Homozygous familial hypercholesterolemia (hoFH) is a rare disorder caused primarily by pathological mutations in the low-density lipoprotein receptor (LDLR), which disrupts LDL-cholesterol (LDL-C) metabolism homeostasis. hoFH patients are at extremely high risk for cardiovascular disease and are resistant to standard therapies. LDLR knockout animals and in vitro cell models overexpressing different mutations have proved useful, but may not fully recapitulate human LDLR mutation biology. We and others have generated induced pluripotent stem cells (iPSC) from hoFH patient's fibroblasts and T cells and demonstrated their ability to recapitulate hoFH biology. In this study, we present the generation and characterization of a cohort of seven hoFH-iPSC lines derived from peripheral blood mononuclear cells (PBMC) collected from four homozygous and three compound heterozygous patients. The hoFH-iPSC cohort demonstrated a wide range of LDLR expression and LDL-C internalization in response to rosuvastatin that correlated with the predicted pathogenicity of the mutation. We were able to confirm that hoFH-iPSC cohort were pluripotent by differentiation toward all three germ layers and specifically to hepatocyte-like cells (HLC), the cell with primary LDL-C metabolic regulatory control, by expression of hepatocyte markers. hoFH patient PBMC-derived iPSC recapitulate the LDLR dysfunction of their specific mutation. They were capable of differentiating to HLC and could be useful for early developmental studies, pharmacology/toxicology, and potentially autologous cell therapy.

中文翻译：

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患者特异性家族性高胆固醇血症诱导的多能干细胞的队列生成和表征

纯合子家族性高胆固醇血症 (hoFH) 是一种罕见的疾病，主要由低密度脂蛋白受体 (LDLR) 的病理突变引起，它破坏了低密度脂蛋白胆固醇 (LDL-C) 代谢稳态。hoFH 患者患心血管疾病的风险极高，并且对标准疗法有抵抗力。LDLR 敲除动物和过表达不同突变的体外细胞模型已被证明是有用的，但可能无法完全概括人类 LDLR 突变生物学。我们和其他人已经从 hoFH 患者的成纤维细胞和 T 细胞中产生了诱导多能干细胞 (iPSC)，并证明了它们能够概括 hoFH 生物学。在这项研究中，我们介绍了从四名纯合子和三名复合杂合子患者收集的外周血单核细胞 (PBMC) 衍生的七种 hoFH-iPSC 系的产生和表征。hoFH-iPSC 队列显示了广泛的 LDLR 表达和 LDL-C 内化，以响应与预测的突变致病性相关的瑞舒伐他汀。通过肝细胞标志物的表达，我们能够通过向所有三个胚层特别是肝细胞样细胞 (HLC)（具有初级 LDL-C 代谢调节控制的细胞）分化来确认 hoFH-iPSC 队列是多能的。hoFH 患者 PBMC 衍生的 iPSC 概括了其特定突变的 LDLR 功能障碍。它们能够区分 HLC，可用于早期发育研究，