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

Mitra Farnoodian, Devika Bose, Vladimir Khristov, Praveen Joseph Susaimanickam, Savitri Maddileti, Indumathi Mariappan, Mones Abu-Asab, Maria Campos, Rafael Villasmil, Qin Wan, Arvydas Maminishkis, David McGaughey, Francesca Barone, Rebekah L. Gundry, Daniel R. Riordon, Kenneth R. Boheler, Ruchi Sharma, Kapil Bharti

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)2438-2450
Number of pages13
JournalStem Cell Reports
Issue number11
StatePublished - Nov 8 2022


  • ABCA1
  • ABCA4
  • AMD
  • RPE
  • lipid deposits
  • lipid handling
  • lysosome dysfunction
  • phagocytosis defects
  • retinal degeneration

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology


Dive into the research topics of 'Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells'. Together they form a unique fingerprint.

Cite this