A cloaked human stem-cell-derived neural graft capable of functional integration and immune evasion in rodent models
Human pluripotent stem cell (hPSC)-derived therapies are a realistic possibility for numerous disorders, including Parkinson's disease. While generating replacement neurons is achievable, immunosuppressive drug challenges, to prevent rejection, remain. Here we adopted a hPSC line (termed H1-FS-8IM), engineered to overexpress 8 immunomodulatory transgenes, to enable transplant immune evasion. In co-cultures, H1-FS-8IM PSC-derived midbrain neurons evaded rejection by T lymphocytes, natural killer cells, macrophages, and dendritic cells. In humanized mice, allogeneic H1-FS-8IM neural grafts evaded rejection, while control hPSC-derived neural grafts evoked activation of human immune cells, elevated inflammatory cytokines in blood and cerebrospinal fluid, and caused spleen and lymph node enlargement. H1-FS-8IM neural grafts retained functionality, reversing motor deficits in Parkinsonian rats. Additional incorporation of a suicide gene into the H1-FS-8IM hPSC line enabled proliferative cell elimination within grafts. Findings demonstrate feasibility of generating a population-wide applicable, safe, off-the-shelf cell product, suitable for treating diseases for which cell-based therapies are a viable option.
Authors
- Dad Abu-Bonsrah (ORCID: https://orcid.org/0000-0002-2687-3526)
- Chiara Pavan (ORCID: https://orcid.org/0000-0002-2890-7021)
- András Nagy (ORCID: https://orcid.org/0000-0003-4311-0413)
- Stefano Frausin (ORCID: https://orcid.org/0000-0001-8536-5241)
- Clare L. Parish (ORCID: https://orcid.org/0000-0001-8212-9884)
- Niamh Moriarty (ORCID: https://orcid.org/0000-0001-5321-465X)
- William Clow
- Marc Pellegrini (ORCID: https://orcid.org/0000-0003-3627-3126)
- Andrew T Quattrocchi
- Huijuan Yang (ORCID: https://orcid.org/0000-0003-4569-6454)
- Lachlan H. Thompson (ORCID: https://orcid.org/0000-0003-2632-0304)
- Cameron J. Hunt (ORCID: https://orcid.org/0000-0002-8495-0542)
- Christine A. Wells (ORCID: https://orcid.org/0000-0003-3133-3628)
- Zahra Elahi (ORCID: https://orcid.org/0000-0002-0697-3917)
- Natalie L. Payne (ORCID: https://orcid.org/0000-0002-2045-2608)
- Le Wang (ORCID: https://orcid.org/0000-0002-7155-7549)
- Kathryn C. Davidson
- M Rubio
Institutions
- Mount Sinai Hospital (CA)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Lunenfeld-Tanenbaum Research Institute (CA)
- Florey Institute of Neuroscience and Mental Health (AU)
- Centenary Institute (AU)
- Australian Regenerative Medicine Institute (AU)
- Monash University (AU)
Publication Details
- Journal
- Cell stem cell
- Published
- 2025-04-09
- DOI
- https://doi.org/10.1016/j.stem.2025.03.008
- Citations
- 17
- Primary Topic
- Neurogenesis and neuroplasticity mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 22.42