Remyelination of the spinal cord following intravenous delivery of bone marrow cells

Abstract

Bone marrow contains a population of pluripotent cells that can differentiate into a variety of cell lineages, including neural cells. When injected directly into the demyelinated spinal cord they can elicit remyelination. Recent work has shown that following systemic delivery of bone marrow cells functional improvement occurs in contusive spinal cord injury and stroke models in rat. We report here that secondary to intravenous introduction of an acutely isolated bone marrow cell fraction (mononuclear fraction) from adult rat femoral bones separated on a density gradient, ultrastructurally defined remyelination occurs throughout a focal demyelinated spinal cord lesion. The anatomical pattern of remyelination was characteristic of both oligodendrocyte and Schwann cell myelination; conduction velocity improved in the remyelinated axons. When the injected bone marrow cells were transfected to express LacZ, β-galactosidase reaction product was observed in some myelin-forming cells in the spinal cord. Intravenous injection of other myelin-forming cells (Schwann cells and olfactory ensheathing cells) or the residual cell fraction of the gradient did not result in remyelination, suggesting that remyelination was specific to the delivery of the mononuclear fraction. While the precise mechanism of the repair, myelination by the bone marrow cells or facilitation of an endogenous repair process, cannot be fully determined, the results demonstrate an unprecedented level of myelin repair by systemic delivery of the mononuclear cells.

Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury

“…This myelin was produced, at least in part, by the transplanted cells, was characteristic of both central and peripheral myelin, and resulted in improved conduction velocity of the remyelinated axons. 81 Similar results were obtained with direct injection of murine MSCs. 82 As with the brain experiments, several groups have explored the possibility of intraventricular, intrathecal or i.v.…”

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

“…Several lines of evidence indicate that the remyelination was from the transplanted bone marrow cells and not from endogenous host cells. Our studies were carried out within 3 weeks after EB-X lesion induction, which is well within the time at which persistent demyelination is confirmed in a large number of control studies (Blakemore and Crang, 1985;Franklin et al, 1996;Honmou et al, 1996;Kato et al, 2000;Akiyama et al, 2001Akiyama et al, , 2002aSasaki et al, 2001). However, the possible facilitation of recruitment of cells outside of the lesion zone from the injection procedure cannot be completely ruled out.…”

“…Transplantation of an acutely isolated bone marrow mononuclear cell fraction by either direct intraspinal microinjection (Sasaki et al, 2001) or intravenous delivery (Akiyama et al, 2002a) into the demyelinated rat spinal cord results in relatively extensive remyelination. Plastic-adherent cells from bone marrow are referred to as stromal cells (Friedenstein, 1976) and are thought to contain nonhematopoietic stem cells that can differentiate along multiple mesenchymal cell lineages (Prockop, 1997).…”

“…Plastic-adherent cells from bone marrow are referred to as stromal cells (Friedenstein, 1976) and are thought to contain nonhematopoietic stem cells that can differentiate along multiple mesenchymal cell lineages (Prockop, 1997). 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).…”

Updates on stem cells and their applications in regenerative medicine

“…Since BMSCs can be successfully differentiated into neuronal cells in vitro (Sanchez-Ramos et al, 2000), a strategy to enhance anxonal regeneration could involve the transplantation of BMSCs into the injured spinal cord. Animal models of spinal cord injury showed axonal regeneration and functional recovery following BMSCs implantation and formation of neural and myelin-producing cells (Akiyama et al, 2002). Clinically, Park et al (2005) carried out a clinical study on five patients with acute spinal cord injury; these were treated by intralesion injection of bone marrow mononuclear cell fraction containing BMSCs and subcutaneous granulocyte-macrophage colony stimulating factor (GM-CSF).…”