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Intrathecal delivery of human ESC-derived mesenchymal stem cell spheres promotes recovery of a primate EAE model

ABSTRACT: Nonhuman primate experimental autoimmune encephalomyelitis (EAE) is a valuable model for multiple sclerosis an inflammatory demyelinating disease in the central nervous system (CNS). Human embryonic stem cell-derived mesenchymal stem cells (EMSC) are effective in treating murine EAE. Yet, it remains unknown whether the EMSC efficacy is translatable to humans. Here we induced a primate EAE model in cynomolgus monkeys and transported EMSC in spheres (EMSCsp) to preserve the cell viability under ambient conditions. First, single cells dissociated from EMSCsp were intravenously infused into normal and EAE monkeys. The cells reached various organs including CNS but diminished rapidly. To increase the number and viability of EMSC in the CNS, we injected EMSCsp intrathecally (i.t.) into the subarachnoid cavity of EAE monkeys multiple times post-onset and upon relapses during a 3-month observation. The clinical symptoms in these animals relieved rapidly following the injections and eventually disappeared. Whereas, symptoms in a vehicle control-injected EAE monkey remained and reduced slowly. Consistently, reduced lesions and active regeneration were found in the CNS of the EMSCsp-treated monkeys compared to the control. EMSC were found in the CNS long after the i.t. injections and some of the cells had differentiated into neurons and oligodendrocytes. Supporting evidence demonstrated that EMSCsp cultured in cerebrospinal fluid from the EAE monkeys largely converted to neural cells with elevated expression of genes for neuronal markers, neurotropic factors, and neuronal myelination. Together, this study suggests that i.t. injection of ambiently transported EMSCsp can treat EAE in nonhuman primates via remyelination and transdifferentiation, which shall expedite the clinical application of EMSC in patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107145 | GEO | 2018/08/30

REPOSITORIES: GEO

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Project description:Obesity is associated with a chronic, low-grade, systemic inflammation that may contribute to the development of insulin resistance and type 2 diabetes. Resveratrol, a natural compound with anti-inflammatory properties, is shown to improve glucose tolerance and insulin sensitivity in obese mice and humans. Here we tested the effect of a 2-year resveratrol administration on the pro-inflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Eighty mg/day of resveratrol for 12-month followed by 480 mg/day for the second year decreased adipocyte size, increased sirtuin 1 expression, decreased NF-kB activation and improved insulin sensitivity in visceral but not subcutaneous WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS +/- resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys. Twenty-four adult (7-13 years old) male rhesus monkeys (Macaca mulatta) were housed individually in standard nonhuman primate caging on a 12h light/12h dark cycle, room temperature (78 +/- 2 degrees F), and humidity at 60 +/- 20%. One pairing was maintained throughout the study; all other monkeys had extensive visual, auditory, and olfactory but limited tactile contact with monkeys housed in the same room. Monkeys received 2 meals per day at estimated ad libitum levels throughout the study. Water was always available ad libitum. Monkeys were monitored minimally 3 times daily by trained animal care staff. During baseline assessments, all monkeys were maintained on a commercially available closed formula monkey chow. After baseline assessment, four male rhesus monkeys remained on the healthy standard diet (SD), 10 male rhesus monkeys were begun on a high fat/high sucrose (HFS) diet and 10 male rhesus monkeys were begun on a high fat/high sucrose (HFS) diet plus Resveratrol, 80mg/day. After one year of dietary intervention, the amount of resveratrol was increased to 480mg/day for one additional year. Tissues were then harvested for the array experiments.

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Intrathecal delivery of human ESC-derived mesenchymal stem cell spheres promotes recovery of a primate EAE model

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