Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells.
Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells.
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DOI：
10.1016/j.stemcr.2022.10.001
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发表时间：
2022-11-08
影响因子：
5.9
通讯作者：
Bharti, Kapil
中科院分区：
文献类型：
--
作者：
Farnoodian, Mitra;Bose, Devika;Khristov, Vladimir;Susaimanickam, Praveen Joseph;Maddileti, Savitri;Mariappan, Indumathi;Abu-Asab, Mones;Campos, Maria;Villasmil, Rafael;Wan, Qin;Maminishkis, Arvydas;McGaughey, David;Barone, Francesca;Gundry, Rebekah L.;Riordon, Daniel R.;Boheler, Kenneth R.;Sharma, Ruchi;Bharti, Kapil
Stargardt视网膜病变是由基因ABCA 4突变引起的黄斑变性的遗传形式，其特征在于视网膜色素上皮（RPE）中富含脂质的沉积物的积累、RPE萎缩和感光细胞死亡。对Stargardt RPE中发生的病理生理学变化的机械见解不足阻碍了疾病治疗。在这里，我们表明，ABCA 4基因敲除和诱导多能干细胞衍生的RPE（STGD 1-iRPE）与Stargardt患者分化正常，但显示细胞内脂质和神经酰胺沉积，让人想起疾病表型。STGD 1-iRPE还显示有缺陷的光感受器外节（POS）加工和降低的组织蛋白酶B活性-指示较高的溶酶体pH。通过增加ABCA 1（脂质转运蛋白）和ABCA 4直系同源物的活性，STGD 1-iRPE中的脂质沉积物降低。我们的工作表明ABCA 4参与RPE细胞中的POS和脂质处理，并为正在进行的基因治疗方法提供指导，以靶向RPE和感光细胞进行有效治疗。ABCA 4功能丧失（LOF）iPSC-RPE正常分化ABCA 4 LOF导致iPSC-RPE中的细胞自主脂质沉积ABCA 4 LOF通过破坏溶酶体功能导致有缺陷的POS消化。和同事表明ABCA 4功能丧失（LOF）促进人iPSC衍生的RPE中细胞自主的细胞内/亚细胞脂质沉积，Stargardt和其他年龄相关性黄斑病变的主要损伤部位。RPE中的ABCA 4 L0 F破坏内-溶酶体功能，从而导致POS消化、脂质处理和脂质沉积物的形成缺陷。
Stargardt retinopathy is an inherited form of macular degeneration caused by mutations in gene ABCA4 and characterized by the accumulation of lipid-rich deposits in the retinal pigment epithelium (RPE), RPE atrophy, and photoreceptor cell death. Inadequate mechanistic insights into pathophysiological changes occurring in Stargardt RPE have hindered disease treatments. Here, we show that ABCA4 knockout and induced pluripotent stem cell-derived RPE (STGD1-iRPE) from patients with Stargardt differentiate normally but display intracellular lipid and ceramide deposits reminiscent of the disease phenotype. STGD1-iRPE also shows defective photoreceptor outer segment (POS) processing and reduced cathepsin B activity—indicating higher lysosomal pH. Lipid deposits in STGD1-iRPE are lowered by increasing the activity of ABCA1, a lipid transporter, and ABCA4 ortholog. Our work suggests that ABCA4 is involved in POS and lipid handling in RPE cells and provides guidance for ongoing gene therapy approaches to target both RPE and photoreceptor cells for an effective treatment. ABCA4 loss-of-function (LOF) iPSC-RPEs differentiate normally ABCA4 LOF causes cell-autonomous lipid deposits in iPSC-RPE ABCA4 LOF causes defective POS digestion via disrupted lysosomal function In this article, Mitra Farnoodian, Kapil Bharti, and colleagues show that ABCA4 loss of function (LOF) promotes cell-autonomous intra/sub-cellular lipid deposits in the human iPSC-derived RPE—a primary site of injury in Stargardt and other age-related maculopathies. ABCA4 LOF in RPE disrupts endo-lysosomal function contributing to defective POS digestion, lipid handling, and the formation of lipid deposits.
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影响因子：
5.5
作者：
JOSEPH, DP;MILLER, SS
通讯作者：
MILLER, SS
影响因子：
3.4
作者：
Mazzoni, Francesca;Safa, Hussein;Finnemann, Silvia C.
通讯作者：
Finnemann, Silvia C.
影响因子：
3.7
作者：
Hussein MA;Shrestha E;Ouimet M;Barrett TJ;Leone S;Moore KJ;Hérault Y;Fisher EA;Garabedian MJ
通讯作者：
Garabedian MJ
DOI：
10.1007/978-1-4939-7553-2_15
发表时间：
2018
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Khristov V;Wan Q;Sharma R;Lotfi M;Maminishkis A;Bharti K
通讯作者：
Bharti K
影响因子：
4.8
作者：
Ahn, J;Wong, JT;Molday, RS
通讯作者：
Molday, RS