Dopaminergic Progenitors Derived From Epiblast Stem Cells Function Similarly to Primary VM-Derived Progenitors When Transplanted Into a Parkinson's Disease Model.

Sophie V Precious,Andreas Heuer,Ines Jaeger,Claire M Kelly,Stephen B Dunnett,Emma L Lane,Anne E Rosser,Gaynor A Smith,Meng Li

doi:10.3389/fnins.2020.00312

Abstract

Neural transplantation in neurodegenerative diseases such as Parkinson’s disease (PD) offers to replace cells lost during the progression of the disease process. Primary fetal ventral mesencephalon (VM), the origin of bona fide midbrain dopaminergic (DAergic) precursors, is currently the gold standard source of cells for transplantation in PD. However, the use of tissue from this source raises ethical and logistical constraints necessitating the need for alternative supplies of donor cells. The requirement of any alternative donor cell source is to have the capability to generate authentic mature DAergic neurons, which could be utilized in cell-replacement strategies. Mouse pluripotent stem cells can efficiently generate electrochemically mature midbrain DAergic precursors in vitro using a stepwise control of FGF signaling. Here, we have compared DAergic transplants derived from two progenitor cell sources in an allograft system: mouse epiblast stem cells (EpiSC) and primary fetal mouse VM tissue. Cells were transplanted into the striatum of 6-OHDA lesioned mice pre-treated with L-DOPA. Drug-induced rotations, a number of motor tests and drug-induced abnormal involuntary movements (AIMs) were assessed. Functional improvements were demonstrated post-transplantation in some behavioral tests, with no difference in graft volume or the number of TH immuno-positive cells in the grafts of the two transplant groups. L-DOPA-induced AIMs and amphetamine-induced AIMs were observed in both transplant groups, with no differences in rate or severity between the two groups. Collectively, in this mouse-to-mouse allograft system, we report no significant differences in the functional ability between the gold standard primary VM derived and pluripotent stem cell-derived DAergic transplants.

Highlights

In Parkinson’s disease (PD), neural transplantation of midbrain dopaminergic (DAergic) precursor cells aims to replace the nigral DAergic supply to the striatum which is lost during progression of this neurodegenerative disorder
Following 14 days of differentiation, around 50% of neurons were tyrosine hydroxylase (TH) positive, and of the TH-positive cells, around 70% were immunopositive for Pitx3, another marker of midbrain DAergic neurons (Jaeger et al, 2011)
We investigated these cells in vivo, assessing their functional capability in a direct comparison to the current gold standard for DAergic transplants: authentic DAergic progenitors harvested from primary fetal ventral mesencephalon (VM)

Summary

Introduction

In Parkinson’s disease (PD), neural transplantation of midbrain dopaminergic (DAergic) precursor cells aims to replace the nigral DAergic supply to the striatum which is lost during progression of this neurodegenerative disorder. Cells from primary fetal VM have been utilized in clinical trials of neural transplantation and have produced encouraging, albeit varied, results with respect to graft survival, and reinnervation within the host striatum and functional improvements (Lindvall et al, 1990, 1992; Mendez et al, 2005; Barker et al, 2013). Following reports of graft side effects, in particular graft-associated dyskinesias (Greene et al, 1999; Freed et al, 2001; Olanow et al, 2003; Barker et al, 2013) there was a pause in clinical fetal tissue transplants. Results from the TRANSEURO trial are not expected until 2021 at the earliest (Barker and TRANSEURO consortium, 2019)

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