Assessing Human Embryonic Stem Cell-Derived Dopaminergic Neuron Progenitor Transplants Using Non-invasive Imaging Techniques

M Mousavinejad,P Murray,V Pisupati,S Skidmore,R A Barker,A Plagge,H Poptani,P Tyers,C J Hill,F G Barone,A Taylor

doi:10.1007/s11307-020-01499-4

Abstract

PurposeHuman pluripotent stem cell (hPSC)-derived dopaminergic neuron progenitor cells (DAPCs) are a potential therapy for Parkinson’s disease (PD). However, their intracranial administration raises safety concerns including uncontrolled proliferation, migration and inflammation. Here, we apply a bimodal imaging approach to investigate the fate of DAPC transplants in the rat striatum.ProceduresDAPCs co-expressing luciferase and ZsGreen or labelled with micron-sized particles of iron oxide (MPIOs) were transplanted in the striatum of RNU rats (n = 6 per group). DAPCs were tracked in vivo using bioluminescence and magnetic resonance (MR) imaging modalities.ResultsTransgene silencing in differentiating DAPCs accompanied with signal attenuation due to animal growth rendered the bioluminescence undetectable by week 2 post intrastriatal transplantation. However, MR imaging of MPIO-labelled DAPCs showed that transplanted cells remained at the site of injection for over 120 days. Post-mortem histological analysis of DAPC transplants demonstrated that labelling with either luciferase/ZsGreen or MPIOs did not affect the ability of cells to differentiate into mature dopaminergic neurons. Importantly, labelled cells did not elicit increased glial reactivity compared to non-labelled cells.ConclusionsIn summary, our findings support the transplantation of hPSC-derived DAPCs as a safe treatment for PD.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disease that results in part from the progressive loss of dopaminergic (DA) neurons in the substantia nigra
Several groups have shown that human pluripotent stem cell-derived dopaminergic neuron progenitor cells (DAPCs) can generate
In addition to evaluating the effectiveness of the imaging modalities themselves, we investigated whether the labels used for tracking affected the differentiation potential of the cells and/or their immunogenicity following implantation into the rat striatum

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disease that results in part from the progressive loss of dopaminergic (DA) neurons in the substantia nigra. Mousavinejad M. et al.: Multimodal imaging of neural progenitor transplants mature DA neurons and improve motor function following intrastriatal transplantation in animal models of PD [1, 2]. This has evolved to the point that the first in human hPSC-based DA neural transplants are being undertaken or planned in patients with PD. Key safety concerns with such therapies for PD and other central nervous system (CNS) disorders include the risk that the implanted cells could proliferate and form space-occupying masses and/or migrate to off-target sites within the CNS and/ or induce major neuroinflammation [3]. In addition to considering the potential risks, it is important to monitor the long-term viability and differentiation capacity of implanted cells, as to be effective, they must differentiate into the appropriate phenotype and persist in the brain

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