The Impact of Cell and Gene Therapy on the Function and Molecular Regulation of Hematopoietic Stem Cells.

细胞和基因治疗对造血干细胞功能和分子调节的影响。

• 批准号: 1942750
• 金额: --
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1942750
• 关键词: Impact; Cell; Gene; Therapy; Function

Haematopoiesis is an intricate cellular process allowing the generation and further maintenance of a diverse repertoire of functional blood cellsthroughout an organisms' lifetime. Hematopoietic stem cells (HSCs) constitute the foundation of the hematopoietic hierarchy and have the potential toboth self-renew and produce lineage specific progenitors. The fundamental properties of HSCs to expand and differentiate have provoked interest intheir application in gene therapy for the treatment of a range of hematopoietic diseases. However, the molecular consequences of gene therapy on theunderlying biology of HSCs remains poorly understood. This project aims to address unanswered areas in the field by combining single celltranscriptomics, lentiviral transduction technology, flow cytometry and single cell functional assays. Importantly, research conducted will both improveour overall understanding of how HSCs respond to stress and help to determine whether gene therapy is a safe and effective means of treatment.Results obtained from this project also have the potential to guide future improvements to the gene therapy protocol in order to increase HSCfunctionality after transduction.

造血是一个复杂的细胞过程，允许在生物体的整个生命周期中产生并进一步维持功能性血细胞的多样性。造血干细胞（hematopoieticstemcells，HSCs）是造血系统的基础，具有自我更新和产生谱系特异性祖细胞的潜能。造血干细胞的扩增和分化的基本特性引起了人们对其在基因治疗中的应用的兴趣，以治疗一系列造血系统疾病。然而，基因治疗对HSC潜在生物学的分子后果仍然知之甚少。该项目旨在通过结合单细胞转录组学，慢病毒转导技术，流式细胞术和单细胞功能测定来解决该领域的未回答领域。重要的是，所进行的研究将提高我们对HSC如何应对应激的整体理解，并有助于确定基因治疗是否是一种安全有效的治疗手段。从该项目获得的结果也有可能指导未来改进基因治疗方案，以增加转导后的HSC功能。

项目成果

Adaptation to ex vivo culture drives human haematopoietic stem cell loss of repopulation capacity in a cell cycle independent manner

• DOI: 10.1101/2022.11.17.516906
• 发表时间: 2023-01
• 期刊: bioRxiv
• 作者: Carys Johnson;Kendig Sham;Serena Belluschi;Xiaonan Wang;Winnie W. Y. Lau;K. Kaufmann;Gabriela Krivdova-Gabriela

Hematopoietic stem cells retain functional potential and molecular identity in hibernation cultures.

• DOI: 10.1016/j.stemcr.2021.04.002
• 发表时间: 2021-06-08
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Oedekoven CA;Belmonte M;Bode D;Hamey FK;Shepherd MS;Che JLC;Boyd G;McDonald C;Belluschi S;Diamanti E;Bastos HP;Bridge KS;Göttgens B;Laurenti E;Kent DG
• 通讯作者: Kent DG

Adaptation to

适应

• DOI: 10.17863/cam.91897
• 发表时间: 2022
• 作者: Johnson C

STAT1 is essential for HSC function and maintains MHCIIhi stem cells that resist myeloablation and neoplastic expansion.

• DOI: 10.1182/blood.2021014009
• 发表时间: 2022-10-06
• 期刊: Blood
• 影响因子: 20.3
• 作者: Li J;Williams MJ;Park HJ;Bastos HP;Wang X;Prins D;Wilson NK;Johnson C;Sham K;Wantoch M;Watcham S;Kinston SJ;Pask DC;Hamilton TL;Sneade R;Waller AK;Ghevaert C;Vassiliou GS;Laurenti E;Kent DG;Göttgens B;Green AR
• 通讯作者: Green AR

The Impact of Clinically Relevant Culture on Human Haematopoietic Stem Cells: A Kinetic Analysis at Single Cell Resolution

临床相关培养对人类造血干细胞的影响：单细胞分辨率的动力学分析

• DOI: 10.17863/cam.86475
• 发表时间: 2022
• 作者: Johnson C