Robust derivation of transplantable dopamine neurons from human pluripotent stem cells by timed retinoic acid delivery

Zhanna Alekseenko, José M. Dias, Andrew F. Adler, Mariya Kozhevnikova, Josina Anna Lunteren, Sara Nolbrant, Ashwini Jeggari, Svitlana Vasylovska, Takashi Yoshitake, Jan Kehr, Marie Carlén, Andrey Alexeyenko, Malin Parmar and Johan Ericson ()
Additional contact information
Zhanna Alekseenko: Karolinska Institutet
José M. Dias: Karolinska Institutet
Andrew F. Adler: Lund University
Mariya Kozhevnikova: Karolinska Institutet
Josina Anna Lunteren: Karolinska Institutet
Sara Nolbrant: Lund University
Ashwini Jeggari: Karolinska Institutet
Svitlana Vasylovska: Karolinska Institutet
Takashi Yoshitake: Karolinska Institutet
Jan Kehr: Karolinska Institutet
Marie Carlén: Karolinska Institutet
Andrey Alexeyenko: Karolinska Institutet
Malin Parmar: Lund University
Johan Ericson: Karolinska Institutet

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Stem cell therapies for Parkinson’s disease (PD) have entered first-in-human clinical trials using a set of technically related methods to produce mesencephalic dopamine (mDA) neurons from human pluripotent stem cells (hPSCs). Here, we outline an approach for high-yield derivation of mDA neurons that principally differs from alternative technologies by utilizing retinoic acid (RA) signaling, instead of WNT and FGF8 signaling, to specify mesencephalic fate. Unlike most morphogen signals, where precise concentration determines cell fate, it is the duration of RA exposure that is the key-parameter for mesencephalic specification. This concentration-insensitive patterning approach provides robustness and reduces the need for protocol-adjustments between hPSC-lines. RA-specified progenitors promptly differentiate into functional mDA neurons in vitro, and successfully engraft and relieve motor deficits after transplantation in a rat PD model. Our study provides a potential alternative route for cell therapy and disease modelling that due to its robustness could be particularly expedient when use of autologous- or immunologically matched cells is considered.

Date: 2022
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DOI: 10.1038/s41467-022-30777-8

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