TNF-NF-κB-p53 axis restricts in vivo survival of hPSC-derived dopamine neurons Journal Article

   


Authors: Kim, T. W.; Koo, S. Y.; Riessland, M.; Chaudhry, F.; Kolisnyk, B.; Cho, H. S.; Russo, M. V.; Saurat, N.; Mehta, S.; Garippa, R.; Betel, D.; Studer, L.
Article Title: TNF-NF-κB-p53 axis restricts in vivo survival of hPSC-derived dopamine neurons
Abstract: Ongoing, early-stage clinical trials illustrate the translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson's disease (PD). However, an unresolved challenge is the extensive cell death following transplantation. Here, we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survival in vivo. We identified p53-mediated apoptotic cell death as a major contributor to dopamine neuron loss and uncovered a causal link of tumor necrosis factor alpha (TNF-α)-nuclear factor κB (NF-κB) signaling in limiting cell survival. As a translationally relevant strategy to purify postmitotic dopamine neurons, we identified cell surface markers that enable purification without the need for genetic reporters. Combining cell sorting and treatment with adalimumab, a clinically approved TNF-α inhibitor, enabled efficient engraftment of postmitotic dopamine neurons with extensive reinnervation and functional recovery in a preclinical PD mouse model. Thus, transient TNF-α inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic hPSC-derived dopamine neurons in PD. © 2024 The Authors
Keywords: immunohistochemistry; signal transduction; controlled study; protein expression; nonhuman; flow cytometry; quality control; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; cell survival; apoptosis; gene expression; animal experiment; animal model; astrocyte; immunoglobulin enhancer binding protein; neural stem cell; cell differentiation; caspase 3; immunofluorescence; drug effect; transplantation; protein p53; histology; disease model; immune response; genetic transfection; tumor necrosis factor-alpha; nf-kappa b; western blotting; immunoblotting; tumor suppressor protein p53; cell therapy; real time polymerase chain reaction; pluripotent stem cell; pluripotent stem cells; graft survival; disease models, animal; parkinson disease; bioinformatics; oligonucleotide; dopamine; dopaminergic nerve cell; rna extraction; tumor necrosis factor; rna sequence; tp53; neurite outgrowth; dopamine neurons; dopaminergic neurons; parkinson's disease; necroptosis; humans; human; male; female; article; immunofluorescence assay; clustered regularly interspaced short palindromic repeat; crispr cas system; organoid; tunel assay; cell purification; crispr-cas systems; genetic screen; single cell rna seq; nf kb signaling; tnf-α inhibition; polyornithine
Journal Title: Cell
Volume: 187
Issue: 14
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2024-07-11
Start Page: 3671
End Page: 3689.e23
Language: English
DOI: 10.1016/j.cell.2024.05.030
PUBMED: 38866017
PROVIDER: scopus
PMCID: PMC11641762
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85197481812&doi=10.1016%2fj.cell.2024.05.030&partnerID=40&md5=e92924c3eb28aaad652802d5d9d98b4f
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK authors are Tae Wan Kim and Lorenz Studer -- Source: Scopus
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MSK Authors
  1. Lorenz Studer
    220 Studer
  2. Ralph James Garippa
    32 Garippa
  3. Hyein Cho
    12 Cho
  4. Nathalie Gael Saurat
    6 Saurat
  5. Taewan Kim
    11 Kim
  6. So Yeon Koo
    5 Koo
  7. Sanjoy Mehta
    8 Mehta
  8. Marco Vincenzo Russo
    7 Russo
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