Institute for Stem Cell Research

Edinburgh, United Kingdom

Institute for Stem Cell Research

Edinburgh, United Kingdom
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Simon C.,Ludwig Maximilians University of Munich | Simon C.,Institute for Stem Cell Research | Gotz M.,Ludwig Maximilians University of Munich | Gotz M.,Institute for Stem Cell Research | And 2 more authors.
GLIA | Year: 2011

The adult brain parenchyma contains a widespread population of progenitors generating different cells of the oligodendrocyte lineage such as NG2+ cells and some mature oligodendrocytes. However, it is still largely unknown how proliferation and lineage decisions of these progenitors are regulated. Here, we first characterized the cell cycle length, proliferative fraction, and progeny of dividing cells in the adult cerebral cortex and then compared these proliferation characteristics after two distinct stimuli, invasive acute brain injury and increased physiological activity by voluntary physical exercise. Our data show that adult parenchymal progenitors have a very long cell cycle due to an extended G1 phase, many of them can divide at least twice and only a limited proportion of the progeny differentiates into mature oligodendrocytes. After stab wound injury, however, many of these progenitors re-enter the cell cycle very fast, suggesting that the normally long G1 phase is subject to regulation and can be abruptly shortened. In striking contrast, voluntary physical exercise shows the opposite effect with increased exit of the cell cycle followed by an enhanced and fast differentiation into mature oligodendrocytes. Taken together, our data demonstrate that the endogenous population of adult brain parenchymal progenitors is subject to profound modulation by environmental stimuli in both directions, either faster proliferation or faster differentiation. © 2011 Wiley-Liss, Inc.


Robel S.,Ludwig Maximilians University of Munich | Robel S.,Institute for Stem Cell Research | Robel S.,University of Alabama at Birmingham | Bardehle S.,Ludwig Maximilians University of Munich | And 5 more authors.
Journal of Neuroscience | Year: 2011

It is generally suggested that astrocytes play important restorative functions after brain injury, yet little is known regarding their recruitment to sites of injury, despite numerous in vitro experiments investigating astrocyte polarity. Here, we genetically manipulated one of the proposed key signals, the small RhoGTPase Cdc42, selectively in mouse astrocytes in vitro and in vivo. We used an in vitro scratch assay as a minimal wounding model and found that astrocytes lacking Cdc42 (Cdc42Δ) were still able to form protrusions, although in a nonoriented way. Consequently, they failed to migrate in a directed manner toward the scratch. When animals were injured in vivo through a stab wound, Cdc42Δastrocytes developed protrusions properly oriented toward the lesion, but thenumberof astrocytes recruited to the lesion site was significantly reduced. Surprisingly, however, lesions in Cdc42Δ animals, harboring fewer astrocytes contained significantly higher numbers of microglial cells than controls. These data suggest that impaired recruitment of astrocytes to sites of injury has a profound and unexpected effect on microglia recruitment. © 2011 the authors.


Behrendt G.,Ludwig Maximilians University of Munich | Baer K.,University of Swansea | Buffo A.,University of Turin | Curtis M.A.,University of Auckland | And 6 more authors.
GLIA | Year: 2013

Myelin loss is frequently observed in human Alzheimer's disease (AD) and may constitute to AD-related cognitive decline. A potential source to repair myelin defects are the oligodendrocyte progenitor cells (OPCs) present in an adult brain. However, until now, little is known about the reaction of these cells toward amyloid plaque deposition neither in human AD patients nor in the appropriate mouse models. Therefore, we analyzed cells of the oligodendrocyte lineage in a mouse model with chronic plaque deposition (APPPS1 mice) and samples from human patients. In APPPS1 mice defects in myelin integrity and myelin amount were prevalent at 6 months of age but normalized to control levels in 9-month-old mice. Concomitantly, we observed an increase in the proliferation and differentiation of OPCs in the APPPS1 mice at this specific time window (6-8 months) implying that improvements in myelin aberrations may result from repair mechanisms mediated by OPCs. However, while we observed a higher number of cells of the oligodendrocyte lineage (Olig2+ cells) in APPPS1 mice, OLIG2+ cells were decreased in number in postmortem human AD cortex. Our data demonstrate that oligodendrocyte progenitors specifically react to amyloid plaque deposition in an AD-related mouse model as well as in human AD pathology, although with distinct outcomes. Strikingly, possible repair mechanisms from newly generated oligodendrocytes are evident in APPPS1 mice, whereas a similar reaction of oligodendrocyte progenitors seems to be strongly limited in final stages of human AD pathology. © 2012 Wiley Periodicals, Inc.


Vigano F.,Ludwig Maximilians University of Munich | Vigano F.,Institute for Stem Cell Research | Vigano F.,University of Milan | Mobius W.,Max Planck Institute for Experimental Medicine | And 6 more authors.
Nature Neuroscience | Year: 2013

To examine the role of gray and white matter niches for oligodendrocyte differentiation, we used homo-and heterotopic transplantations into the adult mouse cerebral cortex. White matter-derived cells differentiated into mature oligodendrocytes in both niches with equal efficiency, whereas gray matter-derived cells did not. Thus, white matter promotes oligodendrocyte differentiation, and cells from this niche differentiate more easily, even in the less supportive gray matter environment. 2013 Nature America, Inc. All rights reserved.


Meek S.,Roslin Institute | Wei J.,Roslin Institute | Sutherland L.,Roslin Institute | Nilges B.,Roslin Institute | And 4 more authors.
Stem Cells | Year: 2013

Stabilization of β-catenin, through inhibition of glycogen synthase kinase 3 (GSK3) activity, in conjunction with inhibition of mitogen-activated protein kinase kinase 1/2 (MEK) promotes self-renewal of naïve-type mouse embryonic stem cells (ESC). In developmentally more advanced, primed-type, epiblast stem cells, however, β-catenin activity induces differentiation. We investigated the response of rat ESCs to β-catenin signaling and found that when maintained on feeder-support cells in the presence of a MEK inhibitor alone (1i culture), the derivation efficiency, growth, karyotypic stability, transcriptional profile, and differentiation potential of rat ESC cultures was similar to that of cell lines established using both MEK and GSK3 inhibitors (2i culture). Equivalent mouse ESCs, by comparison, differentiated in identical 1i conditions, consistent with insufficient β-catenin activity. This interspecies difference in reliance on GSK3 inhibition corresponded with higher overall levels of β-catenin activity in rat ESCs. Indeed, rat ESCs displayed widespread expression of the mesendoderm-associated β-catenin targets, Brachyury and Cdx2 in 2i medium, and overt differentiation upon further increases in β-catenin activity. In contrast, mouse ESCs were resistant to differentiation at similarly elevated doses of GSK3 inhibitor. Interestingly, without feeder support, moderate levels of GSK3 inhibition were necessary to support effective growth of rat ESC, confirming the conserved role for β-catenin in ESC self-renewal. This work identifies β-catenin signaling as a molecular rheostat in rat ESC, regulating self-renewal in a dose-dependent manner, and highlights the potential importance of controlling flux in this signaling pathway to achieve effective stabilization of naïve pluripotency. © AlphaMed Press.


Voronov D.,Scripps Research Institute | Gromova A.,Scripps Research Institute | Liu D.,Scripps Research Institute | Zoukhri D.,Tufts University | And 3 more authors.
Investigative Ophthalmology and Visual Science | Year: 2013

PURPOSE. Lacrimal gland (LG) morphogenesis and repair are regulated by a complex interplay of intrinsic factors (e.g., transcription factors) and extrinsic signals (e.g., soluble growth/ signaling factors). Many of these interconnections remain poorly characterized. Runt-related (Runx) factors belong to a small family of heterodimeric transcription factors known to regulate lineage-specific proliferation and differentiation of stem cells. The purpose of this study was to define the expression pattern and the role of Runx proteins in LG development and regeneration. METHODS. Expression of epithelial-restricted transcription factors in murine LG was examined using immunostaining, qRT-PCR, and RT2Profiler PCR microarrays. The role of Runx transcription factors in LG morphogenesis was studied using siRNA and ex vivo LG cultures. Expression of Runx transcription factors during LG regeneration was assessed using in vivo model of LG regeneration. RESULTS. We found that Runx factors are expressed in the epithelial compartment of the LG; in particular, Runx1 was restricted to the epithelium with highest level of expression in ductal and centroacinar cells. Downregulation of Runx1 to 3 expression using Runx-specific siRNAs abolished LG growth and branching and our data suggest that Runx1, 2, and 3 are partially redundant in LG development. In siRNA-treated LG, reduction of branching correlated with reduction of epithelial proliferation, as well as expression of cyclin D1 and the putative epithelial progenitor cell marker cytokeratin-5. Runx1, Runx3, and cytokeratin-5 expression increased significantly in regenerating LG and there was modest increase in Runx2 expression during LG differentiation. CONCLUSIONS. Runx1 and 2 are new markers of the LG epithelial lineage and Runx factors are important for normal LG morphogenesis and regeneration. © The Association for Research in Vision and Ophthalmology, Inc.


Simon C.,Ludwig Maximilians University of Munich | Simon C.,Institute for Stem Cell Research | Lickert H.,Institute for Stem Cell Research | Lickert H.,Institute of Diabetes and Regeneration Research | And 4 more authors.
Genesis | Year: 2012

SOX10 is a well-conserved and widely expressed transcription factor involved in the regulation of embryonic development and in the determination of cell fate. As it is expressed in neural crest cells, their derivatives and the oligodendrocyte lineage, mutations of the protein contribute to a variety of diseases like neurocristopathies, peripheral demyelinating neuropathies, and melanoma. Here, we report the generation of an inducible Sox10-iCreER T2 BAC transgenic mouse line that labels, depending on the timepoint of induction, distinct derivatives of the otic placode and the neural crest as well as cells of the oligodendrocyte lineage. Surprisingly, we could show a neural crest origin of pericytes in the brain. Besides its use for fate-mapping, the Sox10-iCreER T2 mouse line is a powerful tool to conditionally inactivate genes in the neural crest cells, their progeny and/or the oligodendrocyte lineage in a time-dependent fashion to gain further insights into their function and contribution to diseases. © 2011 Wiley Periodicals, Inc.


van den Berg D.L.C.,Erasmus University Rotterdam | Snoek T.,Erasmus University Rotterdam | Mullin N.P.,Institute for Stem Cell Research | Yates A.,Institute for Stem Cell Research | And 4 more authors.
Cell Stem Cell | Year: 2010

Transcription factors, such as Oct4, are critical for establishing and maintaining pluripotent cell identity. Whereas the genomic locations of several pluripotency transcription factors have been reported, the spectrum of their interaction partners is underexplored. Here, we use an improved affinity protocol to purify Oct4-interacting proteins from mouse embryonic stem cells (ESCs). Subsequent purification of Oct4 partners Sall4, Tcfcp2l1, Dax1, and Esrrb resulted in an Oct4 interactome of 166 proteins, including transcription factors and chromatin-modifying complexes with documented roles in self-renewal, but also many factors not previously associated with the ESC network. We find that Esrrb associated with the basal transcription machinery and also detect interactions between transcription factors and components of the TGF-β, Notch, and Wnt signaling pathways. Acute depletion of Oct4 reduced binding of Tcfcp2l1, Dax1, and Esrrb to several target genes. In conclusion, our purification protocol allowed us to bring greater definition to the circuitry controlling pluripotent cell identity. © 2010 Elsevier Inc. All rights reserved.


Villegas S.N.,Institute for Stem Cell Research | Canham M.,Institute for Stem Cell Research | Brickman J.M.,Institute for Stem Cell Research
Journal of Cellular Biochemistry | Year: 2010

The fibroblast growth factor (FGF) signalling pathway is one of the most ubiquitous in biology. It has diverse roles in development, differentiation and cancer. Embryonic stem (ES) cells are in vitro cell lines capable of differentiating into all the lineages of the conceptus. As such they have the capacity to differentiate into derivatives of all three germ layers and to some extent the extra-embryonic lineages as well. Given the prominent role of FGF signalling in early embryonic development, we explore the role of this pathway in early ES cell differentiation towards the major lineages of the embryo. As early embryonic differentiation is intricately choreographed at the level of morphogenetic movement, adherent ES cell culture affords a unique opportunity to study the basic steps in early lineage specification in the absence of ever shifting complex in vivo microenvironments. Thus recent experiments in ES cell differentiation are able to pinpoint specific FGF dependent lineage transitions that are difficult to resolve in vivo. Here we review the role of FGF signalling in early development alongside the ES cell data and suggest that FGF dependent signalling via phospho-Erk activation maybe a major mediator of transitions in lineage specification. © 2010 Wiley-Liss, Inc.


Dimou L.,Ludwig Maximilians University of Munich | Dimou L.,Institute for Stem Cell Research | Dimou L.,Synergy Systems | Gotz M.,Ludwig Maximilians University of Munich | And 2 more authors.
Physiological Reviews | Year: 2014

The diverse functions of glial cells prompt the question to which extent specific subtypes may be devoted to a specific function. We discuss this by reviewing one of the most recently discovered roles of glial cells, their function as neural stem cells (NSCs) and progenitor cells. First we give an overview of glial stem and progenitor cells during development; these are the radial glial cells that act as NSCs and other glial progenitors, highlighting the distinction between the lineage of cells in vivo and their potential when exposed to a different environment, e.g., in vitro. We then proceed to the adult stage and discuss the glial cells that continue to act as NSCs across vertebrates and others that are more lineage-restricted, such as the adult NG2-glia, the most frequent progenitor type in the adult mammalian brain, that remain within the oligodendrocyte lineage. Upon certain injury conditions, a distinct subset of quiescent astrocytes reactivates proliferation and a larger potential, clearly demonstrating the concept of heterogeneity with distinct subtypes of, e.g., astrocytes or NG2-glia performing rather different roles after brain injury. These new insights not only highlight the importance of glial cells for brain repair but also their great potential in various aspects of regeneration. © 2014 the American Physiological Society.

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