Generating induced pluripotent stem cells for multiple sclerosis therapy.

Over 150 years of research in multiple sclerosis (MS) culminated, during the last two decades, in the approval of several disease-modifying drugs, from the first selfinjectable immunomodulators, to the latest oral compounds and in several promising clinical trials testing the efficacy of monoclonal antibodies against B or T cells, and hematopoietic and mesenchymal stem cells transplantation. All those strategies have more or less succeeded at preventing damage from an immune system gone astray. The next challenge in the MS field is to develop neuroprotective and re-myelinating paradigms. In the meantime, the scientific community has witnessed a stem cell revolution, with the derivation of human embryonic stem cells, followed – less than 10 years later – by the groundbreaking discovery that adult cells could be reprogrammed to revert to an undifferentiated ‘embryonic-like’ stage and become induced pluripotent stem cells (iPSCs). Today, iPSCs play a central role in an increasing number of studies focusing on both disease modeling and cell-replacement therapies including those for neurological, muscular, ocular, cardiac, hematological, metabolic and skin disorders [1]. Needless to say, the question arises of whether iPSCs can effectively impact MS research, supporting the emerging routes of investigation, focusing on neurodegeneration/neuroprotection and de-myelination/re-myelination. Chronic neurodegeneration, etiology of which is mostly unknown, distinguishes patients that switch to a secondary progressive phase over time and patients that are affected by the most severe primary progressive form of MS. The axonal dysfunction has been traditionally seen as the consequence of an autoimmune-mediated demyelination. However increasing evidence is challenging this concept and suggesting that neurodegeneration is an independent phenomenon, occurring from the onset and ultimately leading to an accumulation of physical and cognitive disabilities [2,3]. Understanding the pathogenesis of neurodegeneration in order to develop neuroprotective strategies for progressive patients has become an urgent priority. Thus far, studies conducted with primary focus in this direction have been hampered by the limited access to histopathological specimens from the patients and by the lack of an appropriate animal model that would recapitulate the spontaneous onset of the human disease. iPSCs offer the unprecedented opportunity to generate patient-derived cells in substantial quantity; protocols to generate different type of neurons have been developed at remarkable pace and are constantly improving [4,5]; and most importantly, many independent studies have now proven that iPSC-derived cells can recapitulate in vitro disease-relevant phenotypes and provide crucial information regarding the pathogenesis of the disease [6–8]. Extremely encouraging is the fact that even a complex genetic psychiatric disorder such as schizophrenia has been modeled through iPSCs [7]. The simplicity of cell cultures is certainly a limitation for the analysis of extrinsic factors involved in the development of a disease. On the other hand, they can provide a controlled Generating induced pluripotent stem cells for multiple sclerosis therapy