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

Abstract

Purpose Human 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. Procedures DAPCs 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. Results Transgene 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. Conclusions In summary, our findings support the transplantation of hPSC-derived DAPCs as a safe treatment for PD.

Manufacturing with pluripotent stem cells (PSConf 2021): Key issues for future research and development

“…Dr. Shugo Tohyama (Department of Cardiology, Keio University School of Medicine, Japan) addressed challenges for the manufacture of ventricular cardiomyocyte‐like cells from hiPSCs for the treatment of severe cardiac failure. 14 Dr. Tohyama focused his presentation on issues of cardiomyocyte purity and potential tumorigenicity due to residual undifferentiated iPSCs that, even at levels of 0.02% of cells, were able to form teratomas in animals and were therefore a possible risk to patients. First, he described a means of regulating the metabolism of differentiated cell preparations using a glucose and glutamine‐depleted media supplemented with lactate to eliminate undifferentiated hPSCs.…”

Challenges in the clinical advancement of cell therapies for Parkinson’s disease

“…Alternative current approaches are focused on the development of multimodal imaging platforms, combining bioluminescence imaging with increasingly sensitive techniques such as MRI. Such bi-modal imaging platforms could present a comprehensive method for assessing the safety and efficacy of cell-based therapies in preclinical models 157 – 160 .…”

Challenges involved in cell therapy for Parkinson’s disease using human pluripotent stem cells

“…FGF signaling is triggered using the recombinant protein FGF8b ( Figure 2 ). This combination results in a high yield of vmDA progenitor cells capable of differentiating into vmDA neurons ( Cai et al, 2010 ; Kriks et al, 2011 ; Doi et al, 2012 ; Sanchez-Danes et al, 2012 ; Doi et al, 2014 ; Grealish et al, 2014 ; Grealish et al, 2015 ; Samata et al, 2015 ; Steinbeck et al, 2015 ; Samata et al, 2016 ; Adil et al, 2017 ; Niclis et al, 2017 ; Nolbrant et al, 2017 ; Wakeman et al, 2017 ; Xia et al, 2017 ; Fathi et al, 2018 ; Adler et al, 2019 ; Chang et al, 2019 ; Zygogianni et al, 2019 ; Mousavinejad et al, 2020 ; Schweitzer et al, 2020 ; Song et al, 2020 ; Kim T. W. et al, 2021 ; Xiong et al, 2021 ). Researchers like Perrier and his colleagues have focused on differentiation using SHH and FGF8 and found that approximately 60%–80% of beta tubulin III (TUJ1)-positive neurons express TH ( Perrier et al, 2004 ).…”