Paired pre- and post-transplant human immunoprofiling identifies an IFN-γ-JAK1 axis limiting stem-cell-derived RPE engraftment

  • Cell Stem Cell. 2026 Jul 2;33(7):1127-1143.e10. doi: 10.1016/j.stem.2026.05.006.
Junfeng Ma  1 ,  Lifu Zhu  2 ,  Ping Duan  3 ,  Tao Ding  1 ,  Zhenghang Cheng  1 ,  Bin Li  1 ,  Qingfeng Wang  4 ,  Xiang Ma  5 ,  Youcai Deng  6 ,  Deepak A Lamba  7 ,  Yuan Gao  8
Affiliations
  • 1. Department of Stem Cell Technology, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China; Translational Medicine Research Center, Shanxi Medical University, Taiyuan 030001, China.
  • 2. Department of Stem Cell Technology, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China; Southwest Hospital, Army Medical University, Key Lab of Visual Damage and Regeneration and Restoration of Chongqing, Chongqing 400038, China.
  • 3. Southwest Hospital, Army Medical University, Key Lab of Visual Damage and Regeneration and Restoration of Chongqing, Chongqing 400038, China.
  • 4. Ophthalmology Medical Center, First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China.
  • 5. Key Laboratory of Reproductive Medicine and Offspring Health, Clinical Center for Reproductive Medicine, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
  • 6. Department of Pharmacology, College of Pharmacy, Army Medical University, Chongqing 400038, China.
  • 7. Immunology and Regenerative Medicine, Genentech, South San Francisco, CA 94080, USA; Department of Ophthalmology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 8. Department of Stem Cell Technology, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China; Translational Medicine Research Center, Shanxi Medical University, Taiyuan 030001, China. Electronic address: [email protected].
PMID: 42309064 DOI: 10.1016/j.stem.2026.05.006
Abstract

Neovascular age-related macular degeneration is a major cause of irreversible blindness, and current therapies do not restore photoreceptors or retinal pigment epithelium (RPE). Human embryonic stem-cell-derived RPE (hESC-RPE) transplantation represents a potential regenerative strategy, but immune rejection limits durable engraftment. Here, we combine immune profiling of blood, aqueous humor, and retinal tissue with allogeneic co-cultures and humanized models to define determinants of graft vulnerability and assess a graft-directed intervention. We identify a Th1-skewed, IFN-γ-rich immune milieu across the circulation and eye and show that IFN-γ-JAK1 signaling promotes an immunogenic state in hESC-RPE, marked by increased HLA expression and antigen presentation features. Brief ex vivo conditioning with ruxolitinib attenuates this response while preserving epithelial properties. In humanized retinal degeneration models, conditioned grafts show reduced T/natural killer (NK)-cell infiltration, prolonged survival, and improved visual function without chronic systemic immunosuppression, supporting ex vivo JAK inhibition as a feasible adjunct to RPE cell therapy.

Keywords
JAK-STAT signaling; age-related macular degeneration; cell therapy; graft immunogenicity; immune microenvironment; immune rejection; retinal regeneration; stem cell transplantation; translational medicine; transplant immunology.
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