Remyelination of the Rat Spinal Cord by Transplantation of Identified Bone Marrow Stromal Cells

Abstract

Bone marrow contains a population of stem-like cells that can differentiate into neurons or glia. Stromal cells from green fluorescent protein (GFP)-expressing mice were isolated by initial separation on a density gradient and then cultured as adherent cells on plastic that proliferated in culture to confluency with a typical flattened elongative morphology. The large majority of the isolated stromal cells were GFP expressing and immunopositive for collagen type I, fibronectin, and CD44. Transplantation of these cells by direct microinjection into the demyelinated spinal cord of the immunosuppressed rat resulted in remyelination. The remyelinated axons showed characteristics of both central and peripheral myelination as observed by electron microscopy; conduction velocity of the axons was improved. GFP-positive cells and myelin profiles were observed in the remyelinated spinal cord region, indicating that the donor-isolated stromal cells were responsible for the formation of the new myelin. The GFP-positive cells were colocalized with myelin basic protein-positive and P0-positive cellular elements. These findings indicate that cells contained within the stromal cell fraction of the mononuclear cell layer of bone marrow can form functional myelin during transplantation into demyelinated spinal cord.

Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord

“…Local injection of CD34 + cells (hematopoietic stem cells) did not result in remyelination in our demyelinated model system (Sasaki et al, 2001), suggesting that hematopoietic stem cells are not a candidate cell for remyelination. Bone marrow stromal cells have recently been reported to differentiate into neurons, astrocytes, and myelin-forming cells (Woodbury et al, 2000;Akiyama et al, 2002b), and the stromal or mesenchymal stem cell fraction of the mononuclear cells may be responsible for the myelin repair.…”

“…The mononuclear cell fraction of bone marrow can be readily isolated by density gradient and contains stromal cells, hematopoietic and nonhematopoietic stem and precursor cells, and lymphocytes (Azizi et al, 1998;Phinney et al, 1999;Sasaki et al, 2001;Akiyama et al, 2002a). Transplantation of GFP-expressing mouse stromal cells by direct microinjection into the immunosuppressed rat indicates that these cells can form myelin in the demyelinated spinal cord (Akiyama et al, 2002b). When transplanted into a contusive spinal cord injury model, the cells survive and there is significant improvement of gait (Hofstetter et al, 2001).…”

Cell Therapy for Multiple Sclerosis

“…Specifically, a number of investigators have reported that adult mouse and human BMSCs can differentiate in vitro into other cell types, including muscle, skin, liver, lung, and neural cells [246][247][248][249][250]. It was also suggested that bone marrow-derived stromal cells can generate astrocytes [251], as wedll as produce myelin and remyelinate a demyelinated lesion of the spinal cord of the rat [252,253]. The potential of stromal cells for cell replacement therapy is still controversial in view of reports showing that stromal cells may rather fuse with existing neurons and glia, resulting in the formation of heterokaryons [248,254].…”

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…Stem-like cells, derived from bone marrow, have been reported to myelinate spinal axons when introduced at the site of focal demyelination. 324,325 Intriguingly, these cells also stimulated remyelination -and themselves formed myelinwhen injected into the bloodstream. 325,326 If such cells can reliably overcome the blood-brain barrier, migrate to demyelinated CNS regions and differentiate appropriately, with their proliferation being controlled, then an intravenous delivery route presents an attractive alternative to direct parenchymal injection into the damaged CNS.…”