Lasting benefits of stimulating transplanted stem cells in unilateral 6-OHDA lesioned rats

Kevin A Anderson, Michael I Sandstrom

Research output: Contribution to conferencePosterpeer-review

Abstract

Of the treatments for Parkinson’s disease (PD), a neurodegenerative disorder resulting from the degradation of dopaminergic (DA) neurons in the substantia nigra, stem cell transplantation (TRANS) demonstrates high potential. Preclinical studies demonstrate that intrastriatal transplantation of DA cells derived from stem cells attenuate PD symptoms; however, clinical data indicate that recurrence of symptoms may begin after 10-15 years. Curiously, several postmortem analyses suggest that the grafted cells were still releasing DA and that pathology spread was minimal. We theorized that a gradual adaptive response is occurring due to imprecise regulation of grafted cells. With lack of contextually relevant afferent stimuli, the phasic activity of these cells may become lost to the noise of imprecise DA control. We also theorized that by driving the cells optogenetically in vivo, we could potentially promote cellular integration and derive more behavior support than transplantation alone. With a previous study, we serendipitously discovered that when one stimulates the cells early on—approximately 5 days post-TRANS—it led to reduction of PD symptoms up to 2 days later even without any further stimulation. We thus decided to conduct a follow-up study to see if we could replicate these results as well as determine if these benefits required behavioral context to occur. To start, all rats received unilateral nigrostriatal 6-OHDA, were tested for limb bias pre-transplant, and grafted with light-sensitive DA neuron-like cells derived from mesenchymal stem cells. After 5 days, the animals were grouped for optogenetic stimulation while swimming (Stim-Swim), not stimulated while swimming (NoStim-Swim), or were stimulated while sitting at rest (Stim-NoSwim). Swimming-related limb bias was then assessed 2 days and 7 days later, without stimulation. We thus explored whether stimulation-alone, behavioral context, or both factors were important in mediating the extended reduction of motor deficits. Preliminary data suggests that early stimulation reduces deficits for up to 7 days. This effect is nearly absent in the NoStim-Swim group, suggesting that laser stimulation is responsible for this reduction. Curiously, the Stim-NoSwim group is showing reduced limb bias similar to the Stim-Swim groups, suggesting that in our paradigm, behavioral context has minimum impact compared to stimulation. Further data collection will determine how reliable this effect is, but current indications imply stimulating TRANS cells early might promote long-term integration, a strategy that may also extend the longevity of stem cell transplants in human PD patients.
Original languageEnglish
StatePublished - May 13 2019
Event50 Annual Meeting of Michigan Chapter Society for Neuroscience - Western Michigan University
Duration: May 13 2019May 13 2019

Conference

Conference50 Annual Meeting of Michigan Chapter Society for Neuroscience
Period05/13/1905/13/19

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