Ascl2-Dependent Cell Dedifferentiation Drives Regeneration of Ablated Intestinal Stem Cells
Ascl2-Dependent Cell Dedifferentiation Drives Regeneration of Ablated Intestinal Stem Cells
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DOI：
10.1016/j.stem.2019.12.011
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发表时间：
2020-03-05
期刊：
影响因子：
23.9
通讯作者：
Shivdasani, Ramesh A.
中科院分区：
文献类型：
--
作者：
Murata, Kazutaka;Jadhav, Unmesh;Shivdasani, Ramesh A.
LGR 5（+）肠干细胞（ISC）的消融与ISC区室的快速恢复相关。不同的肠隐窝群体去分化，以提供新的ISCs，但指导这一过程的转录和信号传导轨迹尚不清楚，大量的工作表明，静止的“储备”ISCs有助于再生。通过对LGR 5（+）谱系追踪和致死性损伤之间的时间间隔进行计时，我们发现ISC再生几乎完全由去分化解释，吸收和分泌祖细胞也有贡献。ISC限制性转录因子ASCL 2赋予静息ISC可测量的竞争优势，并且对于恢复ISC区室至关重要。再生细胞在Lgr 5之前2天重新表达Ascl，并且单细胞RNA测序（scRNA-seq）分析揭示了去分化的转录路径。ASCL 2靶基因包括白细胞介素-11（IL-11）受体Il 11 ra 1，重组IL-11可增强隐窝细胞再生潜力。这些发现揭示了细胞去分化作为ISC恢复的主要手段，并强调了ASCL 2调节的信号，使这种适应性反应。
Ablation of LGR5(+) intestinal stem cells (ISCs) is associated with rapid restoration of the ISC compartment. Different intestinal crypt populations dedifferentiate to provide new ISCs, but the transcriptional and signaling trajectories that guide this process are unclear, and a large body of work suggests that quiescent "reserve'' ISCs contribute to regeneration. By timing the interval between LGR5(+) lineage tracing and lethal injury, we show that ISC regeneration is explained nearly completely by dedifferentiation, with contributions from absorptive and secretory progenitors. The ISC-restricted transcription factor ASCL2 confers measurable competitive advantage to resting ISCs and is essential to restore the ISC compartment. Regenerating cells re-express Ascl2 days before Lgr5, and single-cell RNA sequencing (scRNA-seq) analyses reveal transcriptional paths underlying dedifferentiation. ASCL2 target genes include the interleukin-11 (IL-11) receptor Il11ra1, and recombinant IL-11 enhances crypt cell regenerative potential. These findings reveal cell dedifferentiation as the principal means for ISC restoration and highlight an ASCL2-regulated signal that enables this adaptive response.