Low temperature and mTOR inhibition favor stem cell maintenance in human keratinocyte cultures.
Low temperature and mTOR inhibition favor stem cell maintenance in human keratinocyte cultures.
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DOI：
10.15252/embr.202255439
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发表时间：
2023-06-05
期刊：
影响因子：
7.7
通讯作者：
中科院分区：
文献类型：
--
作者：
成人自体人表皮干细胞可以广泛地体外扩增用于细胞和基因治疗。确定干细胞维持中涉及的机制并定义维持干细胞性的培养条件是至关重要的，因为不适当的环境可能导致干细胞快速转化为祖细胞/瞬时扩增细胞（克隆转化），对移植物的质量及其移植能力产生有害后果。在这里，我们证明了培养的人表皮干细胞通过mTOR信号传导通过thermoTRP通道对温度的小幅下降做出反应。细胞暴露于雷帕霉素或温度的小幅下降诱导mTOR的核转位，对基因表达产生影响。我们还通过单细胞分析证明，长期抑制mTORC 1可降低克隆转化，有利于维持干性。总之，我们的结果表明，人类角质形成干细胞可以适应环境变化（例如，温度的小变化）通过mTOR信号传导和mTORC 1的持续抑制有利于干细胞维持，这是一个对再生医学应用非常重要的发现。培养的人表皮角质形成细胞干细胞通过与mTORC 1信号传导相关的thermoTRP通道对温度的小幅下降做出反应。mTORC 1抑制有利于在人角质形成细胞培养物中维持干细胞表型。
Adult autologous human epidermal stem cells can be extensively expanded ex vivo for cell and gene therapy. Identifying the mechanisms involved in stem cell maintenance and defining culture conditions to maintain stemness is critical, because an inadequate environment can result in the rapid conversion of stem cells into progenitors/transient amplifying cells (clonal conversion), with deleterious consequences on the quality of the transplants and their ability to engraft. Here, we demonstrate that cultured human epidermal stem cells respond to a small drop in temperature through thermoTRP channels via mTOR signaling. Exposure of cells to rapamycin or a small drop in temperature induces the nuclear translocation of mTOR with an impact on gene expression. We also demonstrate by single‐cell analysis that long‐term inhibition of mTORC1 reduces clonal conversion and favors the maintenance of stemness. Taken together, our results demonstrate that human keratinocyte stem cells can adapt to environmental changes (e.g., small variations in temperature) through mTOR signaling and constant inhibition of mTORC1 favors stem cell maintenance, a finding of high importance for regenerative medicine applications. Cultured human epidermal keratinocyte stem cells respond to a small drop in temperature through thermoTRP channels connected to mTORC1 signaling. mTORC1 inhibition favors the maintenance of a stem cell phenotype in human keratinocyte cultures.
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影响因子：
3.6
作者：
Denda, Mitsuhiro;Tsutsumi, Moe;Denda, Sumiko
通讯作者：
Denda, Sumiko
DOI：
10.1073/pnas.82.16.5390
发表时间：
1985-01-01
影响因子：
11.1
作者：
BARRANDON, Y;GREEN, H
通讯作者：
GREEN, H
影响因子：
158.5
作者：
GALLICO, GG;OCONNOR, NE;GREEN, H
通讯作者：
GREEN, H
影响因子：
4
作者：
Green, Howard
通讯作者：
Green, Howard
影响因子：
6.5
作者：
Asakawa, Makoto;Yoshioka, Takeshi;Sakata, Tsuneaki
通讯作者：
Sakata, Tsuneaki