Modulation of WNT and FGF18 enhances yield and subtype identity of hPSC-derived midbrain dopamine neurons.
Overview
- Center for Stem Cell Biology and
- Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
- Department of New Biology and
- Department of Biomedical Science and Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea
- Department of Neurosurgery and
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
- Neuroscience program, Graduate School of Medical Sciences, Weill Cornell Medical College, New York, New York, USA
- Department of Psychiatry, Columbia University Medical Center, New York, New York, USA
- Institute for Computational Biomedicine, Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
- Tri-Institutional Ph.D. program in Computational Biology, New York, New York, USA
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.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
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- ebi.ac.uk/
arrayexpress , EMBL-EBI; found in “Data availability.”
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Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 2, 28 September 2026
- Authors: added Lorenz Studer (0000-0003-0741-7987); removed Lorenz Studer
Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 22 authors, 5 keywords, 11 MeSH terms, 3 funders, 59 references.
Cite
This paper
Kim, T. W., Piao, J., Bocchi, V. D., Koo, S. Y., Choi, S. J., Chaudhry, F., Yang, D., Cho, H. S., Hergenreder, E., Ruiz Perera, L., Joshi, S., Abou Mrad, Z., Claros, N., Donohue, S. A., Eun Im, Y., Jeong, H. J., Frank, A. K., Walsh, R. M., Mosharov, E. V., . . . Studer, L. (2026). Modulation of WNT and FGF18 enhances yield and subtype identity of hPSC-derived midbrain dopamine neurons. The Journal of clinical investigation, 136(10), e190954. https://
BibTeX
@article{kim2026modulati
author = {Kim, Tae Wan and Piao, Jinghua and Bocchi, Vittoria D and Koo, So Yeon and Choi, Se Joon and Chaudhry, Fayzan and Yang, Donghe and Cho, Hyein S and Hergenreder, Emiliano and Ruiz Perera, Lucia and Joshi, Subhashini and Abou Mrad, Zaki and Claros, Nidia and Donohue, Shkurte Ademi and Eun Im, Yeong and Jeong, Hyo Jae and Frank, Anika K and Walsh, Ryan M and Mosharov, Eugene V and Betel, Doron and Tabar, Viviane and Studer, Lorenz},
title = {{Modulation of WNT and FGF18 enhances yield and subtype identity of hPSC-derived midbrain dopamine neurons}},
journal = {The Journal of clinical investigation},
year = {2026},
month = may,
volume = {136},
number = {10},
pages = {e190954},
publisher = {American Society for Clinical Investigation},
issn = {0021-9738},
doi = {10.1172/
url = {https://
pmid = {42138078},
pmcid = {PMC13178649}
}
RIS
TY - JOUR
AU - Kim, Tae Wan
AU - Piao, Jinghua
AU - Bocchi, Vittoria D
AU - Koo, So Yeon
AU - Choi, Se Joon
AU - Chaudhry, Fayzan
AU - Yang, Donghe
AU - Cho, Hyein S
AU - Hergenreder, Emiliano
AU - Ruiz Perera, Lucia
AU - Joshi, Subhashini
AU - Abou Mrad, Zaki
AU - Claros, Nidia
AU - Donohue, Shkurte Ademi
AU - Eun Im, Yeong
AU - Jeong, Hyo Jae
AU - Frank, Anika K
AU - Walsh, Ryan M
AU - Mosharov, Eugene V
AU - Betel, Doron
AU - Tabar, Viviane
AU - Studer, Lorenz
TI - Modulation of WNT and FGF18 enhances yield and subtype identity of hPSC-derived midbrain dopamine neurons
T2 - The Journal of clinical investigation
J2 - J Clin Invest
PY - 2026
DA - 2026/
VL - 136
IS - 10
SP - e190954
SN - 0021-9738
PB - American Society for Clinical Investigation
DO - 10.1172/
UR - https://
LA - en
ER -
CSL-JSON
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