Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan; Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan.
Biochem Biophys Res Commun. 2023 Dec 20;687:149211. doi: 10.1016/j.bbrc.2023.149211. Epub 2023 Nov 3.
Reticular dysgenesis (RD) is a rare genetic disease caused by gene mutations in the ATP:AMP phosphotransferase, adenylate kinase 2 (AK2). Patients with RD suffer from severe combined immunodeficiency with neutrophil maturation arrest. Although hematopoietic stem cell transplantation can be a curative option, it is invasive, and complications of agranulocytosis-induced infection worsen the prognosis. Here, we report that the use of UK-5099, an inhibitor of the mitochondrial pyruvate carrier (MPC), on hemo-angiogenic progenitor cells (HAPCs) derived from AK2-deficient induced pluripotent stem cells improved neutrophil maturation. Reactive oxygen species (ROS) levels in AK2-deficient HAPCs remained unchanged throughout all experiments, implying that UK-5099 improved the phenotype without affecting ROS levels. Overall, our results suggest that the MPC is a potential therapeutic target for the treatment of neutrophil maturation defects in RD.
网状发育不良（RD）是一种罕见的遗传性疾病，由三磷酸腺苷：腺嘌呤核苷磷酸转移酶、腺苷酸激酶 2（AK2）基因的基因突变引起。RD 患者患有严重联合免疫缺陷症，伴有中性粒细胞成熟停滞。虽然造血干细胞移植是一种有治愈可能的方法，但它具有侵袭性，并且由于中性粒细胞减少症引起的感染而产生的并发症会使预后恶化。在这里，我们报告称，使用线粒体丙酮酸载体（MPC）抑制剂 UK-5099 可改善 AK2 缺陷诱导多能干细胞衍生的造血祖细胞（HAPCs）中的中性粒细胞成熟。在所有实验中，AK2 缺陷 HAPCs 中的活性氧（ROS）水平保持不变，这意味着 UK-5099 在不影响 ROS 水平的情况下改善了表型。总的来说，我们的研究结果表明，MPC 是治疗 RD 中性粒细胞成熟缺陷的潜在治疗靶点。
