Post-Transplant Administration of G-CSF Impedes Engraftment of Gene Edited Human Hematopoietic Stem Cells by Exacerbating the p53-Mediated DNA Damage Response
Combs Christian 1Redekar Neelam 2Luo Yan 3Dagur Pradeep 4Smith Richard H. 5Chen Vicky 2Salisbury-Ruf Christi 5Li Yuesheng 3Araki Daisuke 5Larochelle Andre 5Liu Poching3
作者信息
- 1. Light Microscopy Core Facility, NHLBI, NIH
- 2. Integrated Data Science Services (IDSS), National Institutes of Allergy and Infectious Diseases (NIAID)
- 3. DNA Sequencing and Genomics Core Facility, NHLBI, NIH
- 4. Flow Cytometry Core Facility, NHLBI, NIH
- 5. Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH)
- 折叠
Abstract
Abstract
Granulocyte colony stimulating factor (G-CSF) is commonly used as adjunct treatment to hasten recovery from neutropenia following chemotherapy and autologous transplantation of hematopoietic stem and progenitor cells (HSPCs) for malignant disorders. However, the utility of G-CSF administration after ex vivo gene therapy procedures targeting human HSPCs has not been thoroughly evaluated. Here, we provide evidence that post-transplant administration of G-CSF impedes engraftment of CRISPR-Cas9 gene edited human HSPCs in xenograft models. G-CSF acts by exacerbating the p53-mediated DNA damage response triggered by Cas9- mediated DNA double-stranded breaks. Transient p53 inhibition in culture attenuates the negative impact of G-CSF on gene edited HSPC function. In contrast, post-transplant administration of G-CSF does not impair the repopulating properties of unmanipulated human HSPCs or HSPCs genetically engineered by transduction with lentiviral vectors. The potential for post-transplant G-CSF administration to aggravate HSPC toxicity associated with CRISPR-Cas9 gene editing should be considered in the design of ex vivo autologous HSPC gene editing clinical trials.
Graphical Abstractbiorxiv;2023.06.29.547089v1/UFIG1F1ufig1引用本文复制引用
Combs Christian,Redekar Neelam,Luo Yan,Dagur Pradeep,Smith Richard H.,Chen Vicky,Salisbury-Ruf Christi,Li Yuesheng,Araki Daisuke,Larochelle Andre,Liu Poching.Post-Transplant Administration of G-CSF Impedes Engraftment of Gene Edited Human Hematopoietic Stem Cells by Exacerbating the p53-Mediated DNA Damage Response[EB/OL].(2025-03-28)[2026-04-03].https://www.biorxiv.org/content/10.1101/2023.06.29.547089.学科分类
基础医学/生物科学研究方法、生物科学研究技术/遗传学
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