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).

在最初的研究建议中，目的是研究诱导的老年造血干细胞（HSC）训练训练的免疫力及其在不确定潜力克隆造血的发病机理中的作用（CHIP）。D2022的重点是建立人类小鼠模型通过传输人类的人体sscs建立人类模型。第一步涉及与脐带血库建立联系，以获取新鲜的人类脐带血样本。然后开发协议以通过细胞分选获得高质量的CD34+ HSC。此外，仔细选择了几种免疫缺陷的小鼠模型，以评估其人类HSC移植的兼容性并评估人源性小鼠的存活率。衰老的人源化小鼠的存活取决于选择性小鼠菌株和HSC植入。在将HSC（CD34+）移植到人源性小鼠中后，将这些细胞的分化为成熟的免疫细胞已清楚地表征和描述。为了实现研究目标，正在进行研究以鉴定分类的人脐带血HSC（CD34+细胞）的靶基因中的遗传突变（CD34+细胞）。

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