Mesenchymal Stem Cells Promote Oligodendroglial Differentiation in Hippocampal Slice Cultures

Rivera, Francisco J.; Siebzehnrubl, Florian A.; Kandasamy, Mahesh; Couillard‐Després, Sébastien; Caioni, Massimiliano; Poehler, Anne-Maria; Berninger, Benedikt; Sandner, Beatrice; Bogdahn, Ulrich; Goetz, Magdalena; Blümcke, Ingmar; Weidner, Norbert; Aigner, Ludwig

doi:10.1159/000233256

Cited by 29 publications

(26 citation statements)

References 28 publications

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“…This study showed that MSCs enhanced OPC migration and maturation into oligodendrocytes promoting myelination in the corpus callosum. Consistent with this study, we have shown that ex vivo co-transplantation of MSCs together with NPCs onto hippocampal slice cultures (free of immune derived cells) induces NPCs to acquire an oligodendrocytic phenotype, while NPCs transplanted alone generated mostly astrocytes (Rivera et al, 2009). Regarding the underlying mechanisms, we have studied the eff ects of MSCs on NPCs in vitro and demonstrated that soluble factors present in MSC-CM strongly activate oligodendrogenesis in postmitotic NPCs (Rivera et al, 2006b).…”

Section: Transplanted Mscs Induce Neuroprotection and Enhance Cns Remsupporting

confidence: 66%

Adult mesenchymal stem cell therapy for myelin repair in Multiple Sclerosis

Rivera¹,

Aigner²

2012

Biol. Res.

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Multiple sclerosis (MS) is a demyelinating immune-mediated disease of the central nervous system (CNS). It is the most frequent neurological disease in young adults and aff ects over 2 million people worldwide. Current treatments reduce the relapse rate and the formation of infl ammatory lesions in the CNS, but with only temporary and limited success. Despite the presence of endogenous oligodendroglial progenitors (OPCs) and of spontaneous remyelination, at least in early MS its levels and its qualities are apparently insuffi cient for a sustained endogenous functional repair. Therefore, novel MS therapies should consider not only immunemodulatory but also myelin repair activities. Mesenchymal stem cells (MSCs) represent an attractive alternative to develop a cell-based therapy for MS. MSCs display stromal features and exert bystander immunemodulatory and neuroprotective activities. Importantly, MSCs induce oligodendrocyte fate decision and diff erentiation/maturation of adult neural progenitors, suggesting the existence of MSC-derived remyelination activity. Moreover, transplanted MSCs promote functional recovery and myelin repair in diff erent MS animal models. Here, we summarize the current knowledge on endogenous mechanisms for remyelination and proposed autologous MSC therapy as a promising strategy for MS treatment.

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Section: Transplanted Mscs Induce Neuroprotection and Enhance Cns Remsupporting

confidence: 66%

Adult mesenchymal stem cell therapy for myelin repair in Multiple Sclerosis

Rivera¹,

Aigner²

2012

Biol. Res.

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“…Moreover, we demonstrated that MSCs promote oligodendroglial differentiation of NPCs that were co-transplanted into a hippocampal slice [23]. Thus, factors derived from MSCs strongly promote oligodendrogenesis of differentiating cells.…”

Section: Introductionmentioning

confidence: 75%

Mesenchymal Stem Cells Prime Proliferating Adult Neural Progenitors Toward an Oligodendrocyte Fate

Steffenhagen

Dechant

Oberbauer

et al. 2012

Stem Cells and Development

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Oligodendrogenesis encompasses lineage specification of neural progenitor cells (NPCs) and differentiation into oligodendrocytes that ultimately culminates in the myelination of central nervous system axons. Each individual process must be tightly regulated by extracellular and cell-intrinsic mechanisms, whose identities are barely understood. We had previously demonstrated that soluble factors derived from rat mesenchymal stem cells (MSCs) induce oligodendrogenesis in differentiating adult NPCs under differentiation conditions. However, since lineage specification predominantly occurs in proliferating progenitors and not necessarily during early differentiation, we investigated if soluble factors derived from MSCs are able to prime NPCs to the oligodendroglial fate already under proliferation conditions. Therefore, we analyzed the effects of a 3 weeks stimulation of adult NPCs under proliferation conditions with conditioned media derived from MSCs (MSC-CM) in terms of cell morphology, proliferation, cell-specific marker expression profile, response to growth factor withdrawal (GFW), cell-lineage restriction, and expression of glial fate determinants. While MSC-CM did not affect the proliferation rate of NPCs, it boosted the formation of 2¢, 3¢-cyclic-nucleotide-3¢-phosphodieesterase (CNPase)-and myelin basic protein-expressing oligodendrocytes after GFW, even when cells were exposed to an astrogenic milieu. Moreover, it reinforced the proper development of oligodendrocytes, since it ensured a sustained expression of the functional marker CNPase. Finally, the presence of MSC-CM reduced the anti-oligodendrogenic determinant Id2 in proliferating NPCs, thus increasing the relative proportion of the pro-oligodendrogenic factor Olig2 expression. In summary, MSCs prime proliferating progenitors and, thus, reinforce cell fate choice and accelerate differentiation toward the oligodendrocyte lineage. The present findings underscore the potential use of MSCs in cell therapies for remyelination such as in multiple sclerosis and spinal cord injury. Moreover, they urge the identification of the oligodendrogenic activity(ies) derived from MSCs to develop novel molecular therapies for demyelinating diseases.

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“…Consistent with our previous in vitro observations, significantly fewer transplanted NSCs expressed GFAP protein when p57kip2 was suppressed prior to transplantation. These modulated cells showed a significant induction of the oligodendroglial precursor marker GST- (Rivera et al, 2009) and tended to induce expression of the oligodendroglial marker CC1 [ Fig. 7A; representative pictures of injection site in the white matter (ISWM) shown in Fig.…”

Section: Transplantation Of P57kip2 Suppressed Stem Cellsmentioning

confidence: 99%

p57kip2 regulates glial fate decision in adult neural stem cells

et al. 2012

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SUMMARYOur recent studies revealed p57kip2 as an intrinsic regulator of late gliogenesis and demonstrated that in oligodendroglial precursor cells p57kip2 inhibition leads to accelerated maturation. Adult neural stem cells have been described as a source of glial progenitors; however, the underlying mechanisms of cell fate specification are still poorly understood. Here, we have investigated whether p57kip2 can influence early events of glial determination and differentiation. We found that Sox2/GFAP double-positive cells express p57kip2 in stem cell niches of the adult brain. Short-hairpin RNA-mediated suppression of p57kip2 in cultured adult neural stem cells was found to strongly reduce astroglial characteristics, while oligodendroglial precursor features were increased. Importantly, this anti-astrogenic effect of p57kip2 suppression dominated the bone morphogenetic protein-mediated promotion of astroglial differentiation. Moreover, we observed that in p57kip2 knockdown cells, the BMP antagonist chordin was induced. Finally, when p57kip2-suppressed stem cells were transplanted into the adult spinal cord, fewer GFAP-positive cells were generated and oligodendroglial markers were induced when compared with control cells, demonstrating an effect of in vivo relevance.

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Mesenchymal Stem Cells Promote Oligodendroglial Differentiation in Hippocampal Slice Cultures

Cited by 29 publications

References 28 publications

Adult mesenchymal stem cell therapy for myelin repair in Multiple Sclerosis

Adult mesenchymal stem cell therapy for myelin repair in Multiple Sclerosis

Mesenchymal Stem Cells Prime Proliferating Adult Neural Progenitors Toward an Oligodendrocyte Fate

p57kip2 regulates glial fate decision in adult neural stem cells

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