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The mammalian central nervous system (CNS) comprises two major stem cell niches: the subventricular zone (SVZ) lining the lateral ventricles (LV), and the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus, as depicted in the human brain (green and yellow areas on magnetic resonance images (MRI) in (A) and (B), respectively) and rodent brain (C); (D) The SVZ (coronal view) can be divided into different microdomains based on the progenies of neural stem cells (NSCs): whereas the dorsal domain (red) produces predominantly oligodendrocytes (OLs) and glutamatergic neurons, the lateral domain (blue) generates mainly GABAergic interneurons, and the medial domain is largely non-neurogenic after 2.5 months of life; (E) A detailed view of the lateral SVZ shows the microarchitecture of this niche, including self-renewing NSCs (Type B/SVZ astrocyte) that can give rise to transit-amplifying cells (Type C cells). These multipotent progenitors can produce neuroblasts (Type A cells) as well as glial cells, including OLs (Box I). Newly formed neuroblasts usually migrate along the rostral-migratory stream (RMS) to the olfactory bulb (OB), whereas cells determined to become OLs usually migrate into nearby white matter tracts; (F) A close-up view of the SGZ depicts how NSCs (Adult neural stem cells) within the hilus of the DG can self-renew or give rise to neurons that are incorporated into the granular cell layer (GCL). In addition to neuronal cells, NSCs within the SGZ also have the potential generate OLs.
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Irreversible functional deficits in multiple sclerosis (MS) are directly correlated to axonal damage and loss. Neurodegeneration results from immune-mediated destruction of myelin sheaths and subsequent axonal demyelination. Importantly, oligodendrocytes, the myelinating glial cells of the central nervous system, can be replaced to some extent to g...
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... more detailed analysis by Allen in 1912 already revealed that a thin layer of tissue surrounding the lateral ventricles is one of the most active sites of cell division in the postnatal CNS [28]. At that time he had thus discovered one of the two main germinal niches that persist in the adult mammalian brain, the subventricular zone (SVZ) of the lateral ventricle wall, the second niche being the subgranular zone (SGZ) in the dentate gyrus of the hippocampus (Figure 1) [29][30][31][32][33]. Both regions contain NSCs, which were found to share molecular and morphological hallmarks with astrocytes [34]. ...
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... 2016, 17, 1895 3 of 17 Figure 1. The mammalian central nervous system (CNS) comprises two major stem cell niches: the subventricular zone (SVZ) lining the lateral ventricles (LV), and the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus, as depicted in the human brain (green and yellow areas on magnetic resonance images (MRI) in (A) and (B), respectively) and rodent brain (C); (D) The SVZ (coronal view) can be divided into different microdomains based on the progenies of neural stem cells (NSCs): whereas the dorsal domain (red) produces predominantly oligodendrocytes (OLs) and glutamatergic neurons, the lateral domain (blue) generates mainly GABAergic interneurons, and the medial domain is largely non-neurogenic after 2.5 months of life; (E) A detailed view of the lateral SVZ shows the microarchitecture of this niche, including self-renewing NSCs (Type B/SVZ astrocyte) that can give rise to transit-amplifying cells (Type C cells). ...
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... walls of the lateral ventricle have different embryonic origins and, although once thought to be a homogeneous population, newer studies show that NSCs give rise to specific neuronal or glial subtypes depending on their time of generation and site of origin, that is the dorsal and lateral (also ventral) SVZ (Figure 1) [13,[67][68][69][70]. Microtransplantation experiments have shown that this fate restriction occurs early in development and is likely to be, at least partly, cell dependent as no re-specification occurs when cells are heterotopically transplanted [71][72][73]. Genome wide transcriptional studies of isolated NSCs from spatially distinct SVZ microdomains of the postnatal and young adult SVZ have been resolved [74,75]. ...
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... Injections of NSC into the central nervous systems (CNS) of mice and rats were investigated both directly and subcutaneously by the researchers [117,118]. Based on research NPCs transplanted into newborns successfully differentiated into oligodendrocytes, demonstrating their potential for restoring function after white matter inflammation (but not in nearby gray matter areas) [3,119]. ...
... Scaffolds and hydrogels can be made entirely of ECM components or modified to include ECM proteins or peptide derivatives [73,176]. A complex tissue replication may be created by modifying the extracellular matrix to produce stem cell and neuronal niches [88,119]. ...
Multiple sclerosis (MS) is an immunological and neurological disease of the central nervous system. Demyelination and neuronal death are the outcome of autoreactive T lymphocytes attacking the myelin sheath, resulting in functional neurological impairment. Relapses in MS are caused by extrinsic causes such as viral infections, although the disease's complicated etiology remains unexplained. Even though there are several disease-modifying drugs approved by the FDA for the treatment of multiple sclerosis (MS), none of them prevent inflammation from causing damage to the central nervous system (CNS) or encourage repair. This emphasizes the unmet clinical need for treatments that can halt and even reverse the increasing worsening of MS-related disability (P-MS). Transplantation of NSCs into the chronically inflamed CNS has been shown in preclinical research to give neurotrophic support and suppress harmful host immune responses in vivo. This article discusses the history and current applications of neural stem cell treatment for multiple sclerosis. The review also discusses the incorporation of these cells into existing brain structure and the risks involved in this therapy. Finally, the prospects of MS neural stem cell treatment are addressed, as well as its ethical concerns.
... The well documented effects of EGF on ODCs and OPCs include promoting the in vitro induction of SVZ ASTs to differentiate into migratory OPCs and ODCs [159,160], whereas anti-EGF antibodies (Abs) greatly reduce in vitro OPC migration, and silence EGF receptor activation [161]. EGF is, therefore, one of the most powerful and multifarious epigenetic chemical messengers determining the fate and maturation of NSCs, ASTs, and the OPC→ODC lineage, although other myelin-and/or ODC-trophic growth factors, such as platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), fibroblast growth factor, brain-derived neurotrophic factor, transforming growth factor-β, and ciliary neurotrophic factor, play a role in the differentiation and proliferation of the different CNS cell lineages [57,87,91,[162][163][164][165][166][167]. ...
... The CNS myelin status depends on the balance between myelin-building and myelindestroying factors located within ODCs and the ECM [56,154,164,170,202,216,218,[259][260][261][262][263][264][265][266][267][268][269][270][271]. The intrinsic factors and extrinsic factors that impose oligodendrogenic effects on NSCs and OPCs have been thoroughly reviewed [167,176]. Furthermore, physiological and repair myelination, and myelin maintenance in the CNS, require the correct expression and combination of various CNS growth factors and membrane-bound cell molecules, particularly integrins [272][273][274]. EGF increases NSC membrane levels of the β 1 -integrin,which is involved in axonal-glial interactions [275], Akt-dependent myelin wrapping [276], crosstalk with the Notch pathway [277], and interactions with several growth factors that regulate the number and development of ODCs in time and space [273], and control axonal ensheathment by ODCs [273,276]. ...
... The primary aim after severe CNS myelin insult and/or diseases (including MS) is to develop and reinforce the CNS regenerative capacity before resorting to stem cell transplantation. Mobilizing NSCs for CNS remyelination is a rather unexplored perspective in MS therapy [167,279], and EGF seems to be able to perform this task (see above). It is also clear that the basal approach to any successful remyelinating therapy is to identify ways of enhancing the endogenous remyelination process based on the precise knowledge of why the remyelination process fails in MS. ...
The pathogenesis of multiple sclerosis (MS) remains enigmatic and controversial. Myelin sheaths in the central nervous system (CNS) insulate axons and allow saltatory nerve conduction. MS brings about the destruction of myelin sheaths and the myelin-producing oligodendrocytes (ODCs). The conundrum of remyelination failure is, therefore, crucial in MS. In this review, the roles of epidermal growth factor (EGF), normal prions, and cobalamin in CNS myelinogenesis are briefly summarized. Thereafter, some findings of other authors and ourselves on MS and MS-like models are recapitulated, because they have shown that: (a) EGF is significantly decreased in the CNS of living or deceased MS patients; (b) its repeated administration to mice in various MS-models prevents demyelination and inflammatory reaction; (c) as was the case for EGF, normal prion levels are decreased in the MS CNS, with a strong correspondence between liquid and tissue levels; and (d) MS cobalamin levels are increased in the cerebrospinal fluid, but decreased in the spinal cord. In fact, no remyelination can occur in MS if these molecules (essential for any form of CNS myelination) are lacking. Lastly, other non-immunological MS abnormalities are reviewed. Together, these results have led to a critical reassessment of MS pathogenesis, partly because EGF has little or no role in immunology.
... Properly regulated astrocytes may provide neuroprotection, axonal guidance and vascular integrity after CNS injury 20 . Oligodendrocytes are myelinating glial cells that are important for neuronal electrical insulation, facilitating saltatory signal conduction 21 . Oligodendrocytes also provide the axons of neurons with metabolic and trophic support, including lactate, pyruvate and neurotrophic factors such as brain-derived neurotrophic factor (BDNF), via the myelin membrane 22 . ...
The differentiation of neural stem cells (NSCs) into neurons is proposed to be critical in devising potential cell-based therapeutic strategies for central nervous system (CNS) diseases, however, the determination and prediction of differentiation is complex and not yet clearly established, especially at the early stage. We hypothesize that deep learning could extract minutiae from large-scale datasets, and present a deep neural network model for predictable reliable identification of NSCs fate. Remarkably, using only bright field images without artificial labelling, our model is surprisingly effective at identifying the differentiated cell types, even as early as 1 day of culture. Moreover, our approach showcases superior precision and robustness in designed independent test scenarios involving various inducers, including neurotrophins, hormones, small molecule compounds and even nanoparticles, suggesting excellent generalizability and applicability. We anticipate that our accurate and robust deep learning-based platform for NSCs differentiation identification will accelerate the progress of NSCs applications. The differentiation of neural stem cells (NSCs) into neurons is a critical part in devising potential cell-based therapeutic strategies for central nervous system diseases but NSCs fate determination and prediction is problematic. Here, the authors present a deep neural network model for predictable reliable identification of NSCs fate.
... In demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis, myelin repair activities can be observed on the basis of recruitment, activation, and differentiation of resident precursor and stem cells [1]. Besides oligodendroglial precursor cells (OPCs), multipotent adult neural stem cells (aNSCs) located in the subventricular zone (SVZ) or the dentate gyrus of the hippocampus serve as an additional source for the generation of myelinating oligodendrocytes [2][3][4][5][6][7]. Yet, their regeneration capacity and overall degree of remyelination remains limited, which is likely a result of multiple extrinsic and intrinsic inhibitory factors [8][9][10][11][12][13][14]. ...
... In demyelinating diseases, neural stem cells can be actively recruited for myelin repair [1,[3][4][5][6][7]. However, despite of their ability to differentiate into oligodendrocytes, the extent of regeneration and remyelination in the adult CNS remains limited [11][12][13]. ...
Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far. In addition to missing information on active ingredients, the degree to which MSC-dependent lineage instruction is functional in vivo also remains to be established. We here demonstrate that MSC-derived factors can indeed stimulate oligodendrogenesis and myelin sheath generation of aNSCs transplanted into different rodent central nervous system (CNS) regions, and furthermore, we provide insights into the underlying mechanism on the basis of a comparative mass spectrometry secretome analysis. We identified a number of secreted proteins known to act on oligodendroglia lineage differentiation. Among them, the tissue inhibitor of metalloproteinase type 1 (TIMP-1) was revealed to be an active component of the MSC-conditioned medium, thus validating our chosen secretome approach.
... Similarly, Nestin + neural stem/progenitor cells (NSPCs) in the subventricular zone (SVZ) of the lateral ventricle are recruited and differentiate into OPCs to repair demyelinating lesions in the corpus callosum and adjacent white matter (Menn et al., 2006;Xing et al., 2014). These adult stem cells, as wells as OPCs or equivalent progenitors, are the targets of attempts at regenerative therapies that aim to induce endogenous myelin recovery in demyelinating and other neurological diseases (Akkermann et al., 2016;Franklin and Ffrench-Constant, 2008;Kang et al., 2013). However, the cellular kinetics and regulatory mechanisms of these cells in adult brain largely remain unknown. ...
Oligodendrocyte progenitor cells (OPCs) are widely distributed cells of ramified morphology in adult brain that express PDGFRα and NG2. They retain mitotic activities in adulthood and contribute to oligodendrogenesis and myelin turnover; however, the regulatory mechanisms of their cell dynamics in adult brain largely remain unknown. Here, we found that global Pdgfra inactivation in adult mice rapidly led to elimination of OPCs due to synchronous maturation toward oligodendrocytes. Surprisingly, OPC densities were robustly reconstituted by the active expansion of Nestin ⁺ immature cells activated in meninges and brain parenchyma, as well as a few OPCs that escaped from Pdgfra inactivation. The multipotent immature cells were induced in the meninges of Pdgfra-inactivated mice, but not of control mice. Our findings revealed powerful homeostatic control of adult OPCs, engaging dual cellular sources of adult OPC formation. These properties of the adult oligodendrocyte lineage and the alternative OPC source may be exploited in regenerative medicine.
... Both NSCs and OPCs contribute to the replacement of oligodendrocytes in EAE mice (Picard-Riera et al., 2002;Menn et al., 2006) and MS patients (Nait-Oumesmar et al., 1999. It is shown in cuprizone-treated mice that remyelination in the corpus callosum surrounding the SVZ results from NSC-derived OPCs rather than resident OPCs (Xing et al., 2014;Akkermann et al., 2016). In EAE animals, however, proliferation and differentiation of NSCs in the SVZ have a minor contribution in remyelination, as compared to the main effectors, resident OPCs (Grade et al., 2013). ...
Experimental autoimmune encephalomyelitis (EAE) is primarily used as an animal model of autoimmune demyelinating disease, multiple sclerosis. In this study, we found the proliferative rate of oligodendrocyte progenitor cells (OPCs) in the medulla elevated twofold above control levels during EAE and new generation of mature oligodendrocytes was increased as well. Although astrocytes showed hypertrophic reactive phenotype, a new generation of them was rare. Astrocyte- and tanycyte-like neural stem cells (NSCs), multipotent NSCs, did not augment their low proliferative rate. Thus, the present study demonstrates that resident OPCs derived from NSCs contribute to remyelination in the medulla oblongata in EAE mice.
... Both NSCs and OPCs contribute to the replacement of oligodendrocytes in EAE mice (Picard-Riera et al., 2002;Menn et al., 2006) and MS patients (Nait-Oumesmar et al., 1999. It is shown in cuprizone-treated mice that remyelination in the corpus callosum surrounding the SVZ results from NSC-derived OPCs rather than resident OPCs (Xing et al., 2014;Akkermann et al., 2016). In EAE animals, however, proliferation and differentiation of NSCs in the SVZ have a minor contribution in remyelination, as compared to the main effectors, resident OPCs (Grade et al., 2013). ...
Experimental autoimmune encephalomyelitis (EAE) is primarily used as an animal model of autoimmune demyelinating disease, multiple sclerosis. In this study, we found the proliferative rate of oligodendrocyte progenitor cells (OPCs) in the medulla elevated twofold above control levels during EAE and new generation of mature oligodendrocytes was increased as well. Although astrocytes showed hypertrophic reactive phenotype, a new generation of them was rare. Astrocyte- and tanycyte-like neural stem cells (NSCs), multipotent NSCs, did not augment their low proliferative rate. Thus, the present study demonstrates that resident OPCs derived from NSCs contribute to remyelination in the medulla oblongata in EAE mice.
... In contrast to the SVZ, SGZ NSCs appear to solely produce neurons unless genetically reprogrammed or trophically manipulated to induce oligodendrogenesis (Figure 2) (Rivera et al., 2006;Jessberger et al., 2008;Jadasz et al., 2012b;Steffenhagen et al., 2012;Chetty et al., 2014;Braun et al., 2015;Sun et al., 2015;Rolando et al., 2016). Besides those molecules known to exert pro-oligodendrogenic effects on both, parenchymal as well as on NSC-derived oligodendroglial lineages, several factors were identified which exclusively drive oligodendrogenesis from NSCs, a current compilation of which has recently been published (Akkermann et al., 2016). Importantly, it was demonstrated that SVZ NSC-derived OLs naturally and significantly contribute to remyelination in experimental demyelination such as observed in experimental autoimmune encephalomyelitis (EAE) or following cuprizone application (Menn et al., 2006;Aguirre et al., 2007;Mecha et al., 2013;Xing et al., 2014;Brousse et al., 2015). ...
... It will also be of interest to see whether molecules can be identified that enhance this regenerative capacity and to what degree NSC subpopulations show heterogeneous responses towards such stimulation. Whilst a number of factors have been identified which drive oligodendrogenesis in both NSCs as well as parenchymal OPCs a few were found to exert this effect on NSCs exclusively (Akkermann et al., 2016). This disparity in the responsiveness of these two cell populations, possibly reflecting differences in certain molecular profiles and pathways, may account for the heterogeneity in oligodendrogenesis between NSCs and OPCs. ...
... Given the endogenous capacity of NSCs to give rise to new myelinating OLs in response to demyelination, as well as the life-long potential of neurogenic niches for oligodendrogenesis pharmacological stimulation of this process is a promising strategy for the establishment of myelin repair approaches. Moreover, manipulation of NSCs has already been shown to effectively enhance remyelination in different contexts (Akkermann et al., 2016). While one study suggests that NSC progeny is capable of migrating some distances, subsequently taking on a glial fate in the MS brain (Nait- Oumesmar et al., 2007), the scattered and widespread distribution of lesions along great distances in this context still poses a problem in the process of myelin repair, particularly when taking into account the dimensions of the human CNS. ...
As ingenious as nature's invention of myelin sheaths within the mammalian nervous system is, as fatal can be damage to this specialized lipid structure. Long-term loss of electrical insulation and of further supportive functions myelin provides to axons, as seen in demyelinating diseases such as multiple sclerosis (MS), leads to neurodegeneration and results in progressive disabilities. Multiple lines of evidence have demonstrated the increasing inability of oligodendrocyte precursor cells (OPCs) to replace lost oligodendrocytes (OLs) in order to restore lost myelin. Much research has been dedicated to reveal potential reasons for this regeneration deficit but despite promising approaches no remyelination-promoting drugs have successfully been developed yet. In addition to OPCs neural stem cells of the adult central nervous system also hold a high potential to generate myelinating OLs. There are at least two neural stem cell niches in the brain, the subventricular zone lining the lateral ventricles and the subgranular zone of the dentate gyrus, and an additional source of neural stem cells has been located in the central canal of the spinal cord. While a substantial body of literature has described their neurogenic capacity, still little is known about the oligodendrogenic potential of these cells, even if some animal studies have provided proof of their contribution to remyelination. In this review, we summarize and discuss these studies, taking into account the different niches, the heterogeneity within and between stem cell niches and present current strategies of how to promote stem cell-mediated myelin repair.
... In contrast to the SVZ, SGZ NSCs appear to solely produce neurons unless genetically reprogrammed or trophically manipulated to induce oligodendrogenesis (Figure 2) (Rivera et al., 2006;Jessberger et al., 2008;Jadasz et al., 2012b;Steffenhagen et al., 2012;Chetty et al., 2014;Braun et al., 2015;Sun et al., 2015;Rolando et al., 2016). Besides those molecules known to exert pro-oligodendrogenic effects on both, parenchymal as well as on NSC-derived oligodendroglial lineages, several factors were identified which exclusively drive oligodendrogenesis from NSCs, a current compilation of which has recently been published (Akkermann et al., 2016). Importantly, it was demonstrated that SVZ NSC-derived OLs naturally and significantly contribute to remyelination in experimental demyelination such as observed in experimental autoimmune encephalomyelitis (EAE) or following cuprizone application (Menn et al., 2006;Aguirre et al., 2007;Mecha et al., 2013;Xing et al., 2014;Brousse et al., 2015). ...
... It will also be of interest to see whether molecules can be identified that enhance this regenerative capacity and to what degree NSC subpopulations show heterogeneous responses towards such stimulation. Whilst a number of factors have been identified which drive oligodendrogenesis in both NSCs as well as parenchymal OPCs a few were found to exert this effect on NSCs exclusively (Akkermann et al., 2016). This disparity in the responsiveness of these two cell populations, possibly reflecting differences in certain molecular profiles and pathways, may account for the heterogeneity in oligodendrogenesis between NSCs and OPCs. ...
... Given the endogenous capacity of NSCs to give rise to new myelinating OLs in response to demyelination, as well as the life-long potential of neurogenic niches for oligodendrogenesis pharmacological stimulation of this process is a promising strategy for the establishment of myelin repair approaches. Moreover, manipulation of NSCs has already been shown to effectively enhance remyelination in different contexts (Akkermann et al., 2016). While one study suggests that NSC progeny is capable of migrating some distances, subsequently taking on a glial fate in the MS brain (Nait-Oumesmar et al., 2007), the scattered and widespread distribution of lesions along great distances in this context still poses a problem in the process of myelin repair, particularly when taking into account the dimensions of the human CNS. ...
Schwann cells are the myelinating glial cells of the peripheral nervous system (PNS). By establishing lipid-rich myelin sheaths around large-caliber axons, they ensure that electrical signal transmission is accelerated–a process referred to as saltatory signal propagation. Apart from this prominent physiological function, these cells also exert important pathophysiological roles in PNS injuries or diseases. In contrast to the central nervous system (CNS), the adult PNS retains a remarkably high degree of intrinsic regeneration. As a consequence, transected axons and damaged myelin sheaths can be repaired and nerve functionality can be restored. This spontaneous regenerative capacity depends on (inter) actions of macrophages, neurons, and Schwann cells. Although highly specialized and tightly interacting with axons, Schwann cells can revert upon nerve injury or disease to an immature and repair-mediating phenotype (Arthur-Farraj et al., 2012). Dedifferentiated Schwann cells participate in myelin clearance and attract macrophages for further clearance, enabling Wallerian degeneration of distal nerve stumps to proceed. They were also shown to positively influence injured axons and to stimulate regrowth of their tips toward their target cells in the periphery. Finally, re-established axons can be wrapped up again by redifferentiating Schwann cells, thereby generating new isolating myelin sheaths. Thus, spontaneous peripheral nerve regeneration can be mainly attributed to Schwann cells and their particular and specific responses to trauma and disease. This is remarkable cell behavior and implies that these cells have a large capacity to switch and adjust their transcriptional programs, most likely by means of epigenetic controls (Jacob et al., 2011; Heinen et al., 2012). Moreover, multiple interactions with cells and components of the immune system were recently revealed (Tzekova et al., 2014).
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.
