Haematopoetic stem cells in MSSaturday, October 13, 2007, 10:30 - 10:50
Animal studies with haematopoetic and non-haematopoetic bone marrow-derived stem cells: their properties and the scientific basis for clinical applications in MSD. Karussis (Jerusalem, IL)
Two types of stem cells can be isolated from the adult bone marrow (BM): 1. Haematopoietic stem cells, (HSCs) which can give rise to the whole haematopoietic system (including all types of immune cells), and 2. Mesenchymal stromal stem cells (MSCs) which were initially thought to be only of support for the normal engrafting and development of the HSCs, and can give rise to various cells of the mesodermal origin as fat and bone.
We have shown in previous works, that autologous HSC transplantation following acute high dose immunosuppression could prevent or improve the development of paralytic signs in models of acute and chronic EAE and re-induce long standing self tolerance towards myelin antigens. These experiments led to the application of autologous bone marrow transplantation in severe cases of MS with promising results. Still, the toxicity of the used conditioning protocols limit the extensive use of such treatment in the majority of MS patients. We have also suggested and applied an experimental model of semi-allogeneic mini-transplant which induces a stage of mixed chimerism with resulting graft vs autoimmunity effects.
During the last years, several lines of evidence have depicted the plasticity potential of both BM stem cells populations and especially of the MSCs. MSCs were shown to differentiate under certain circumstances into cells from exodermal tissues We and others have shown the ability of BM-MSCs to migrate into CNS inflamed tissue in the model of EAE and differentiate into cells of the neural-glial lineage, exerting a beneficial clinical and histopathological effect on this experimental disease, mainly through systemic and in situ immunomodulation.
In our experiments, MSCs were obtained from GFP-transgenic mice. Cells were cultured with a combination of growth factors (FGF-2/BDNF/FGF-8) and checked for their differentiation properties. MSCs were injected intraventricularly (icv) in C57Bl mice with chronic-EAE at the initial phase of the disease. All animals were followed up clinically for at least two months. In vitro, MSCs showed the ability to differentiate into cells with neural and glial-like morphology and were stained with GFAP+ (~30%), O4+ (~ 10%), Nestin+ (~10%) and NF160+ (~20%). Cultured MSCs showed immunomodulatory properties and significantly downregulated lymphocyte proliferations against myelin antigens. In vivo, icv injection of MSCs suppressed the clinical (mortality 0%, vs 16% in the controls; mean maximal score: 3.08, vs 3.85) and histopathological manifestations of chronic-EAE and induced significant neuroprotection (>90% of axons unaffected in the treated animals vs 40% in the controls). MSCs migrated into the inflamed lesions and were found to present immunohistological characteristics of neuronal and glial cells.
These results indicate that autologous BM can provide a source of stem cells which downregulate the clinicopathological signs of chronic-EAE and carry a neuroprotective and immunomodulating potential. Based on these data, an intrathecal administration protocol using autologous MSCs has been initiated in our center in severe cases of MS.