Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells

被引：18

作者：

Farnoodian, Mitra ^{[1
]}

Bose, Devika ^{[1
]}

Khristov, Vladimir ^{[1
]}

Susaimanickam, Praveen Joseph ^{[2
]}

Maddileti, Savitri ^{[2
]}

Mariappan, Indumathi ^{[2
]}

Abu-Asab, Mones ^{[3
]}

Campos, Maria ^{[3
]}

Villasmil, Rafael ^{[4
]}

Wan, Qin ^{[1
]}

Maminishkis, Arvydas ^{[1
]}

McGaughey, David ^{[5
]}

Barone, Francesca ^{[1
]}

Gundry, Rebekah L. ^{[6
]}

Riordon, Daniel R. ^{[7
]}

Boheler, Kenneth R. ^{[8
]}

Sharma, Ruchi ^{[1
]}

Bharti, Kapil ^{[1
]}

机构：

[1] NEI, Ocular & Stem Cell Translat Res Sect, NIH, Bethesda, MD 20892 USA

[2] LV Prasad Eye Inst, Hyderabad Eye Res Fdn, Prof Brien Holden Eye Res Ctr, Ctr Ocular Regenerat, Hyderabad 500034, Telangana, India

[3] NEI, Histopathol Core, NIH, Bethesda, MD 20892 USA

[4] NEI, Flow Cytometry Core, NIH, Bethesda, MD 20892 USA

[5] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA

[6] Univ Nebraska Med Ctr, Ctr Heart & Vasc Res, Dept Cellular & Integrat Physiol, Cardi Program,Div Cardiovasc Med, Omaha, NE 68198 USA

[7] NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD USA

[8] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA

来源：

STEM CELL REPORTS | 2022年 / 17卷 / 11期

关键词：

RPE CELLS; PLASMA-MEMBRANE; OUTER SEGMENTS; CULTURED HUMAN; MOUSE MODEL; ABCA4; ACIDIFICATION; DEGENERATION; PHAGOCYTOSIS; INFLAMMATION;

D O I：

10.1016/j.stemcr.2022.10.001

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Stargardt retinopathy is an inherited form of macular degeneration caused by mutations in gene ABCA4 and characterized by the accu-mulation of lipid-rich deposits in the retinal pigment epithelium (RPE), RPE atrophy, and photoreceptor cell death. Inadequate mecha-nistic 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 effec-tive treatment.

引用

页码：2438 / 2450

页数：13

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