Understanding the regulation of adult stem cell migration during regeneration.

了解再生过程中成体干细胞迁移的调节。

• 批准号: MR/T028165/1
• 负责人: Aziz Aboobaker
• 金额: $ 67.84万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT028165%2F1
• 关键词: Understanding; regulation; adult; stem; cell

Throughout our lives the cells in our body actively maintain our tissues and organs by dividing and moving to replace aged or damaged cells. Cells can be damaged by normal wear and tear, by physical damage like a cut or a burn or because of various diseases. Much of this repair and maintenance is carried out by a special set of cells called "stem cells" that make the cell types in our bodies, as and when required. We now think that much of the aging process, many developmental disorders and in fact many cancers are caused by stem cells going wrong. Damage to the DNA of stem cells can lead to them being unable to divide further to help maintain our tissues and organs leading eventually to aging, but even more importantly this damage can also lead to changes in how stem cells behave so that they over proliferate and over migrate to cause cancer. So understanding how stem cells maintain tissues and the factors that can contribute to them going wrong is important. In this project we are specifically interested in how stem cells migrate correctly to the site of a wound and what can go wrong during this process. In order to study this we are using a simple animal model system that is capable of amazing regenerative feats because of a population of adult stem cells, that allow it to regenerate all adult tissues and organs, including the brain. These stem cells in these animals, called planarian worms, can be more easily and ethically accessed and studied than the stem cells of more complex animals. As many genes have been conserved over evolutionary time what we have discovered working with planarians continues to provide useful insights into our own biology. For example, we have recently described new genes and genetic interactions that are directly relevant to humans cancers. We have also found out that the process of migration can in itself cause damage to the genes of migrating stem cells during normal migration, as the physical progress of cell migration causes stress upon the nucleus that contains the genome. It is important that this damage is repaired properly as cells migrate, and our data so far indicate that without repair migration stops.We will use state-of-the-art molecular approaches to understand the how normal stem cell migration is controlled at the genetic level and what happens to this normal control when stem cells in planarians over-migrate to form tumor-like outgrowths.We will also investigate the interplay between cell migration and DNA repair, as this could be particularly important as a potential source of previously unappreciated source of damage to stem cells. The findings of out project will provide new fundamental insights into processes relevant to human diseases, including cancer.

在我们的一生中，我们体内的细胞通过分裂和移动来替换老化或受损的细胞，从而积极地维护我们的组织和器官。细胞可能会因正常磨损、割伤或烧伤等物理损伤或各种疾病而受损。这种修复和维护大部分是由一组称为“干细胞”的特殊细胞进行的，这些细胞在需要时在我们体内形成细胞类型。我们现在认为，许多衰老过程，许多发育障碍，事实上许多癌症都是由干细胞出错引起的。对干细胞DNA的损伤可能导致它们无法进一步分裂以帮助维持我们的组织和器官，最终导致衰老，但更重要的是，这种损伤也可能导致干细胞行为的变化，使它们过度增殖和过度迁移导致癌症。因此，了解干细胞如何维持组织以及可能导致它们出错的因素非常重要。在这个项目中，我们特别感兴趣的是干细胞如何正确地迁移到伤口部位，以及在这个过程中会出现什么问题。为了研究这一点，我们使用了一个简单的动物模型系统，该系统能够实现惊人的再生能力，因为有一群成体干细胞，使其能够再生所有成人组织和器官，包括大脑。这些动物体内的干细胞，称为真蠕虫，比更复杂动物的干细胞更容易获得和研究。由于许多基因在进化过程中被保存下来，我们在研究真涡虫时发现的东西继续为我们自己的生物学提供有用的见解。例如，我们最近描述了与人类癌症直接相关的新基因和遗传相互作用。我们还发现，在正常迁移过程中，迁移过程本身会对迁移干细胞的基因造成损害，因为细胞迁移的物理过程会对包含基因组的细胞核造成压力。重要的是这种损伤在细胞迁移时得到适当的修复，到目前为止，我们的数据表明，如果没有修复，迁移就会停止。我们将使用最先进的分子方法来了解正常的干细胞迁移是如何在遗传水平上受到控制的，以及当真涡虫中的干细胞过度迁移形成肿瘤时，这种正常的控制会发生什么。我们还将研究细胞迁移和DNA修复之间的相互作用，因为这可能是以前未被认识到的干细胞损伤的潜在来源。该项目的发现将为人类疾病（包括癌症）相关过程提供新的基本见解。

项目成果

ACME dissociation: a versatile cell fixation-dissociation method for single-cell transcriptomics.

• DOI: 10.1186/s13059-021-02302-5
• 发表时间: 2021-04-08
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: García-Castro H;Kenny NJ;Iglesias M;Álvarez-Campos P;Mason V;Elek A;Schönauer A;Sleight VA;Neiro J;Aboobaker A;Permanyer J;Irimia M;Sebé-Pedrós A;Solana J
• 通讯作者: Solana J

Identification of putative enhancer-like elements predicts regulatory networks active in planarian adult stem cells

• DOI: 10.1101/2022.02.03.479047
• 发表时间: 2022-02
• 期刊: eLife
• 影响因子: 7.7
• 作者: Jakke Neiro;Divya Sridhar;Anish Dattani;A. Aboobaker

Monitoring Chromatin Regulation in Planarians Using Chromatin Immunoprecipitation Followed by Sequencing (ChIP-seq).

使用染色质免疫沉淀和测序 (ChIP-seq) 监测涡虫的染色质调控。

• DOI: 10.1007/978-1-0716-2172-1_28
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Sridhar D

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

• DOI: 10.7554/elife.63779
• 发表时间: 2021-04-23
• 期刊: eLife
• 影响因子: 7.7
• 作者: Sahu S;Sridhar D;Abnave P;Kosaka N;Dattani A;Thompson JM;Hill MA;Aboobaker A
• 通讯作者: Aboobaker A