Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. Nowadays, available therapies for MS can help to manage MS course and symptoms, but new therapeutic approaches are required. Stem cell therapy using mesenchymal stem cells (MSCs) appeared promising in different neurodegenerative conditions, thanks to their beneficial capacities, including the immunomodulation ability, and to their secretome. The secretome is represented by growth factors, cytokines, and extracellular vesicles (EVs) released by MSCs. In this review, we focused on studies performed on in vivo MS models involving the administration of MSCs and on clinical trials evaluating MSCs administration. Experimental models of MS evidenced that MSCs were able to reduce inflammatory cell infiltration and disease score. Moreover, MSCs engineered to express different genes, preconditioned with different compounds, differentiated or in combination with other compounds also exerted beneficial actions in MS models, in some cases also superior to native MSCs. Secretome, both conditioned medium and EVs, also showed protective effects in MS models and appeared promising to develop new approaches. Clinical trials highlighted the safety and feasibility of MSC administration and reported some improvements, but other trials using larger cohorts of patients are needed.

https://www.mdpi.com/1422-0067/21/22/8662/pdf

Mesenchymal Stem Cells in Multiple Sclerosis: Recent Evidence from Pre-Clinical to Clinical Studies

Injection of bone marrow mesenchymal stem cells by intravenous or intraperitoneal routes is a viable alternative to spinal cord injury treatment in mice.

Die vorliegende Dissertationsarbeit befasst sich mit den Mechanismen glialer Differenzierung und der Frage, inwieweit diese im Rahmen inflammatorischer Erkrankungen des Zentralen Nerversystems (ZNS) wie der Multiplen Sklerose (MS) von Bedeutung sind. Multiple Sklerose ist eine autoimmune inflammatorische ZNS Erkrankung, die eine Zerstorung der axon-isolierenden Myelinscheiden zur Folge hat. Hierdurch kommt es zunachst zu einer Herabsetzung der elektrischen Uberleitungsgeschwindigkeit in den neuronalen Axonen und schlieslich zum direkten axonalen Schaden. Die myelinbildenden Zellen des ZNS, die Oligodendrozyten, konnen die zerstorten Myelinscheiden in der Folge nur unvollstandig erneuern, wobei dies nicht zuletzt mit der eingeschrankten Fahigkeit von residenten Oligodendrozytenvorlauferzellen zu differenzieren in Verbindung gebracht wird. In der vorgelegten Arbeit konnte nun gezeigt werden, dass eine anhaltende Reduzierung der Genexpression von p57kip2, eines Zyklin abhangigen Kinaseinhibitors, in oligodendroglialen Vorlauferzellen zu einer erleichterten und verstarkten Differenzierung dieser myelinisierenden Zellen fuhrt. Zu diesem Zweck wurden primare Rattenoligodendrozyten aus dem neugeborenen Rattenhirn mit einem Gensuppressionsvektor fur p57kip2 transfiziert und anschliesend immunzytochemisch und morphologisch analysiert. Neben diesen in vitro Studien wurde gezeigt, dass p57kip2 im Rahmen der MOG-EAE (Myelin-Oligodendrozyten- Glykoprotein induzierte experimentelle autoimmune Enzephalomyelitis), einer Modellerkrankung der MS in der Ratte, fast ausschlieslich von Oligodendrozyten und ihren Vorlauferzellen exprimiert und schubabhangig reguliert wird. Hierfur wurde Material aus dem gesunden und dem EAE-Rattenhirn mittels qRT-PCR und Immunhistochemie aufgearbeitet und miteinander verglichen. Gemeinsam legen die in dieser Arbeit vorgestellten Ergebnisse nahe, dass es sich bei p57kip2 um einen neuartigen negativen Regulator der (Re-) Myelinisierung handelt, der sich an der Schnittstelle zwischen Genexpression und Zellmorphogenese befindet. Insbesondere in Hinblick auf das immer noch begrenzte Verstandnis der zerebralen (Re-) Myelinisierungsmechanismen kann die vorgelegte Arbeit neue Wege in Richtung auf alternative Therapiestrategien, wie der Stimulierung hirneigener Regenerationsprozesse weisen. Die im Rahmen dieser Doktorarbeit generierten Daten konnten in einem Fachjournal publiziert werden (Kremer et al., PNAS 2009 106:9087-9092).

p57kip2 is dynamically regulated in experimental autoimmune encephalomyelitis

Purpose of reviewMedications for relapsing multiple sclerosis (MS) effectively reduce relapse rate, mitigate disability progression and improve MRI measures of inflammation. However, they have virtually no impact on remyelination which is the major mechanism preventing MS-associated neurodegeneratio

Remyelination in multiple sclerosis: from concept to clinical trials.

A pool of different types of neural progenitor cells resides in the adult hippocampus. Apart from doublecortin-expressing (DCX+) neuronal progenitor cells (NPCs), the hippocampal parenchyma also contains oligodendrocyte precursor cells (OPCs), which can differentiate into myelinating oligodendrocytes. It is not clear yet to what extent the functions of these different progenitor cell types overlap and how plastic these cells are in response to pathological processes. The aim of this study was to investigate whether hippocampal DCX+ NPCs can generate new oligodendrocytes under conditions in which myelin repair is required. For this, the cell fate of DCX-expressing NPCs was analyzed during cuprizone-induced demyelination and subsequent remyelination in two regions of the hippocampal dentate gyrus of DCX-CreERT2/Flox-EGFP transgenic mice. In this DCX reporter model, the number of GFP+ NPCs co-expressing Olig2 and CC1, a combination of markers typically found in mature oligodendrocytes, was significantly increased in the hippocampal DG during remyelination. In contrast, the numbers of GFP+PDGFRα+ cells, as well as their proliferation, were unaffected by de- or remyelination. During remyelination, a higher portion of newly generated BrdU-labeled cells were GFP+ NPCs and there was an increase in new oligodendrocytes derived from these proliferating cells (GFP+Olig2+BrdU+). These results suggest that DCX-expressing NPCs were able to contribute to the generation of mature oligodendrocytes during remyelination in the adult hippocampus.

/pdf/dcx-neuronal-progenitors-contribute-to-new-oligodendrocytes-5gmi0ggtwo.pdf

DCX+ neuronal progenitors contribute to new oligodendrocytes during remyelination in the hippocampus.

The generation of new oligodendrocytes is essential for adult brain repair in diseases such as multiple sclerosis We previously identified the multifunctional p57kip2 protein as a negative regulator of myelinating glial cell differentiation and as an intrinsic switch of glial fate decision in adult neural stem cells (aNSCs) In oligodendroglial precursor cells (OPCs), p57kip2 protein nuclear exclusion was recently found to be rate limiting for differentiation to proceed Furthermore, stimulation with mesenchymal stem cell (MSC)-derived factors enhanced oligodendrogenesis by yet unknown mechanisms To elucidate this instructive interaction, we investigated to what degree MSC secreted factors are species dependent, whether hippocampal aNSCs respond equally well to such stimuli, whether apart from oligodendroglial differentiation also tissue integration and axonal wrapping can be promoted and whether the oligodendrogenic effect involved subcellular translocation of p57kip2 We found that CC1 positive oligodendrocytes within the hilus express nuclear p57kip2 protein and that MSC dependent stimulation of cultured hippocampal aNSCs was not accompanied by nuclear p57kip2 exclusion as observed for parenchymal OPCs after spontaneous differentiation Stimulation with human MSC factors was observed to equally promote rat stem cell oligodendrogenesis, axonal wrapping and tissue integration As forced nuclear shuttling of p57kip2 led to decreased CNPase- but elevated GFAP expression levels, this indicates heterogenic oligodendroglial mechanisms occurring between OPCs and aNSCs We also show for the first time that dominant pro-oligodendroglial factors derived from human fetal MSCs can instruct human induced pluripotent stem cell-derived NSCs to differentiate into O4 positive oligodendrocytes

Human mesenchymal factors induce rat hippocampal‐ and human neural stem cell dependent oligodendrogenesis

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Human mesenchymal factors induce rat hippocampal‐ and human neural stem cell dependent oligodendrogenesis