Induced Cognitive Impairments Reversed by Grafts of Neural Precursors: A Longitudinal Study in a Macaque Model of Parkinson's Disease

Abstract

Parkinson's disease (PD) evolves over an extended and variable period in humans; years prior to the onset of classical motor symptoms, sleep and biological rhythm disorders develop, significantly impacting the quality-of-life of patients. Circadian-rhythm disorders are accompanied by mild cognitive deficits that progressively worsen with disease progression and can constitute a severe burden for patients at later stages. The gold-standard 6-methyl-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) macaque model of PD recapitulates the progression of motor and nonmotor symptoms over contracted periods of time. Here, this multidisciplinary/multiparametric study follows, in five animals, the steady progression of motor and nonmotor symptoms and describes their reversal following grafts of neural precursors in diverse functional domains of the basal ganglia. Results show unprecedented recovery from cognitive symptoms in addition to a strong clinical motor recuperation. Both motor and cognitive recovery and partial circadian rhythm recovery correlate with the degree of graft integration, and in a subset of animals, with in vivo levels of striatal dopaminergic innervation and function. The present study provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian nonhuman primates and, given interindividuality of disease progression and recovery, underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation.

Genetically engineered mesenchymal stem cells with dopamine synthesis for Parkinson’s disease in animal models

“…For example, the outcomes from fetal mesencephalic tissues are mixed and associated with dyskinesia, primarily due to undefined and unstandardized donor tissues 55,56 . In addition, after dopaminergic neuron precursors were transplanted into the monkey, <53% or 1% of cells in the graft survived in the brain 37,38,57 , even in PD monkeys that had received autologous transplantation from iPS-derived dopamine neurons 39,58 . Furthermore, before functioning in vivo, transplanted dopamine neurons or progenitors are required to differentiate into mature dopamine neurons and establish a functional circuit with host neurons.…”

Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs

“…17,123 Despite being more complex and expensive than murine models, nonhuman primates share more closely activity patterns with humans, which may provide stronger evidence support for chronotherapy research. 131 The generalization of these conclusions to other species will re-…”

“… 17 , 123 Despite being more complex and expensive than murine models, nonhuman primates share more closely activity patterns with humans, which may provide stronger evidence support for chronotherapy research. 131 The generalization of these conclusions to other species will require additional systematic study. Besides, several non‐invasive imaging modalities, including quantitative parametric images of O‐(2‐[F]fluoroethyl)‐L‐tyrosine kinetics analysis and MRI approach for noninvasive TME visualization, have been developed for quantitatively assessing the oxygen and energy metabolism within glioma or the microenvironment surrounding glioma.…”

“…In addition, tumor cell‐intrinsic circadian rhythms can regulate TMZ cytotoxicity in mice, which showed a strong correlation between drug sensitivity and circadian rhythm, 82 while the effect of TMZ in glioma chronotherapy treatment is still controversial and needs further large‐population‐based trials for validation 17,123 . Despite being more complex and expensive than murine models, nonhuman primates share more closely activity patterns with humans, which may provide stronger evidence support for chronotherapy research 131 . The generalization of these conclusions to other species will require additional systematic study.…”

Application and prospects of high-throughput screening for in vitro neurogenesis

“…Before clinical trials, studies of stem cell trans plantation were conducted on animal disease models to examine the safety and efficiency of stem cell therapy. Recently, various studies have been carried out using primary NS/PCs, neural precursors, immortalized neural stem cell lines, iPSC-derived NS/PCs, and directly reprogrammed neural precursor cells to treat spinal cord injury (SCI)[ 189 , 190 ], AD[ 191 , 192 ], PD[ 193 - 195 ], Huntington’s disease (HD)[ 196 , 197 ] and ALS[ 198 ] in animal models, and the symptoms of those diseases were relieved to some extent. For instance, the long-term selective stimulation of hM3Dq-expressing human iPSCs (hiPSCs)-derived NS/PCs enhanced their BDNF secretion, neuron-to-neuron interactions and synaptic activity in the surrounding host tissue in mouse SCI models, suggesting that enhancing neural activity and interactions with other cells in the neural circuit can be an effective way to improve the therapeutic effect of stem cell transplantation[ 199 ].…”