Abstract
Cell replacement is a long-standing and realistic goal for the treatment of Parkinsonʼs disease (PD). Cells for transplantation can be obtained from fetal brain tissue or from stem cells. However, after transplantation, dopamine (DA) neurons are seen to be a minor component of grafts, and it has remained difficult to determine the identity of other cell types. Here, we report analysis by single-cell RNA sequencing (scRNA-seq) combined with comprehensive histological analyses to characterize intracerebral grafts from human embryonic stem cells (hESCs) and fetal tissue after functional maturation in a pre-clinical rat PD model. We show that neurons and astrocytes are major components in both fetal and stem cell-derived grafts. Additionally, we identify a cell type closely resembling a class of recently identified perivascular-like cells in stem cell-derived grafts. Thus, this study uncovers previously unknown cellular diversity in a clinically relevant cell replacement PD model.
Highlights
Cell replacement is a long-standing and realistic goal for the treatment of Parkinsons disease (PD)
To compare the developmental potential of human embryonic stem cells (hESCs)-derived ventral midbrain (VM) progenitors with fetal VM cells after transplantation in a rat model of PD, hESCs were subjected to VMpatterning by a well-established protocol intended for generation of clinical-grade cell preparations[4] and human fetal tissue was dissociated from the VM of a 7.5-week-old human embryo by the same protocol used for the fetal cell clinical transplantation trial, TRANSEURO5
The number of fetal cells sequenced after transplantation was very low, limiting the conclusions that could be derived from these data alone; key findings were validated by histological analysis and by analysis of in vitro-cultured cells
Summary
Cell replacement is a long-standing and realistic goal for the treatment of Parkinsons disease (PD). We report analysis by single-cell RNA sequencing (scRNA-seq) combined with comprehensive histological analyses to characterize intracerebral grafts from human embryonic stem cells (hESCs) and fetal tissue after functional maturation in a pre-clinical rat PD model. Authentic and functional midbrain dopamine (DA) neurons and their progenitors can be generated from human pluripotent stem cells (hPSCs) via a floor plate intermediate[1,2] These cell preparations are both safe and functional when transplanted to animal models of Parkinson’s disease (PD)[3]. We use single-cell RNA sequencing (scRNA-seq) combined with 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.
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