Ongoing repair of migration-coupled DNA damage allows planarian adult stem cells to reach wound sites.
Ongoing repair of migration-coupled DNA damage allows planarian adult stem cells to reach wound sites.
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DOI：
10.7554/elife.63779
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发表时间：
2021-04-23
期刊：
影响因子：
7.7
通讯作者：
Aboobaker A
中科院分区：
文献类型：
--
作者：
Sahu S;Sridhar D;Abnave P;Kosaka N;Dattani A;Thompson JM;Hill MA;Aboobaker A
细胞迁移过程中的机械应力可能是基因组不稳定的一个以前未被意识到的来源，但在活体动物中发生这种情况的程度尚不清楚。我们考虑了一个体内系统，在这个系统中，扁虫的成体干细胞需要迁移到远端的伤口部位。我们观察到成体干细胞迁移与组织再生过程中持续的DNA损伤和修复之间的关系。迁徙的浮游生物干细胞会经历核形状的变化，并表现出更高的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。在创伤前诱导DNA损伤的干细胞需要更长的时间才能启动迁移，而且迁移的干细胞群体比静止的干细胞对进一步的DNA损伤更敏感。RNAi介导的DNA修复途径组件的敲除阻止了正常的干细胞迁移，证实了活跃的DNA修复途径是允许成功迁移到远端伤口部位所必需的。总之，这些发现提供了证据，表明迁移偶联DNA损伤水平在成人干细胞中是显著的，并且正在进行的迁移需要DNA修复机制。我们的发现表明，正常干细胞在体内的迁移是一个未被认识到的损害来源，这可能是动物在发育过程中或长期组织动态平衡期间突变的一个重要来源。
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.