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Disease-specific iPSC Model Highlights New Therapeutic Avenue for Vision Loss

Review of “Complement modulation reverses pathology in Y402H-retinal pigment epithelium cell model of AMD by restoring lysosomal function” from STEM CELLS Translational Medicine by Stuart P. Atkinson

In a previous STEM CELLS article, researchers from the laboratory of Majlinda Lako (Newcastle University, Newcastle upon Tyne, UK) described the development of a physiologically relevant model of human age‐related macular degeneration (AMD) [1] that they hoped would allow for the development of novel therapeutic approaches for this common cause of vision loss [2]. To create their model, the authors first generated induced pluripotent stem cells (iPSCs) from patients possessing the complement factor H (CFH) polymorphism Y402H risk factor and then generated retinal pigment epithelial (RPE) cells that recapitulated critical features of AMD.

Interestingly, recent studies have provided evidence that complement activation contributes to lysosomal regulation in infective and inflammatory disease [3-5], and recently, the Lako group employed their iPSC-derived AMD RPE model to explore the possible dysregulation of lysosomal function in AMD patients and investigate the interplay between lysosome function and complement activation in the hope of revealing new therapeutic targets.

Reporting recently in STEM CELLS Translational Medicine [6], Cerniauskas et al. discovered that iPSC-derived AMD RPE displayed a significant reduction in the numbers of melanosomes (organelles where the light-absorbing pigment melanin is synthesized, stored, and transported), an increase in the number of swollen lysosome‐like‐vesicles with fragile membranes, leakage of the lysosomal aspartyl protease Cathepsin D into drusen‐like deposits, and a decrease in lysosomal function.

CFH controls the activation of the classical and alternative complement activation pathways by regulating the activity of complement component 3 (C3), and the authors discovered that the presence of the CFH polymorphism Y402H risk factor prompted a significant increase in the turnover of C3 and the production of higher levels of C3b in iPSC-derived AMD RPE. In turn, the cells exhibited an increased capacity for internalization and deposition of the C5b‐9 terminal complement complex in lysosomes, which prompted the overloading of the lysosomal compartment and the disease-associated lysosomal malfunctions. However, treatment with a small peptide (Cp40 compstatin analog) to inhibit C3 processing reversed AMD-associated RPE cell phenotypes, restored typical lysosomal number, size, and function, increased Cathepsin D expression, and significantly reduced drusen‐like deposits.

Overall, the authors provide evidence for an important association between uncontrolled complement activation and lysosomal dysfunction in AMD; however, they also highlight a possible means to reverse disease-associated phenotypes by inhibiting the complement cascade through the central C3 component.

For more on how disease-specific iPSC models can aid in the search for novel therapeutics for vision loss, stay tuned to the Stem Cells Portal!



  1. Hallam D, Collin J, Bojic S, et al., An Induced Pluripotent Stem Cell Patient Specific Model of Complement Factor H (Y402H) Polymorphism Displays Characteristic Features of Age-Related Macular Degeneration and Indicates a Beneficial Role for UV Light Exposure. STEM CELLS 2017;35:2305-2320.
  2. Nowak JZ, Age-related macular degeneration (AMD): pathogenesis and therapy. Pharmacol Rep 2006;58:353-63.
  3. Liu WJ, Li Z-h, Chen X-c, et al., Blockage of the lysosome-dependent autophagic pathway contributes to complement membrane attack complex-induced podocyte injury in idiopathic membranous nephropathy. Scientific Reports 2017;7:8643.
  4. King BC, Kulak K, Krus U, et al., Complement Component C3 Is Highly Expressed in Human Pancreatic Islets and Prevents Cell Death via ATG16L1 Interaction and Autophagy Regulation. Cell Metabolism 2019;29:202-210.e6.
  5. Liszewski MK, Kolev M, Le Friec G, et al., Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation. Immunity 2013;39:1143-1157.
  6. Cerniauskas E, Kurzawa-Akanbi M, Xie L, et al., Complement modulation reverses pathology in Y402H-retinal pigment epithelium cell model of age-related macular degeneration by restoring lysosomal function. STEM CELLS Translational Medicine 2020;9:1585-1603.