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Peer-reviewedCC BYJournal of Clinical Investigation

Modulation of WNT and FGF18 enhances yield and subtype identity of hPSC-derived midbrain dopamine neurons

  • T Kim1,2,3,4
  • Jinghua Piao5,1,6
  • Vittoria Dickinson Bocchi1,4
  • So Yeon Koo1,4,7
  • Se Joon Choi8
  • Fayzan F. Chaudhry9,10
  • Donghe Yang1,4
  • H Cho1,4
  • Emiliano Hergenreder1,4,7
  • Lucia Ruiz Perera5,1,6
  • Subhashini Joshi5,6
  • Zaki Abou-Mrad5,1,6
10 more authors
  • Nidia Claros5,1,6
  • Shkurte Ademi Donohue5,1,6
  • Yeong Eun Im2
  • Hyo Jae Jeong2
  • Anika K. Frank8
  • Ryan M. Walsh1,4
  • Eugene V. Mosharov8
  • Doron Betel8
  • Viviane Tabar5,1,6
  • Lorenz Studer1,4
10 affiliations
  1. 1Center for Stem Cell Biology and
  2. 2Department of Biomedical Science and Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea
  3. 3Department of New Biology and
  4. 4Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
  5. 5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
  6. 6Department of Neurosurgery and
  7. 7Neuroscience program, Graduate School of Medical Sciences, Weill Cornell Medical College, New York, New York, USA
  8. 8Department of Psychiatry, Columbia University Medical Center, New York, New York, USA
  9. 9Institute for Computational Biomedicine, Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
  10. 10Tri-Institutional Ph.D. program in Computational Biology, New York, New York, USA
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Abstract

While clinical trials of human pluripotent stem cell-derived midbrain dopamine (mDA) neuron precursor grafts for Parkinson's disease (PD) are ongoing, current protocols remain suboptimal. In particular, the yield of TH+ mDA neurons after in vivo grafting and the expression of certain mDA neuron and subtype-specific markers require improvement. Single-cell transcriptomic analyses of grafts have revealed low proportions of mDA neurons and substantial off-target contamination. Here, we present an optimized mDA neuron differentiation strategy that builds on our clinical-grade ("Boost") protocol by adding FGF18 and IWP2 treatment ("Boost+") at the neurogenesis stage. Boost+ mDA neurons show higher expression of EN1, PITX3, and ALDH1A1. Improvements in mDA neuron yield and transcriptional similarity to primary mDA neurons are observed in vitro and following transplantation. Single-nucleus RNA sequencing demonstrates enrichment of A9 mDA neurons within Boost+ grafts. Functional studies in vitro demonstrate increased dopamine production and release and improved electrophysiological properties. In vivo analyses show higher percentages of TH+ mDA neurons, resulting in efficient rescue of amphetamine-induced rotation behavior in the 6-OHDA rat model and rescue of deficits in some nondrug-induced assays, including the ladder rung assay, which are not improved by Boost mDA neurons. The Boost+ conditions present an optimized differentiation protocol with advantages for disease modeling and mDA neuron grafting paradigms.

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Cite

BibTeXRIS
BibTeX
@article{kim2026modulation,
  title = {{Modulation of WNT and FGF18 enhances yield and subtype identity of hPSC-derived midbrain dopamine neurons}},
  author = {T Kim and Jinghua Piao and Vittoria Dickinson Bocchi and So Yeon Koo and Se Joon Choi and Fayzan F. Chaudhry and Donghe Yang and H Cho and Emiliano Hergenreder and Lucia Ruiz Perera and Subhashini Joshi and Zaki Abou-Mrad and Nidia Claros and Shkurte Ademi Donohue and Yeong Eun Im and Hyo Jae Jeong and Anika K. Frank and Ryan M. Walsh and Eugene V. Mosharov and Doron Betel and Viviane Tabar and Lorenz Studer},
  journal = {Journal of Clinical Investigation},
  year = {2026},
  month = may,
  doi = {10.1172/jci190954},
  url = {https://doi.org/10.1172/jci190954},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Modulation of WNT and FGF18 enhances yield and subtype identity of hPSC-derived midbrain dopamine neurons
AU  - T Kim
AU  - Jinghua Piao
AU  - Vittoria Dickinson Bocchi
AU  - So Yeon Koo
AU  - Se Joon Choi
AU  - Fayzan F. Chaudhry
AU  - Donghe Yang
AU  - H Cho
AU  - Emiliano Hergenreder
AU  - Lucia Ruiz Perera
AU  - Subhashini Joshi
AU  - Zaki Abou-Mrad
AU  - Nidia Claros
AU  - Shkurte Ademi Donohue
AU  - Yeong Eun Im
AU  - Hyo Jae Jeong
AU  - Anika K. Frank
AU  - Ryan M. Walsh
AU  - Eugene V. Mosharov
AU  - Doron Betel
AU  - Viviane Tabar
AU  - Lorenz Studer
PY  - 2026
DA  - 2026/05/15
JO  - Journal of Clinical Investigation
DO  - 10.1172/jci190954
UR  - https://doi.org/10.1172/jci190954
AB  - While clinical trials of human pluripotent stem cell-derived midbrain dopamine (mDA) neuron precursor grafts for Parkinson's disease (PD) are ongoing, current protocols remain suboptimal. In particular, the yield of TH+ mDA neurons after in vivo grafting and the expression of certain mDA neuron and subtype-specific markers require improvement. Single-cell transcriptomic analyses of grafts have revealed low proportions of mDA neurons and substantial off-target contamination. Here, we present an optimized mDA neuron differentiation strategy that builds on our clinical-grade ("Boost") protocol by adding FGF18 and IWP2 treatment ("Boost+") at the neurogenesis stage. Boost+ mDA neurons show higher expression of EN1, PITX3, and ALDH1A1. Improvements in mDA neuron yield and transcriptional similarity to primary mDA neurons are observed in vitro and following transplantation. Single-nucleus RNA sequencing demonstrates enrichment of A9 mDA neurons within Boost+ grafts. Functional studies in vitro demonstrate increased dopamine production and release and improved electrophysiological properties. In vivo analyses show higher percentages of TH+ mDA neurons, resulting in efficient rescue of amphetamine-induced rotation behavior in the 6-OHDA rat model and rescue of deficits in some nondrug-induced assays, including the ladder rung assay, which are not improved by Boost mDA neurons. The Boost+ conditions present an optimized differentiation protocol with advantages for disease modeling and mDA neuron grafting paradigms.
SN  - 0021-9738
SN  - 1558-8238
ER  -