Parkinson's Disease and Mesenchymal Stem Cells: Potential for Cell-Based Therapy

Cell transplantation is a strategy with great potential for the treatment of Parkinson's disease, and many types of stem cells, including neural stem cells and embryonic stem cells, are considered candidates for transplantation therapy. Mesenchymal stem cells are a great therapeutic cell source because they are easy accessible and can be expanded from patients or donor mesenchymal tissues without posing serious ethical and technical problems. They have trophic effects for protecting damaged tissues as well as differentiation ability to generate a broad spectrum of cells, including dopamine neurons, which contribute to the replenishment of lost cells in Parkinson's disease. This paper focuses mainly on the potential of mesenchymal stem cells as a therapeutic cell source and discusses their potential clinical application in Parkinson's disease

Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Muse cells are endogenous reparative pluripotent-like stem cells distributed in various tissues. They can selectively home to damaged sites after intravenous injection by sensing sphingosine-1-phosphate produced by damaged cells, then exert pleiotropic effects, including tissue protection and spontaneous differentiation into tissue-constituent cells. In G93A-transgenic ALS mice, intravenous injection of 5.0x10(4) cells revealed successful homing of human-Muse cells to the lumbar spinal cords, mainly at the pia-mater and underneath white matter, and exhibited glia-like morphology and GFAP expression. In contrast, such homing or differentiation were not recognized in human mesenchymal stem cells but were instead distributed mainly in the lung. Relative to the vehicle groups, the Muse group significantly improved scores in the rotarod, hanging-wire and muscle strength of lower limbs, recovered the number of motor neurons, and alleviated denervation and myofiber atrophy in lower limb muscles. These results suggest that Muse cells homed in a lesion site-dependent manner and protected the spinal cord against motor neuron death. Muse cells might also be a promising cell source for the treatment of ALS patients

The Role of c-fos in Cell Death and Regeneration of Retinal Ganglion Cells

PURPOSE. To investigate the effect of c-fos on apoptotic cell death and regeneration of damaged retinal ganglion cells (RGCs) in tissue culture of retinal explants. METHODS. Retinas from transgenic mice carrying the exogenous c-fos gene under the control of the interferon (IFN)-␣/␤ inducible Mx-promoter (Mx-c-fos), c-fos-deficient mice, and littermate control mice were dissected and cultured in a threedimensional collagen gel culture system, followed by an analysis of TdT-dUTP terminal nick-end labeling (TUNEL) staining and measurement of neurites that emerged from explants. RESULTS. Compared with littermate control mice, Mx-c-fos transgenic animals showed a higher ratio of TUNEL positivity in the RGC layer from early in the culture period that correlated with the small number of regenerating neurites. In contrast, the c-fos-null mutated mice showed a still-lower ratio of TUNEL-positive cells. Nevertheless, the number of regenerating neurites was significantly lower in the initial phase, although the drastic increase in density of neurite regeneration was observed in the late period of culture. CONCLUSIONS. These findings suggest that c-fos is involved in both apoptotic cell death and regeneration of damaged RGCs. Elucidation of the precise c-fos-mediated cascade involved in RGC apoptosis and regeneration is significant in realizing neuronal survival and regeneration. (Invest Ophthalmol Vis Sci

Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice

Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis, hemolytic uremic syndrome, and acute encephalopathies that may lead to sudden death or severe neurologic sequelae. Current treatments, including immunoglobulin G (IgG) immunoadsorption, plasma exchange, steroid pulse therapy, and the monoclonal antibody eculizumab, have limited effects against the severe neurologic sequelae. Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative non-tumorigenic stem cells that naturally reside in the body and are currently under clinical trials for regenerative medicine. When administered intravenously, Musecells accumulate to the damaged tissue, where they exert anti-inflammatory, anti-apoptotic, anti-fibrotic, and immunomodulatory effects, and replace damaged cells by differentiating into tissue-constituent cells. Here, severely immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice orally inoculated with 9 × 109 colony-forming units of STEC O111 and treated 48 h later with intravenous injection of 5 × 104 Muse cells exhibited 100% survival and no severe after-effects of infection. Suppression of granulocyte-colony-stimulating factor (G-CSF) by RNAi abolished the beneficial effects of Muse cells, leading to a 40% death and significant body weight loss, suggesting the involvement of G-CSF in the beneficial effects of Muse cells in STEC-infected mice. Thus, intravenous administration of Muse cells could be a candidate therapeutic approach for preventing fatal encephalopathy after STEC infection

Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice

Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis, hemolytic uremic syndrome, and acute encephalopathies that may lead to sudden death or severe neurologic sequelae. Current treatments, including immunoglobulin G (IgG) immunoadsorption, plasma exchange, steroid pulse therapy, and the monoclonal antibody eculizumab, have limited effects against the severe neurologic sequelae. Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative non-tumorigenic stem cells that naturally reside in the body and are currently under clinical trials for regenerative medicine. When administered intravenously, Musecells accumulate to the damaged tissue, where they exert anti-inflammatory, anti-apoptotic, anti-fibrotic, and immunomodulatory effects, and replace damaged cells by differentiating into tissue-constituent cells. Here, severely immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice orally inoculated with 9 × 109 colony-forming units of STEC O111 and treated 48 h later with intravenous injection of 5 × 104 Muse cells exhibited 100% survival and no severe after-effects of infection. Suppression of granulocyte-colony-stimulating factor (G-CSF) by RNAi abolished the beneficial effects of Muse cells, leading to a 40% death and significant body weight loss, suggesting the involvement of G-CSF in the beneficial effects of Muse cells in STEC-infected mice. Thus, intravenous administration of Muse cells could be a candidate therapeutic approach for preventing fatal encephalopathy after STEC infection

The Role of Schwann Cells During Retinal Ganglion Cell Regeneration Induced by Peripheral Nerve Transplantation

Purpose. To investigate the key role of Schwann cells in retinal ganglion cell regeneration elicited by peripheral nerve autotransplantation. Methods. Three kinds of autografts, Schwann-cell graft (intact sciatic nerve, consisting of living Schwann cells and their basal laminae), Schwann-cell-eliminated graft (consisting mainly of Schwann cell basal laminae) and partial Schwann-cell graft (consisting of basal laminae and diffusible factors secreted by Schwann cells) were prepared and autotransplanted to the adult rat optic nerve. The membrane specialization between regenerating axons and Schwann cells was observed by electron microscopy. The expression of cell adhesion molecules was demonstrated by Western blot analysis and immunohistochemistry. Results. Retinal ganglion cell axons were observed to regenerate into the Schwann-cell graft, in contact with Schwann cells but not into the Schwann-cell-eliminated graft. The regeneration was not observed in the empty basal laminae of the partial Schwann-cell graft. Most of regenerating axons contacted astrocytes in the optic nerve segment, and Schwann cells in the graft. At the interface of regenerating axon and Schwann cell, in addition to immunoreactivity of N-CAM and LI, short focal tight junctions were observed. Conclusions. These results suggested that viable Schwann cells are good substrate for retinal ganglion cell regeneration, the intimate contact with viable Schwann cell surface plays an important role in retinal ganglion cell regeneration, tight junctions, and cell adhesion molecules (LI, N-CAM) are observed between the regenerating axon and Schwann cell. Invest Ophthalmol Vis Sci. 1997;38:140T-1410. At is well known that the injured retinal ganglion cell (RGC) is incapable of regeneration. This inability appears to be related to the glial environment, in that RGC axons are known to regenerate into the autotransplanted peripheral nerve graft, providing evidence of the intrinsic capacity of RGC axons to regenerate when provided with a permissive environment. 1 " Although increasingly more is known about the factors and conditions that contribute to a successful regeneration in vitro, precise interactions between regenerating RGC axons and glial cells including Schwann cells in vivo are poorly understood. To observe the association of these factors with RGC regeneration in vivo, we transplanted three kinds of peripheral nerve autografts (Schwann-cell graft, Schwann-cell eliminated graft, and partial Schwanncell graft) into the cut end of the adult rat optic nerve. An intact fresh sciatic nerve segment was used for a Schwann-cell (SC) graft, which contains viable Schwann cells and their basal laminae for the entire length, so that diffusible factors, extracellular matrix molecules, and cell adhesion molecules on Schwann cell surfaces are thought to be present. Schwann-cell eliminated (SCE) grafts containing mainly Schwann cell basal laminae (i.e., extracellular matrix) were prepared by compressing sciatic nerve segments, which eliminates living Schwann cells. Particularly, we prepared partial Schwann cell (PSC) grafts, in which the Schwann-cell containing cellular and the Schwann-cell Investigative Ophthalmology & Visual Sci