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持续修复迁移偶联的 DNA 损伤可使涡虫成体干细胞到达创伤部位。

Ongoing repair of migration-coupled DNA damage allows planarian adult stem cells to reach wound sites.

机构信息

Department of Zoology, University of Oxford, Oxford, United Kingdom.

CRUK/MRC Oxford Institute for Radiation Oncology, ORCRB Roosevelt Drive, University of Oxford, Oxford, United Kingdom.

出版信息

Elife. 2021 Apr 23;10:e63779. doi: 10.7554/eLife.63779.

DOI:10.7554/eLife.63779
PMID:33890575
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8104965/
Abstract

Mechanical stress during cell migration may be a previously unappreciated source of genome instability, but the extent to which this happens in any animal in vivo remains unknown. We consider an in vivo system where the adult stem cells of planarian flatworms are required to migrate to a distal wound site. We observe a relationship between adult stem cell migration and ongoing DNA damage and repair during tissue regeneration. Migrating planarian stem cells undergo changes in nuclear shape and exhibit increased levels of DNA damage. Increased DNA damage levels reduce once stem cells reach the wound site. Stem cells in which DNA damage is induced prior to wounding take longer to initiate migration and migrating stem cell populations are more sensitive to further DNA damage than stationary stem cells. RNAi-mediated knockdown of DNA repair pathway components blocks normal stem cell migration, confirming that active DNA repair pathways are required to allow successful migration to a distal wound site. Together these findings provide evidence that levels of migration-coupled-DNA-damage are significant in adult stem cells and that ongoing migration requires DNA repair mechanisms. Our findings reveal that migration of normal stem cells in vivo represents an unappreciated source of damage, which could be a significant source of mutations in animals during development or during long-term tissue homeostasis.

摘要

细胞迁移过程中的机械压力可能是基因组不稳定性的一个以前未被重视的来源，但在任何体内动物中，这种情况发生的程度尚不清楚。我们考虑一种体内系统，其中扁形动物的成年干细胞需要迁移到远端伤口部位。我们观察到成年干细胞迁移与组织再生过程中持续的 DNA 损伤和修复之间存在关系。正在迁移的扁形动物干细胞经历核形状的变化，并表现出增加的 DNA 损伤水平。一旦干细胞到达伤口部位，DNA 损伤水平就会降低。在受伤前诱导 DNA 损伤的干细胞需要更长的时间才能开始迁移，并且与静止干细胞相比，迁移的干细胞群体对进一步的 DNA 损伤更为敏感。RNAi 介导的 DNA 修复途径成分的敲低阻止了正常干细胞的迁移，这证实了活跃的 DNA 修复途径是允许其成功迁移到远端伤口部位所必需的。这些发现共同表明，与迁移相关的 DNA 损伤水平在成年干细胞中是显著的，并且持续的迁移需要 DNA 修复机制。我们的发现表明，体内正常干细胞的迁移代表了一种以前未被重视的损伤来源，这可能是动物在发育过程中或长期组织稳态过程中突变的一个重要来源。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/30a7/8104965/eae952bfeaea/elife-63779-fig4.jpg
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