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Patient-specific iPSCs Aid the Development of New Age-related Macular Degeneration Model

Review of “Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Changes to the Bruch's membrane followed by dysfunction and atrophy of retinal pigment epithelial (RPE) cells characterize age‐related macular degeneration (AMD), a major cause of blindness. Given the lack of adequate in vivo models for aging Bruch's membrane, researchers led by Mark A. Fields (Yale University, New Haven, CT, USA) devised a new approach based on a “stress-inducing” nitrite‐modified extracellular matrix [1] that allows the study of RPE dysfunction in a compromised environment and then validated this approach ex vivo using aged or diseased Bruch's membrane [2-4]. 

Now, in their new STEM CELLS Translational Medicine article [5], Gong et al. describe the combination of their model Bruch's membrane with RPE generated from human induced pluripotent stem cells (iPSC) derived from AMD patients [6, 7] in the hope of providing a robust platform for the development of novel and effective therapeutics.

Following the generation of iPSCs from fibroblasts isolated from AMD and age‐matched healthy control patients, the authors derived RPE and comparatively characterized the resultant cells. While both AMD and control iPSC-RPE displayed similar cell‐specific morphology, RPE-associated mRNA and protein expression, transepithelial electrical resistance, and phagocytosis of rod photoreceptor outer segments, transcriptomic analyses did highlight some critical variations. These differences included the downregulated expression of genes associated with metabolism and cell attachment in AMD iPSC-RPE. 

As a consequence, AMD iPSC‐RPE displayed a general reduction in mitochondrial function, although both cell types displayed similar levels of cell attachment and survival to an unmodified extracellular matrix; however, AMD iPSC-RPE displayed a significant attachment and survival disadvantage when faced with the stress of interacting with the nitrite‐modified extracellular matrix that models the aged Bruch's membrane. Furthermore, those AMP iPSC-RPE attaching to the nitrite‐modified extracellular matrix displayed a general upregulation in the expression of complement‐related genes, which have been previously associated with disease pathology in AMD.

In summary, the authors describe the development of an in vitro patient-specific AMD model that may contribute to the discovery of previously unappreciated disease mechanisms and significantly aid the development of novel therapeutic strategies. 

For more on patient-specific iPSCs, optimized disease models, and potentially sight-saving therapies, stay tuned to the Stem Cells Portal!

References

  1. Paik DC, Dillon J, Galicia E, et al., The Nitrite/Collagen Reaction: Non-Enzymatic Nitration as a Model System for Age-Related Damage. Connective Tissue Research 2001;42:111-122.
  2. Fields MA, Bowrey HE, Gong J, et al., Extracellular matrix nitration alters growth factor release and activates bioactive complement in human retinal pigment epithelial cells. PLOS ONE 2017;12:e0177763.
  3. Fields MA, Cai H, Bowrey HE, et al., Nitrite Modification of Extracellular Matrix Alters CD46 Expression and VEGF Release in Human Retinal Pigment Epithelium. Investigative Ophthalmology & Visual Science 2015;56:4231-4238.
  4. Moreira EF, Cai H, Tezel TH, et al., Reengineering Human Bruch's Membrane Increases Rod Outer Segment Phagocytosis by Human Retinal Pigment Epithelium. Translational Vision Science & Technology 2015;4:10-10.
  5. Gong J, Cai H, Team NGSCA, et al., Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions. STEM CELLS Translational Medicine 2020;9:364-376.
  6. Golestaneh N, Chu Y, Cheng SK, et al., Repressed SIRT1/PGC-1α pathway and mitochondrial disintegration in iPSC-derived RPE disease model of age-related macular degeneration. Journal of Translational Medicine 2016;14:344.
  7. Saini JS, Corneo B, Miller JD, et al., Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration. Cell Stem Cell 2017;20:635-647.e7.