响因子：
64.5
通讯作者：
Rafii S
中科院分区：
文献类型：
--
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
ETS转录因子ETV 2、FLI 1和ERG 1将多能干细胞指定为内皮细胞（EC）。然而，这些EC是不稳定的，并向非血管细胞命运漂移。我们发现，人妊娠中期c-Kit-谱系定型羊膜细胞（AC）可以很容易地重编程为诱导血管内皮细胞（iVEC）。在AC中瞬时表达ETV 2产生增殖但不成熟的iVEC，而与FLI 1/ERG 1共表达赋予iVEC与成熟稳定EC匹配的血管库和形态。简要的TGFβ抑制功能化VEGFR 2信号传导，增强AC向iVEC的特化。全基因组转录分析表明，iVEC与成人EC相似，其中血管特异性基因被打开，非血管基因被沉默。在功能上，iVEC在基质胶栓塞和再生肝脏中形成持久的通畅脉管系统。因此，短期ETV 2表达和TGFβ抑制沿着组成性ERG 1/FLI 1共表达将成熟AC重编程为具有临床规模扩增潜力的持久和功能性iVEC。HLA型iVEC的公共库将建立用于治疗遗传多样性疾病的血管库存。
ETS transcription factors ETV2, FLI1 and ERG1 specify pluripotent stem cells into endothelial cells (ECs). However, these ECs are unstable and drift towards non-vascular cell fates. We show that human mid-gestation c-Kit− lineage-committed amniotic cells (ACs) can be readily reprogrammed into induced vascular endothelial cells (iVECs). Transient ETV2 expression in ACs generated proliferative but immature iVECs, while co-expression with FLI1/ERG1 endowed iVECs with a vascular repertoire and morphology matching mature stable ECs. Brief TGFβ-inhibition functionalized VEGFR2 signaling, augmenting specification of ACs to iVECs. Genome-wide transcriptional analyses showed that iVECs are similar to adult ECs in which vascular-specific genes are turned on and non-vascular genes are silenced. Functionally, iVECs form long-lasting patent vasculature in Matrigel plugs and regenerating livers. Thus, short-term ETV2 expression and TGFβ-inhibition along with constitutive ERG1/FLI1 co-expression reprogram mature ACs into durable and functional iVECs with clinical-scale expansion potential. Public banking of HLA-typed iVECs would establish a vascular inventory for treatment of genetically diverse 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：
4.1
作者：
Benavides, Omar M.;Petsche, Jennifer J.;Jacot, Jeffrey G.
通讯作者：
Jacot, Jeffrey G.
影响因子：
20.3
作者：
Birdsey, Graeme M.;Dryden, Nicola H.;Randi, Anna M.
通讯作者：
Randi, Anna M.
影响因子：
23.9
作者：
Lee, Dongjun;Park, Changwon;Choi, Kyunghee
通讯作者：
Choi, Kyunghee
DOI：
10.1073/pnas.1205526109
发表时间：
2012-08-21
影响因子：
11.1
作者：
Margariti, Andriana;Winkler, Bernhard;Xu, Qingbo
通讯作者：
Xu, Qingbo