Robust Derivation of Transplantable Dopamine Neurons from Human Pluripotent Stem Cells by Timed Retinoic Acid Delivery

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Jun 1

PMID 35650213

Authors

Zhanna Alekseenko

Jose M Dias

Andrew F Adler

Mariya Kozhevnikova

Josina Anna van Lunteren

Sara Nolbrant

Ashwini Jeggari

Svitlana Vasylovska

Takashi Yoshitake

Jan Kehr

Marie Carlen

Andrey Alexeyenko

Malin Parmar

Johan Ericson

Affiliations

Soon will be listed here.

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.

Citing Articles

Induced pluripotent stem cell-related approaches to generate dopaminergic neurons for Parkinson's disease.

Yi L, Woon H, Saw G, Zeng L, Tan E, Zhou Z Neural Regen Res. 2024; 20(11):3193-3206.

PMID: 39665833 PMC: 11881713. DOI: 10.4103/NRR.NRR-D-24-00771.

TARGET-seq: Linking single-cell transcriptomics of human dopaminergic neurons with their target specificity.

Fiorenzano A, Storm P, Sozzi E, Bruzelius A, Corsi S, Kajtez J Proc Natl Acad Sci U S A. 2024; 121(47):e2410331121.

PMID: 39541349 PMC: 11588066. DOI: 10.1073/pnas.2410331121.

Transcription Factor-Mediated Generation of Dopaminergic Neurons from Human iPSCs-A Comparison of Methods.

McDonald K, Lyons N, Gray L, Xu J, Schoderboeck L, Hughes S Cells. 2024; 13(12.

PMID: 38920646 PMC: 11201854. DOI: 10.3390/cells13121016.

Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies.

Pazzin D, Previato T, Goncalves J, Zanirati G, Xavier F, Da Costa J Cells. 2024; 13(9.

PMID: 38727281 PMC: 11083827. DOI: 10.3390/cells13090745.

Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells.

Maimaitili M, Chen M, Febbraro F, Ucuncu E, Kelly R, Niclis J Nat Commun. 2023; 14(1):7871.

PMID: 38052784 PMC: 10698156. DOI: 10.1038/s41467-023-43471-0.

References

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

Kirkeby A, Grealish S, Wolf D, Nelander J, Wood J, Lundblad M . Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep. 2012; 1(6):703-14. DOI: 10.1016/j.celrep.2012.04.009. View

Barker R, Parmar M, Studer L, Takahashi J . Human Trials of Stem Cell-Derived Dopamine Neurons for Parkinson's Disease: Dawn of a New Era. Cell Stem Cell. 2017; 21(5):569-573. DOI: 10.1016/j.stem.2017.09.014. View

Toledo E, Gyllborg D, Arenas E . Translation of WNT developmental programs into stem cell replacement strategies for the treatment of Parkinson's disease. Br J Pharmacol. 2017; 174(24):4716-4724. PMC: 5727333. DOI: 10.1111/bph.13871. View

Brignani S, Pasterkamp R . Neuronal Subset-Specific Migration and Axonal Wiring Mechanisms in the Developing Midbrain Dopamine System. Front Neuroanat. 2017; 11:55. PMC: 5502286. DOI: 10.3389/fnana.2017.00055. View

Schilling T, Nie Q, Lander A . Dynamics and precision in retinoic acid morphogen gradients. Curr Opin Genet Dev. 2012; 22(6):562-9. PMC: 3790664. DOI: 10.1016/j.gde.2012.11.012. View

Pattyn A, Vallstedt A, Dias J, Abdel Samad O, Krumlauf R, Rijli F . Coordinated temporal and spatial control of motor neuron and serotonergic neuron generation from a common pool of CNS progenitors. Genes Dev. 2003; 17(6):729-37. PMC: 196019. DOI: 10.1101/gad.255803. View

Zeltner N, Studer L . Pluripotent stem cell-based disease modeling: current hurdles and future promise. Curr Opin Cell Biol. 2015; 37:102-10. DOI: 10.1016/j.ceb.2015.10.008. View

Kim T, Piao J, Koo S, Kriks S, Chung S, Betel D . Biphasic Activation of WNT Signaling Facilitates the Derivation of Midbrain Dopamine Neurons from hESCs for Translational Use. Cell Stem Cell. 2021; 28(2):343-355.e5. PMC: 8006469. DOI: 10.1016/j.stem.2021.01.005. View

10.

Fan Y, Winanto , Ng S . Replacing what's lost: a new era of stem cell therapy for Parkinson's disease. Transl Neurodegener. 2020; 9:2. PMC: 6945567. DOI: 10.1186/s40035-019-0180-x. View

11.

Sif Asgrimsdottir E, Arenas E . Midbrain Dopaminergic Neuron Development at the Single Cell Level: and in Stem Cells. Front Cell Dev Biol. 2020; 8:463. PMC: 7357704. DOI: 10.3389/fcell.2020.00463. View

12.

Avantaggiato V, Acampora D, Tuorto F, Simeone A . Retinoic acid induces stage-specific repatterning of the rostral central nervous system. Dev Biol. 1996; 175(2):347-57. DOI: 10.1006/dbio.1996.0120. View

13.

Chambers S, Fasano C, Papapetrou E, Tomishima M, Sadelain M, Studer L . Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009; 27(3):275-80. PMC: 2756723. DOI: 10.1038/nbt.1529. View

14.

Nolbrant S, Heuer A, Parmar M, Kirkeby A . Generation of high-purity human ventral midbrain dopaminergic progenitors for in vitro maturation and intracerebral transplantation. Nat Protoc. 2017; 12(9):1962-1979. DOI: 10.1038/nprot.2017.078. View

15.

White J, Ramshaw H, Taimi M, Stangle W, Zhang A, EVERINGHAM S . Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism. Proc Natl Acad Sci U S A. 2000; 97(12):6403-8. PMC: 18615. DOI: 10.1073/pnas.120161397. View

16.

Riessland M, Kolisnyk B, Kim T, Cheng J, Ni J, Pearson J . Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons. Cell Stem Cell. 2019; 25(4):514-530.e8. PMC: 7493192. DOI: 10.1016/j.stem.2019.08.013. View

17.

Cooper O, Hargus G, Deleidi M, Blak A, Osborn T, Marlow E . Differentiation of human ES and Parkinson's disease iPS cells into ventral midbrain dopaminergic neurons requires a high activity form of SHH, FGF8a and specific regionalization by retinoic acid. Mol Cell Neurosci. 2010; 45(3):258-66. PMC: 2945816. DOI: 10.1016/j.mcn.2010.06.017. View

18.

Lopez-Real R, Budge J, Marder T, Whiting A, Hunt P, Przyborski S . Application of synthetic photostable retinoids induces novel limb and facial phenotypes during chick embryogenesis in vivo. J Anat. 2013; 224(4):392-411. PMC: 4098675. DOI: 10.1111/joa.12147. View

19.

Liu A, Joyner A . Early anterior/posterior patterning of the midbrain and cerebellum. Annu Rev Neurosci. 2001; 24:869-96. DOI: 10.1146/annurev.neuro.24.1.869. View

20.

Simon H, SAUERESSIG H, Wurst W, Goulding M, OLeary D . Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J Neurosci. 2001; 21(9):3126-34. PMC: 6762576. View