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Cell, June 11, 2024 | https://doi.org/10.1016/j.cell.2024.05.030 TNF-NF-κB-p53 axis restricts in vivo survival of hPSC-derived dopamine neurons

Tae Wan Kim,^1,2,3,4,13,* So Yeon Koo,^1,2,5,13 Markus Riessland,^6,14 Fayzan Chaudhry,^7,14 Benjamin Kolisnyk,^8,14 Hyein S. Cho,^1,2,14 Marco Vincenzo Russo,^9,10 Nathalie Saurat,^1,2,4 Sanjoy Mehta,⁹ Ralph Garippa,⁹ Doron Betel,^11,12 and Lorenz Studer ^1,2,4,15,*

¹The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA

²Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA

³Department of Interdisciplinary Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea

⁴Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA

⁵Weill Cornell Neuroscience PhD Program, New York, NY, USA

⁶Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY 11794, USA

⁷Tri-Institutional PhD program in Computational Biology, New York, NY, USA

⁸Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA

⁹Gene Editing and Screening Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA

¹⁰Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA

¹¹Division of Hematology & Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA

¹²Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA

¹³These authors contributed equally

¹⁴These authors contributed equally

¹⁵Lead contact

^*Corresponding authors: correspondence to Tae Wan Kim or Lorenz Studer

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.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-12)
연구진국내(교신)+국외 연구진
분야 생명과학 > 분자생물학

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