Abstract
Demyelination contributes to the functional impairment of irradiation injured spinal cord. One potential therapeutic strategy involves replacing the myelin-forming cells. Here, we asked whether transplantation of Olig2+-GFP+-oligodendrocyte precursor cells (OPCs), which are derived from Olig2-GFP-mouse embryonic stem cells (mESCs), could enhance remyelination and functional recovery after spinal cord irradiation injury. We differentiated Olig2-GFP-mESCs into purified Olig2+-GFP+-OPCs and transplanted them into the rats’ cervical 4–5 dorsal spinal cord level at 4 months after irradiation injury. Eight weeks after transplantation, the Olig2+-GFP+-OPCs survived and integrated into the injured spinal cord. Immunofluorescence analysis showed that the grafted Olig2+-GFP+-OPCs primarily differentiated into adenomatous polyposis coli (APC+) oligodendrocytes (54.6±10.5%). The staining with luxol fast blue, hematoxylin & eosin (LFB/H&E) and electron microscopy demonstrated that the engrafted Olig2+-GFP+-OPCs attenuated the demyelination resulted from the irradiation. More importantly, the recovery of forelimb locomotor function was enhanced in animals receiving grafts of Olig2+-GFP+-OPCs. We concluded that OPC transplantation is a feasible therapy to repair the irradiated lesions in the central nervous system (CNS).
Highlights
The spinal cord is one of the important dose-limiting normal tissues in clinical radiotherapy
This was confirmed by immunostaining for myelin basic protein (MBP) and neurofilment (NF), showing the presence of many axons but sharply reduced MBP staining (Fig. 1E)
We have directed mouse embryonic stem cells (mESCs) to a purified population of oligodendrocyte precursor cells (OPCs) based on the GFP expression in the Olig2 locus, which differentiate into oligodendrocytes in vitro and in vivo
Summary
The spinal cord is one of the important dose-limiting normal tissues in clinical radiotherapy. Excessive doses of radiation to the spinal cord result in radiation injury, which is a rare but serious complication of radiotherapy for cancer [1,2]. The pathophysiology involved in irradiation-induced spinal cord injury is demyelination caused by death of oligodendrocytes [3,4]. There is a persistent decline in the number of OPCs from two weeks to three months after X-ray irradiation [7,8]. Persistent demyelination may result in further axonal loss. Such changes could be associated with permanent motor and sensory deficits [10], which become fatal if the damage occurs at the upper cervical level [11]. There are currently no therapeutic approaches that promote remyelination available in a clinical setting
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