Liquid-biopsy proteomics combined with AI identifies cellular drivers of eye aging and disease in vivo.

Journal: Cell
PMID: 37863056

Abstract

Single-cell analysis in living humans is essential for understanding disease mechanisms, but it is impractical in non-regenerative organs, such as the eye and brain, because tissue biopsies would cause serious damage. We resolve this problem by integrating proteomics of liquid biopsies with single-cell transcriptomics from all known ocular cell types to trace the cellular origin of 5,953 proteins detected in the aqueous humor. We identified hundreds of cell-specific protein markers, including for individual retinal cell types. Surprisingly, our results reveal that retinal degeneration occurs in Parkinson's disease, and the cells driving diabetic retinopathy switch with disease stage. Finally, we developed artificial intelligence (AI) models to assess individual cellular aging and found that many eye diseases not associated with chronological age undergo accelerated molecular aging of disease-specific cell types. Our approach, which can be applied to other organ systems, has the potential to transform molecular diagnostics and prognostics while uncovering new cellular disease and aging mechanisms.

Authors

  • Julian Wolf
    Molecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.
  • Ditte K Rasmussen
    Molecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA; Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark.
  • Young Joo Sun
    Molecular Surgery Laboratory, Stanford University, Palo Alto, California, United States of America.
  • Jennifer T Vu
    Molecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.
  • Elena Wang
    Molecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.
  • Camilo Espinosa
    Department of Anesthesiology, Pain and Perioperative Medicine, Stanford University, Stanford, California, USA.
  • Fabio Bigini
    Molecular Surgery Laboratory, Stanford University, Palo Alto, CA 94304, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.
  • Robert T Chang
    Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California.
  • Artis A Montague
    Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.
  • Peter H Tang
    Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN 55455, USA; Retina Consultants of Minnesota, Edina, MN 55435, USA.
  • Prithvi Mruthyunjaya
    Department of Ophthalmology, Byers Eye Institute at Stanford, Palo Alto, CA, USA.
  • Nima Aghaeepour
    Departments of Anesthesiology, Pain, and Peri-operative Medicine and Biomedical Data Sciences, Stanford University, Stanford, CA, USA.
  • Antoine Dufour
    Departments of Physiology and Pharmacology & Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
  • Alexander G Bassuk
    Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America.
  • Vinit B Mahajan
    Department of Ophthalmology, Byers Eye Institute at Stanford, Palo Alto, CA, USA.

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