Mapping the Pairwise Choices Leading from Pluripotency to Human Bone, Heart, and Other Mesoderm Cell Types.
Mapping the Pairwise Choices Leading from Pluripotency to Human Bone, Heart, and Other Mesoderm Cell Types.
复制标题
DOI：
10.1016/j.cell.2016.06.011
复制
发表时间：
2016-07-14
期刊：
影响因子：
64.5
通讯作者：
Weissman IL
中科院分区：
文献类型：
--
作者：
Loh KM;Chen A;Koh PW;Deng TZ;Sinha R;Tsai JM;Barkal AA;Shen KY;Jain R;Morganti RM;Shyh-Chang N;Fernhoff NB;George BM;Wernig G;Salomon REA;Chen Z;Vogel H;Epstein JA;Kundaje A;Talbot WS;Beachy PA;Ang LT;Weissman IL
干细胞分化为所需的谱系需要导航交替的发育路径，通常会导致不需要的细胞类型。因此，全面的发育路线图对于引导干细胞分化走向预期的命运至关重要。为此，我们绘制了从多能性到包括骨、肌肉和心脏在内的12个人类中胚层谱系的分支选择图。我们定义了控制每个二元谱系决定的外在信号，使我们能够在逻辑上阻止分化向不想要的命运，并在大多数分支点快速引导多能干细胞向80-99%纯人类中胚层谱系发展。这一策略使得人类骨和心脏祖细胞能够在各自的体内模型中移植。在中胚层发育过程中逐步绘制染色质和单细胞基因表达变化图谱，揭示了体裂，这是一个以前无法观察到的人类胚胎事件，由HOPX的表达短暂标记。总的来说，这一路线图使中胚层发育的导航能够产生可移植的人类组织祖细胞，并揭示发育过程。
Stem-cell differentiation to desired lineages requires navigating alternating developmental paths often leading to unwanted cell-types. Hence comprehensive developmental roadmaps are crucial to channel stem-cell differentiation towards desired fates. To this end, here we map bifurcating lineage choices leading from pluripotency to twelve human mesodermal lineages, including bone, muscle and heart. We defined the extrinsic signals controlling each binary lineage decision, enabling us to logically block differentiation towards unwanted fates and rapidly steer pluripotent stem cells towards 80–99% pure human mesodermal lineages at most branchpoints. This strategy enabled the generation of human bone and heart progenitors that could engraft in respective in vivo models. Mapping stepwise chromatin and single-cell gene expression changes in mesoderm development uncovered somite segmentation, a previously-unobservable human embryonic event transiently marked by HOPX expression. Collectively this roadmap enables navigation of mesodermal development to produce transplantable human tissue progenitors and uncover developmental processes.