Mesenchymal Stem Cells

Mesenchymal Stem Cells (MSC) are a kind of adult stem cells which can be isolated from different tissues, including bone marrow and fat. MSC are characterized by the expression of connective tissue markers and by the absence of hematopoietic markers. Their normal fate is to differentiate in chondrocytes, adipocytes, and osteocytes, i.e. cartilage, fat and bone. Within the bone marrow, MSC are an essential component of the hematopoietic niche, where they support hematopoiesis. MSC have been used in clinical settings since the Nineties, when the first clinical trials with MSC were performed under the hypothesis that the administration of MSC (either autologous, i.e. derived from the same individual, or allogeneic, i.e. derived from a donor) may promote the engraftment of hematopoietic stem cells (HSC) in subjects with neoplasms.
At that time, it was hypothesized that MSC, given their plasticity, could ameliorate the course of genetic diseases of of tissues of mesenchymal origin , such as bone in osteogenesis imperfecta, or repair tissues damaged by ischemic or traumatic injuries.
More recently, it was demonstrated that MSC significantly modulate several functions of the immune system, both in vitro and in vivo [1], possibly through the release of soluble mediators, and they were shown to be an effective treatment for graft-versus-host disease [2] .

The discovery of immunomodulating properties of MSC was the basis of the first studies on the animal model of MS, called experimental autoimmune encephalomyelitis (EAE).  Such studies showed that intravenous administration of MSC shortly after disease onset, or at the peak of severity, significantly ameliorates its course, with reduced demyelination and infiltration of inflammatory cells, and induces a peripheral tolerance towards myelin antigens [3]. Subsequently it was shown that MSC have a neuroprotective effect [4] and promote remyelination [5], but do not differentiate into neural cells. Given the results of preclinical in vitro and in vivo studies, a consensus between clinicians and researchers interested in trying MSC as a treatment for MSC was reached: on the grounds of this consensus, the MESEMS study was designed [6-8] . The need for a phase II study enrolling an adequate number of subjects stems from the observation that some small studies have already provided comforting information about safety of MSC in MS treatment and some preliminary data supporting a possible efficacy of MSC, although these are not sufficient to provide conclusive and reliable evidence [9-13] .

Bibliography

1.         Uccelli, A., L. Moretta, and V. Pistoia, Mesenchymal stem cells in health and disease. Nat Rev Immunol, 2008. 8(9): p. 726-36.

2.         Le Blanc, K., et al., Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. The Lancet, 2008. 371(9624): p. 1579-86
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3.         Zappia, E., et al., Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T cell anergy. Blood, 2005. 106(5): p. 1755-1761.

4.         Gerdoni, E., et al., Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol, 2007. 61(3): p. 219-27.

5.         Bai, L., et al., Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models. Nat Neurosci, 2012.

6.         Freedman, M.S., et al., The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler, 2010. 16(4): p. 503-10.

7.         Laroni, A., et al., Towards Clinical Application of Mesenchymal Stem Cells for Treatment of Neurological Diseases of the Central Nervous System. J Neuroimmune Pharmacol, 2013.

8.         Uccelli, A., A. Laroni, and M.S. Freedman, Mesenchymal stem cells as treatment for MS - progress to date. Mult Scler, 2013. 19(5): p. 515-9.

9.         Karussis, D., et al., Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol, 2010. 67(10): p. 1187-94.

10.       Mohyeddin Bonab, M., et al., Does mesenchymal stem cell therapy help multiple sclerosis patients? Report of a pilot study. Iran J Immunol, 2007. 4(1): p. 50-7.

11.       Yamout, B., et al., Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: A pilot study. Journal of neuroimmunology, 2010. 227(1): p. 185-189.

12.       Connick, P., et al., The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments. Trials, 2011. 12: p. 62.

13.       Bonab, M.M., et al., Autologous Mesenchymal Stem Cell Therapy in Progressive Multiple Sclerosis: an open label study. Curr Stem Cell Res Ther, 2012.


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