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Single Cell Gene Expression Analysis Reveals Human Stem Cell-Derived Graft Composition in a Cell Therapy Model of Parkinson’s Disease

Katarína Tiklová, Sara Nolbrant, Alessandro Fiorenzano, Åsa K. Björklund, Yogita Sharma, Andreas Heuer, Linda Gillberg, Deirdre B. Hoban, Tiago Cardoso, Andrew F. Adler, Marcella Birtele, Hilda Lundén-Miguel, Nikolaos Volakakis, Agnete Kirkeby, Thomas Perlmann, Malin Parmar
doi: https://doi.org/10.1101/720870
Katarína Tiklová
1Ludwig Institute for Cancer Research, Box 240, SE-171 77, Stockholm, Sweden
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Sara Nolbrant
2Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
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Alessandro Fiorenzano
2Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
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Åsa K. Björklund
3Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Husargatan 3, SE-752 37 Uppsala, Sweden
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Yogita Sharma
2Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
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Andreas Heuer
2Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
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Linda Gillberg
1Ludwig Institute for Cancer Research, Box 240, SE-171 77, Stockholm, Sweden
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Deirdre B. Hoban
2Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
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Tiago Cardoso
2Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
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Andrew F. Adler
2Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
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Marcella Birtele
2Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
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Hilda Lundén-Miguel
1Ludwig Institute for Cancer Research, Box 240, SE-171 77, Stockholm, Sweden
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Nikolaos Volakakis
1Ludwig Institute for Cancer Research, Box 240, SE-171 77, Stockholm, Sweden
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Agnete Kirkeby
2Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
4Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark
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Thomas Perlmann
5Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77, Stockholm, Sweden
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  • For correspondence: thomas.perlmann@ki.se malin.parmar@med.lu.se
Malin Parmar
2Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
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  • For correspondence: thomas.perlmann@ki.se malin.parmar@med.lu.se
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Abstract

Since the pioneering studies using fetal cell transplants in Parkinson’s disease (PD), brain repair by cell replacement has remained a long-standing and realistic goal for the treatment of neurodegenerative disorders including PD. Authentic and functional midbrain dopamine (DA) neurons can now be generated from human pluripotent stem cells (hPSCs) via a floor plate intermediate1,2, and these cell preparations are both safe and functional when transplanted to animal models of PD3. However, although resulting grafts from fetal brain tissue and hPSCs contain large numbers of desired DA neurons, these therapeutic cells are a minor component of the grafts. Moreover, the cellular composition of the graft has remained difficult to assess due to limitations in histological methods that rely on pre-conceived notions concerning cell types. Here, we used single cell RNA sequencing (scRNA-seq) combined with comprehensive histological analyses to characterize intracerebral grafts from ventral midbrain (VM)-patterned human embryonic stem cells (hESCs) and VM fetal tissue after long-term survival and functional maturation in a pre-clinical rat model of PD. The analyses revealed that while both cell preparations gave rise to neurons and astrocytes, oligodendrocytes were only detected in grafts of fetal tissue. On the other hand, a cell type closely resembling a class of newly identified perivascular-like cells was identified as a unique component of hESC-derived grafts. The presence of these cells was confirmed in transplants from three different hESC lines, as well as from iPSCs. Thus, these experiments have addressed one of the major outstanding questions in the field of cell replacement in neurological disease by revealing graft composition and differences between hESC- and fetal cell-derived grafts, which can have important implications for clinical trials.

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Posted August 05, 2019.
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Single Cell Gene Expression Analysis Reveals Human Stem Cell-Derived Graft Composition in a Cell Therapy Model of Parkinson’s Disease
Katarína Tiklová, Sara Nolbrant, Alessandro Fiorenzano, Åsa K. Björklund, Yogita Sharma, Andreas Heuer, Linda Gillberg, Deirdre B. Hoban, Tiago Cardoso, Andrew F. Adler, Marcella Birtele, Hilda Lundén-Miguel, Nikolaos Volakakis, Agnete Kirkeby, Thomas Perlmann, Malin Parmar
bioRxiv 720870; doi: https://doi.org/10.1101/720870
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Single Cell Gene Expression Analysis Reveals Human Stem Cell-Derived Graft Composition in a Cell Therapy Model of Parkinson’s Disease
Katarína Tiklová, Sara Nolbrant, Alessandro Fiorenzano, Åsa K. Björklund, Yogita Sharma, Andreas Heuer, Linda Gillberg, Deirdre B. Hoban, Tiago Cardoso, Andrew F. Adler, Marcella Birtele, Hilda Lundén-Miguel, Nikolaos Volakakis, Agnete Kirkeby, Thomas Perlmann, Malin Parmar
bioRxiv 720870; doi: https://doi.org/10.1101/720870

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