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

Li Yan,Yanchao Duan,Enqin Li,Bin Jiang,Guokai Chen,Huiyan Sun,Weizhi Ji,Yuyu Niu,Ren-He Xu,Shaohui Chang,Wei Si,Yaping Yan,Hongxuan Wang

doi:10.1038/s41420-018-0091-0

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 delivered EMSC in spheres (EMSCsp) to preserve the cell viability during long-distance transportation. EMSCsp intrathecally injected into the CNS, remarkably reduced the clinical symptoms, brain lesions, and neuronal demyelination in the EAE monkeys during a 3-month observation. Whereas, symptoms in the vehicle control-injected EAE monkey remained and reduced slowly and MRI lesions in brain expanded. Moreover, EMSC could transdifferentiate into neural cells in vivo in the CNS of the treated animals. Supporting evidence demonstrated that EMSCsp cells cultured in cerebrospinal fluid from the EAE monkeys largely converted to neural cells with elevated expression of genes for neuronal markers, neurotrophic factors, and neuronal myelination. Thus, this study demonstrates that EMSCsp injected directly into the CNS, can attenuate the disease progression in the primate EAE model, highly encouraging for clinical translation.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) featured by demyelination of neural fibers and malfunction of the neural signal transmission with high prevalence in Caucasians and females
The symptomless C2 was left as a control for C1 for EMSC in vivo distribution assay
11 ng/μg gDNA in the spinal cord of C3 is about ninefold lower than that in C1 at d4 (Fig. S2Cd). These results suggest that (1) EMSC, following i.v. injection, distributed to all the isolated tissues, in which the spinal cord had the highest concentration of EMSC especially in the EAE monkeys; (2) EMSC declined in all the tested tissues from d4 to d7, and no obvious symptom improvement was observed in C1 in short time window

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) featured by demyelination of neural fibers and malfunction of the neural signal transmission with high prevalence in Caucasians and females. Lesions detected in the CNS via MRI Upon the symptom onset in C1, magnetic resonance imaging (MRI) was conducted on the brain of the monkey (Fig. 1b).

Results

Conclusion