Cell-Based Strategies for Restoration of Function
Loss of myelin surrounding the axons is a major cause for conduction deficits in people with MS, and in many cases, people with SCI as well. Our previous studies of cell transplantation in the repair of demyelinated rodent CNS have successfully demonstrated that a variety of myelin-forming cells including oligodendrocytes (Kato et al 2000), Schwann cells (Kohama et al 2001) and stem cells derived from the adult and fetal brain (Akiyama et al 2002; Kocsis et al 2004) can remyelinate and restore function in demyelinated spinal cord axons. Research projects underway include the following:

i) Remyelination of nonhuman primate spinal cord by transplanted transgenic adult pig olfactory ensheathing cells: Having previously demonstrated that olfactory ensheathing cells can remyelinate bare axons within spinal cord injured rats, we tested the approach in non-human primate models of spinal cord injury. In this study, we harvested genetically modified olfactory ensheathing cells from transgenic pigs and transplanted them directly into demyelinated lesions within the injured spinal cord of African green monkeys. Within four weeks of transplantation, we observed a robust remyelination in over 60% of the demyelinated regions within the injured axons. This is by far the first demonstration that xenotransplantation (transplantation from one species to another) of olfactory ensheathing cells into the primate spinal cord can result in successful remyelination. This demonstration is an important milestone toward identifying effective treatments for restoration of function in people with spinal cord injuries, MS and other related disorders of demyelination.

Radtke C, Akiyama Y, Brokaw J, Lankford KL, Wewetzer K, Fodor WL, Kocsis JD. Remyelination of the nonhuman primate spinal cord by transplantation of H-transferase transgenic adult pig olfactory ensheathing cells. FASEB J. 2004 Feb;18(2):335-7. .
ii) Transplanted olfactory ensheathing cells bridge the transected lesion and form myelin within the injured spinal cord: In another recent study, we transplanted olfactory ensheathing cells expressing green fluorescent protein (GFP, a marker) into a transected lesion within the spinal cord of rodents to study the potential of olfactory ensheathing cells in repairing transected lesions within spinal cord axons. Five weeks following transplantation, the transplanted cells not only survived within the transplanted zone but also oriented longitudinally along the axons that bridged the transection site, and formed myelin. Behavioral analyses revealed that these animals exhibited improved locomotor behavior compared to control animals that did not receive the treatment.

Sasaki M, Lankford KL, Zemedkun M, Kocsis JD. Identified olfactory ensheathing cells transplanted into the transected dorsal funiculus bridge the lesion and form myelin.
J Neurosci. 2004 Sep 29; 24(39):8485-93.

iii) Remyelinating potential of focal and intravenous administrated bone marrow cells: In earlier studies we demonstrated that remyelination of the demyelinated spinal cord can be achieved both by intravenous injection of bone marrow derived stromal cells as well as via transplantation of these cells directly into the lesion (Akiyama et al 2002a; Akiyama et al 2002b; Sasaki et al 2001). As a follow up of these studies, and to better understand the potential of bone marrow cells in nerve repair, we performed a comparative analysis of the remyelinating potential of the two modes of administration of autologous bone marrow cells into the rat demyelinated spinal cord. Our analysis demonstrated that while intravenous injection of cells required delivery of substantially more cells (two orders of magnitude) to achieve the same density of remyelination as achieved via direct injection, it is still an attractive therapeutic approach considering that a) it is minimally invasive, requiring no risky, neurosurgical intervention and b) easy availability of relatively large number of bone marrow cells for autologous transplantation.

Inoue M, Honmou O, Oka S, Houkin K, Hashi K, Kocsis JD. Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord. Glia. 2003 Nov; 44(2):111-8.

iv) Nerve repair in a model of cerebral ischemia: We then went on to test the efficacy of intravenous injection of bone marrow cells in animal models of cerebral ischemia (i.e., stroke) and determine the specific time windows for efficacy. Our results demonstrated reduced infarction size and improved functional outcome in rats that received the intravenous treatment with bone marrow cells. Furthermore, our findings suggest that early intervention with intravenous administration of autologous mononuclear cells from bone marrow can reduce lesion size in the rat model of stroke, and improve functional outcome

Iihoshi S, Honmou O, Houkin K, Hashi K, Kocsis JD. A therapeutic window for intravenous administration of autologous bone marrow after cerebral ischemia in adult rats. Brain Res. 2004 May 8; 1007(1-2):1-9.

v) Transplantation of autologous neural precursor cells into the demyelinated monkey spinal cord: In a study published in December 2004, we demonstrated that autologous transplantation of neural precursor cells can remyelinate demyelinated CNS axons in adult non-human primates (marmoset). Specifically we established that neural precursor cells could safely be isolated by biopsy of the subventricular zone (source of CNS progenitor cells within the rodent brain), expanded in culture while retaining their myelinating potential after autologous transplantation into a demyelinated lesion in the spinal cord. These results suggest the potential utility of such an approach in repairing demyelinated lesions in humans.

Oka S, Honmou O, Akiyama Y, Sasaki M, Houkin K, Hashi K, Kocsis JD. Autologous transplantation of expanded neural precursor cells into the demyelinated monkey spinal cord. Brain Res. 2004 Dec 24; 1030(1):94-102.

All of the above findings are extremely encouraging and suggest the possibility of CNS repair in MS and SCI via a variety of cell-based approaches. We are currently planning a human clinical study of nerve repair in acute SCI through intravenous injection of autologous cells derived from the bone marrow.

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