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| Status |
Public on Apr 26, 2024 |
| Title |
TNF-NFkB-p53 axis restricts in vivo survival of hPSC-derived dopamine neuron (CRISPR screen) |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
First-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapy in Parkinson’s disease (PD). However, a major unresolved challenge is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo. We identified TP53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. A surface marker screen enabled the purification of midbrain dopamine neurons obviating the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition may present a clinically relevant strategy to enhance survival of human PSC-derived lineages in PD and beyond.
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| Overall design |
CRISPR screen study of TP53 WT dopamine neurons, in vitro and in vivo
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| Contributor(s) |
Cho H, Chaudhry F, Betel D, Studer L |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Nov 02, 2022 |
| Last update date |
Apr 26, 2024 |
| Contact name |
Hyein Sophia Cho |
| E-mail(s) |
choh@mskcc.org
|
| Organization name |
Memorial Sloan Kettering Cancer Center
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| Department |
Developmental Biology
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| Street address |
430 E 67th St
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10065 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (8)
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| This SubSeries is part of SuperSeries: |
| GSE216365 |
TNF-NFkB-p53 axis restricts in vivo survival of hPSC-derived dopamine neuron |
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| Relations |
| BioProject |
PRJNA896993 |
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