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Single cell transcriptional and functional analysis of human dopamine neurons in 3D fetal ventral midbrain organoid like cultures

Marcella Birtele, Yogita Sharma, Petter Storm, Janko Kajtez, Jenny Nelander Wahlestedt, Edoardo Sozzi, Fredrik Nilsson, Simon Stott, Xiaoling L He, Bengt Mattsson, Daniella Rylander Ottosson, Roger A Barker, Alessandro Fiorenzano, Malin Parmar
doi: https://doi.org/10.1101/2020.10.01.322495
Marcella Birtele
1Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, Sweden
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Yogita Sharma
1Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, Sweden
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Petter Storm
1Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, Sweden
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Janko Kajtez
1Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, Sweden
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Jenny Nelander Wahlestedt
1Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, Sweden
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Edoardo Sozzi
1Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, Sweden
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Fredrik Nilsson
1Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, Sweden
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Simon Stott
3Department of Clinical Neuroscience and WT-MRC Cambridge Stem Cell Institute, University of Cambridge, UK
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Xiaoling L He
3Department of Clinical Neuroscience and WT-MRC Cambridge Stem Cell Institute, University of Cambridge, UK
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Bengt Mattsson
1Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, Sweden
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Daniella Rylander Ottosson
2Regenerative Neurophysiology, Wallenberg Neuroscience Center, Lund Stem Cell Center, Department of Experimental Medical Science, Lund University, Sweden
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Roger A Barker
3Department of Clinical Neuroscience and WT-MRC Cambridge Stem Cell Institute, University of Cambridge, UK
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Alessandro Fiorenzano
1Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, Sweden
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Malin Parmar
1Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, Sweden
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  • For correspondence: malin.parmar@med.lu.se
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SUMMARY

Transplantation of midbrain dopamine (DA) neurons for the treatment of Parkinson’s disease (PD) is a strategy that has being extensively explored and clinical trials using fetal and stem cell-derived DA neurons are ongoing. An increased understanding of the mechanisms promoting the generation of distinct subtypes of midbrain DA during normal development will be essential for guiding future efforts to precisely generate molecularly defined and subtype specific DA neurons from pluripotent stem cells. In this study, we used droplet-based scRNA-seq to transcriptionally profile a large number of fetal cells from human embryos at different stages of ventral midbrain (VM) development (6, 8, and 11 weeks post conception). This revealed that the emergence of transcriptionally distinct cellular populations was evident already at these early timepoints. To study late events of human DA differentiation and functional maturation, we established a primary fetal 3D culture system that recapitulates key molecular aspects of late human DA neurogenesis and sustains differentiation and functional maturation of DA neurons in a physiologically relevant cellular context. This approach allowed us to define the molecular identities of distinct human DA progenitors and neurons at single cell resolution and construct developmental trajectories of cell types in the developing fetal VM.

Overall these findings provide a unique transcriptional profile of developing fetal VM and functionally mature human DA neurons, which can be used to quality control stem cell-derived DA neurons and guide stem cell-based therapies and disease modeling approaches in PD.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 01, 2020.
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Single cell transcriptional and functional analysis of human dopamine neurons in 3D fetal ventral midbrain organoid like cultures
Marcella Birtele, Yogita Sharma, Petter Storm, Janko Kajtez, Jenny Nelander Wahlestedt, Edoardo Sozzi, Fredrik Nilsson, Simon Stott, Xiaoling L He, Bengt Mattsson, Daniella Rylander Ottosson, Roger A Barker, Alessandro Fiorenzano, Malin Parmar
bioRxiv 2020.10.01.322495; doi: https://doi.org/10.1101/2020.10.01.322495
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Single cell transcriptional and functional analysis of human dopamine neurons in 3D fetal ventral midbrain organoid like cultures
Marcella Birtele, Yogita Sharma, Petter Storm, Janko Kajtez, Jenny Nelander Wahlestedt, Edoardo Sozzi, Fredrik Nilsson, Simon Stott, Xiaoling L He, Bengt Mattsson, Daniella Rylander Ottosson, Roger A Barker, Alessandro Fiorenzano, Malin Parmar
bioRxiv 2020.10.01.322495; doi: https://doi.org/10.1101/2020.10.01.322495

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