Deterministic HOX patterning in human pluripotent stem cell-derived neuroectoderm.
Deterministic HOX patterning in human pluripotent stem cell-derived neuroectoderm.
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DOI：
10.1016/j.stemcr.2015.02.018
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发表时间：
2015-04-14
影响因子：
5.9
通讯作者：
Ashton, Randolph S.
中科院分区：
文献类型：
--
作者：
Lippmann, Ethan S.;Williams, Clay E.;Ruhl, David A.;Estevez-Silva, Maria C.;Chapman, Edwin R.;Coon, Joshua J.;Ashton, Randolph S.
在后脑和脊髓发育过程中共线HOX表达多样化，并分配区域神经表型离散菱形和椎骨域。尽管体内HOX模式化的精确性，但用于将人多能干细胞（hPSC）分化为后部神经命运的体外方法粗略地模式化HOX表达，从而产生广泛特异于后脑或脊髓区域的培养物。在这里，我们证明了在hPSC分化期间成纤维细胞生长因子、Wnt/β-连环蛋白和生长分化因子信号传导的连续活化产生稳定的、均质的S 0X 2 +/Brachyury+神经中胚层，其在7天内表现出进行性的、完全共线的HOX活化。在该过程中的任何时间点转换为视黄酸处理停止共线HOX活化，并将神经中胚层转变为具有可预测的离散HOX基因/蛋白质谱的SOX 2 +/PAX 6+神经外胚层，其可以进一步分化为区域特异性细胞，例如，运动神经元这种完全定义的方法显著扩展了从不同的后脑和脊髓域获得区域神经表型的能力。H 0X在hPSC衍生的神经中胚层祖细胞（NMP）中的确定性表达Wnt/β-连环蛋白，FGF，视黄酸（RA）将NMPs转变为神经外胚层并停止HOX激活神经细胞可以被模式化为任何嘴尾侧后脑或脊髓结构域先前尝试从人类多能干细胞（hPSC）产生后部CNS组织产生随机或异质性的rostrocaudal区域的身份定义HOX表达。在这里，Ashton及其同事使用化学定义的系统和FGF、Wnt/β-catenin、GDF和视黄酸信号传导的时间调节，证明了神经祖细胞对整个后脑和脊髓中定义的域的确定性模式。
Colinear HOX expression during hindbrain and spinal cord development diversifies and assigns regional neural phenotypes to discrete rhombomeric and vertebral domains. Despite the precision of HOX patterning in vivo, in vitro approaches for differentiating human pluripotent stem cells (hPSCs) to posterior neural fates coarsely pattern HOX expression thereby generating cultures broadly specified to hindbrain or spinal cord regions. Here, we demonstrate that successive activation of fibroblast growth factor, Wnt/β-catenin, and growth differentiation factor signaling during hPSC differentiation generates stable, homogenous SOX2+/Brachyury+ neuromesoderm that exhibits progressive, full colinear HOX activation over 7 days. Switching to retinoic acid treatment at any point during this process halts colinear HOX activation and transitions the neuromesoderm into SOX2+/PAX6+ neuroectoderm with predictable, discrete HOX gene/protein profiles that can be further differentiated into region-specific cells, e.g., motor neurons. This fully defined approach significantly expands capabilities to derive regional neural phenotypes from diverse hindbrain and spinal cord domains. Deterministic HOX expression in hPSC-derived neuromesoderm progenitors (NMPs) Wnt/β-catenin, FGF, and GDF signaling regulate HOX activation in NMPs Retinoic acid (RA) transitions NMPs to neuroectoderm and halts HOX activation Neural cells can be patterned to any rostrocaudal hindbrain or spinal cord domain Previous attempts to generate posterior CNS tissues from human pluripotent stem cells (hPSCs) yielded stochastic or heterogeneous rostrocaudal regional identity defined by HOX expression. Here, Ashton and colleagues demonstrate deterministic patterning of neural progenitors to defined domains throughout the hindbrain and spinal cord using a chemically defined system and temporal modulation of FGF, Wnt/β-catenin, GDF, and retinoic acid signaling.
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影响因子：
64.8
作者：
Kriks, Sonja;Shim, Jae-Won;Piao, Jinghua;Ganat, Yosif M.;Wakeman, Dustin R.;Xie, Zhong;Carrillo-Reid, Luis;Auyeung, Gordon;Antonacci, Chris;Buch, Amanda;Yang, Lichuan;Beal, M. Flint;Surmeier, D. James;Kordower, Jeffrey H.;Tabar, Viviane;Studer, Lorenz
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Studer, Lorenz
影响因子：
64.5
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Dasen, Jeremy S.;De Camilli, Alessandro;Jessell, Thomas M.
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Jessell, Thomas M.
影响因子：
64.8
作者：
Dasen, JS;Liu, JP;Jessell, TM
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Jessell, TM
影响因子：
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作者：
Kaplan A;Spiller KJ;Towne C;Kanning KC;Choe GT;Geber A;Akay T;Aebischer P;Henderson CE
通讯作者：
Henderson CE
影响因子：
64.5
作者：
Dasen, JS;Tice, BC;Jessell, TM
通讯作者：
Jessell, TM