1. TNF-NF-κB-p53 axis restricts in vivo survival of hPSC-derived dopamine neurons.
- Author
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Kim TW, Koo SY, Riessland M, Chaudhry F, Kolisnyk B, Cho HS, Russo MV, Saurat N, Mehta S, Garippa R, Betel D, and Studer L
- Subjects
- Animals, Humans, Mice, Signal Transduction, Parkinson Disease metabolism, Pluripotent Stem Cells metabolism, Apoptosis, Disease Models, Animal, CRISPR-Cas Systems, Dopaminergic Neurons metabolism, NF-kappa B metabolism, Tumor Suppressor Protein p53 metabolism, Tumor Necrosis Factor-alpha metabolism, Cell Survival drug effects
- 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., Competing Interests: Declaration of interests L.S. is a scientific cofounder and paid consultant of BlueRock Therapeutics, Inc., and a scientific cofounder of DaCapo Brainscience. T.W.K. and S.Y.K. are listed as inventors on a patent application owned by the Memorial Sloan Kettering Center on the technologies described here to promote dopamine neuron survival and to enable dopamine neuron purification., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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