Deciphering regulatory mechanism of trained immunity in aged HSCs and clonal hematopoiesis of indeterminate potential (CHIP)

破译老年造血干细胞训练免疫的调节机制和不确定潜力克隆造血（CHIP）

• 批准号: 22K16302
• 负责人: Afroj Tania
• 金额: $ 1.83万
• 依托单位: Kobe University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Early-Career Scientists
• 财政年份: 2022
• 资助国家: 日本
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-22K16302/
• 关键词: Hematopoietic stem cell; Humanized mice; Trained immunity; Aging; CHIP; Clonal hematopoiesis; Xenograft model

In the original research proposal, the objective was to investigate the functional impact of induced trained immunity in aged hematopoietic stem cells (HSCs) and its role in the pathogenesis of clonal hematopoiesis of indeterminate potential (CHIP).During FY2022, the focus was on establishing a humanized mouse model by transplanting human cord blood-derived HSCs. The initial step involved establishing a connection with a cord blood bank to acquire fresh samples of human cord blood. A protocol was then developed to obtain high-quality CD34+ HSCs through cell sorting. Additionally, several immunodeficient mouse models were carefully selected to assess their compatibility for human HSC transplantation and evaluate the survival rates of humanized mice. The survival of humanized mice with aging depends on selective mouse strains and HSCs engraftment. Following the transplantation of HSCs (CD34+) into the humanized mice, the differentiation of these cells into mature immune cells has been clearly characterized and delineated.To achieve the research goals, investigations are underway to identify genetic mutations in the target genes of the sorted human cord blood HSCs (CD34+ cells).

在最初的研究计划中，目的是研究诱导训练免疫对老年造血干细胞（HSC）的功能影响及其在克隆性不确定潜能造血（CHIP）发病机制中的作用。在2022财年，重点是通过移植人脐带血来源的HSC建立人源化小鼠模型。第一步是与脐带血库建立联系，以获取新鲜的人类脐带血样本。然后开发了通过细胞分选获得高质量CD34+ HSC的方案。此外，仔细选择了几种免疫缺陷小鼠模型，以评估它们对人HSC移植的相容性并评估人源化小鼠的存活率。人源化小鼠随衰老的存活取决于选择性小鼠品系和HSC移植。将人脐带血造血干细胞（CD34+）移植到人源化小鼠体内后，这些细胞分化为成熟的免疫细胞的过程已经被清楚地描述和描述，为了实现研究目标，正在进行研究以鉴定分选的人脐带血造血干细胞（CD34+细胞）的靶基因中的基因突变。

项目成果

Preclinical evaluation of the anti-tumor effect of anti-human SIRPα antibody in a novel humanized mouse model

抗人SIRPα抗体在新型人源化小鼠模型中抗肿瘤作用的临床前评估

• 发表时间: 2023
• 作者: Tania Afroj;Yasuyuki Saito;Rie Iida-Norita;Satomi Komori;Takenori Kotani;Yoji Murata;Takashi Matozaki
• 通讯作者: Takashi Matozaki

Identification of fibrocyte cluster in tumors reveals the role in antitumor immunity by PD-L1 blockade

• DOI: 10.1016/j.celrep.2023.112162
• 发表时间: 2023-03-28
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Mitsuhashi，Atsushi;Koyama，Kazuya;Nishioka，Yasuhiko
• 通讯作者: Nishioka，Yasuhiko