Abstract
BackgroundSpinocerebellar ataxia (SCA) refers to a disease entity in which polyglutamine aggregates are over-produced in Purkinje cells (PCs) of the cerebellum as well as other neurons in the central nervous system, and the formation of intracellular polyglutamine aggregates result in the loss of neurons as well as deterioration of motor functions. So far there is no effective neuroprotective treatment for this debilitating disease although numerous efforts have been made. Mesenchymal stem cells (MSCs) possess multi-lineage differentiation potentials as well as immuno-modulatory properties, and are theoretically good candidates for SCA treatment. The purpose of this study is to investigate whether transplantation of human MSCs (hMSCs) can rescue cerebellar PCs and ameliorate motor function deterioration in SCA in a pre-clinical animal model.MethodTransgenic mice bearing poly-glutamine mutation in ataxin-2 gene (C57BL/6J SCA2 transgenic mice) were serially transplanted with hMSCs intravenously or intracranially before and after the onset of motor function loss. Motor function of mice was evaluated by an accelerating protocol of rotarod test every 8 weeks. Immunohistochemical stain of whole brain sections was adopted to demonstrate the neuroprotective effect of hMSC transplantation on cerebellar PCs and engraftment of hMSCs into mice brain.ResultsIntravenous transplantation of hMSCs effectively improved rotarod performance of SCA2 transgenic mice and delayed the onset of motor function deterioration; while intracranial transplantation failed to achieve such neuroprotective effect. Immunohistochemistry revealed that intravenous transplantation was more effective in the preservation of the survival of cerebellar PCs and engraftment of hMSCs than intracranial injection, which was compatible to rotarod performance of transplanted mice.ConclusionIntravenous transplantation of hMSCs can indeed delay the onset as well as improve the motor function of SCA2 transgenic mice. The results of this preclinical study strongly support further exploration of the feasibility to transplant hMSCs for SCA patients.
Highlights
Spinocerebellar ataxia (SCA) refers to a disease entity in which polyglutamine aggregates are overproduced in Purkinje cells (PCs) of the cerebellum as well as other neurons in the central nervous system, and the formation of intracellular polyglutamine aggregates result in the loss of neurons as well as deterioration of motor functions
Immunohistochemistry revealed that intravenous transplantation was more effective in the preservation of the survival of cerebellar PCs and engraftment of human MSCs (hMSCs) than intracranial injection, which was compatible to rotarod performance of transplanted mice
Confirmation of Successful Intracranial Delivery of hMSCs Whole brain tissue of control mouse which was injected with trypan blue through foramen magnum into position of cerebellum was inspected after sacrifice, and most of the areas staining by trypan blue were located at cerebellum, medulla and nearby regions (Figure 1A)
Summary
Spinocerebellar ataxia (SCA) refers to a disease entity in which polyglutamine aggregates are overproduced in Purkinje cells (PCs) of the cerebellum as well as other neurons in the central nervous system, and the formation of intracellular polyglutamine aggregates result in the loss of neurons as well as deterioration of motor functions. The purpose of this study is to investigate whether transplantation of human MSCs (hMSCs) can rescue cerebellar PCs and ameliorate motor function deterioration in SCA in a pre-clinical animal model. Spinocerebellar ataxias (SCAs) are a group of inherited neurological disorders that are clinically and genetically very heterogeneous. They are progressive neurodegenerative diseases that are characterised by cerebellar ataxia, resulting in unsteady gait, clumsiness, and dysarthria. The surface phenotype and multilineage potential of mMSCs used in this study [11] was not demonstrated completely, these results suggested that MSC transplantation may be beneficial to SCA2 transgenic mice
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