携带HTRA1杂合R302Q突变的遗传性脑血管病患者的人诱导多能干细胞模型

IF 5 3区 医学 Q2 IMMUNOLOGY Inflammation and Regeneration Pub Date : 2023-04-03 DOI:10.1186/s41232-023-00273-7
Emi Qian, Masahiro Uemura, Hiroya Kobayashi, Shiho Nakamura, Fumiko Ozawa, Sho Yoshimatsu, Mitsuru Ishikawa, Osamu Onodera, Satoru Morimoto, Hideyuki Okano
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摘要

脑常染色体隐性动脉病变伴皮质下梗死和白质脑病(CARASIL)是一种遗传性脑小血管疾病(CSVD),由高温需要丝氨酸肽酶A1 (HTRA1)基因双等位基因突变引起。甚至HTRA1的杂合突变最近也被发现引起CSVD的主要临床特征。在这里,我们报告了首次从患有杂合htra1相关CSVD的患者中建立的人类诱导多能干细胞(hiPSC)系。通过转染episomal载体编码人OCT3/4 (POU5F1)、SOX2、KLF4、L-MYC、LIN28和小鼠p53显性阴性突变体(mp53DD),对外周血单个核细胞(PBMCs)进行重编程。所建立的iPSCs具有人类多能干细胞的正常形态和正常核型(46XX)。此外,我们发现HTRA1错义突变(c.905G>A, p.R302Q)是杂合的。这些iPSCs表达多能性相关标记物,并具有在体外分化为所有三种胚层的潜力。与对照组相比,患者iPSCs中HTRA1和假定的疾病相关基因NOG的mRNA水平存在差异。iPSC细胞系将有助于体外研究HTRA1突变引起的细胞病理机制,包括其显性负作用。
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A human induced pluripotent stem cell model from a patient with hereditary cerebral small vessel disease carrying a heterozygous R302Q mutation in HTRA1.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an inherited cerebral small vessel disease (CSVD) caused by biallelic mutations in the high-temperature requirement serine peptidase A1 (HTRA1) gene. Even heterozygous mutations in HTRA1 are recently revealed to cause cardinal clinical features of CSVD. Here, we report the first establishment of a human induced pluripotent stem cell (hiPSC) line from a patient with heterozygous HTRA1-related CSVD. Peripheral blood mononuclear cells (PBMCs) were reprogrammed by the transfection of episomal vectors encoding human OCT3/4 (POU5F1), SOX2, KLF4, L-MYC, LIN28, and a murine dominant-negative mutant of p53 (mp53DD). The established iPSCs had normal morphology as human pluripotent stem cells and normal karyotype (46XX). Moreover, we found that the HTRA1 missense mutation (c.905G>A, p.R302Q) was heterozygous. These iPSCs expressed pluripotency-related markers and had the potential to differentiate into all three germ layers in vitro. HTRA1 and the supposed disease-associated gene NOG were differentially expressed in the patient iPSCs at mRNA levels compared to those of control lines. The iPSC line would facilitate in vitro research for understanding the cellular pathomechanisms caused by the HTRA1 mutation including its dominant-negative effect.

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来源期刊
CiteScore
11.10
自引率
1.20%
发文量
45
审稿时长
11 weeks
期刊介绍: Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration (JSIR). This journal provides an open access forum which covers a wide range of scientific topics in the basic and clinical researches on inflammation and regenerative medicine. It also covers investigations of infectious diseases, including COVID-19 and other emerging infectious diseases, which involve the inflammatory responses. Inflammation and Regeneration publishes papers in the following categories: research article, note, rapid communication, case report, review and clinical drug evaluation.
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