Direct cell–cell contact with the vascular niche maintains quiescent neural stem cells

Ottone, Cristina; Krusche, Benjamin; Whitby, A.; Clements, Melanie; Quadrato, Giorgia; Pitulescu, Mara E.; Adams, Ralf H.; Parrinello, Simona

doi:10.1038/ncb3045

Cited by 240 publications

(258 citation statements)

References 53 publications

(72 reference statements)

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“…It is conceivable that ROS originating from dysfunctional mitochondria synergize with ROS produced by growth factor signaling, as NPCs are cultured in the presence of highly mitogenic growth factors. In vivo, elevated ROS levels within the highly vascular SVZ niche have been proposed to fuel NPC expansion via growth factor signaling (38,39). However, ROS can also lead to respiratory chain dysfunction via ROS-mediated damage to ETC components and mtDNA (30,(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

Bartesaghi

Graziano

Galavotti

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

Bartesaghi

Graziano

Galavotti

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…We further examined if this method allows us to distinguish between two distinct states, direct contact and noncontact with a small distance, in the context of forming cell-cell contact for intercellular communication studies (17,18). GJIC requires direct contact between cells, whereas communication that relies upon soluble factors is highly dependent upon the distance between the cells sending and receiving the signals.…”

Section: Resultsmentioning

confidence: 99%

Controlling cell–cell interactions using surface acoustic waves

Guo

French

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

353

257

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The interactions between pairs of cells and within multicellular assemblies are critical to many biological processes such as intercellular communication, tissue and organ formation, immunological reactions, and cancer metastasis. The ability to precisely control the position of cells relative to one another and within larger cellular assemblies will enable the investigation and characterization of phenomena not currently accessible by conventional in vitro methods. We present a versatile surface acoustic wave technique that is capable of controlling the intercellular distance and spatial arrangement of cells with micrometer level resolution. This technique is, to our knowledge, among the first of its kind to marry high precision and high throughput into a single extremely versatile and wholly biocompatible technology. We demonstrated the capabilities of the system to precisely control intercellular distance, assemble cells with defined geometries, maintain cellular assemblies in suspension, and translate these suspended assemblies to adherent states, all in a contactless, biocompatible manner. As an example of the power of this system, this technology was used to quantitatively investigate the gap junctional intercellular communication in several homotypic and heterotypic populations by visualizing the transfer of fluorescent dye between cells.cell-cell interaction | intercellular communication | surface acoustic waves | acoustic tweezers | acoustofluidics M ulticellular systems rely on the interaction between cells to coordinate cell signaling and regulate cell functions. Understanding the mechanism and process of cell-cell interaction is critical to many physiological and pathological processes, such as embryogenesis, differentiation, cancer metastasis, immunological interactions, and diabetes (1-3). Despite significant advances in this field, to further understand how cells interact and communicate with each other, a robust, biocompatible method to precisely control the spatial and temporal association of cells and to create defined cellular assemblies is urgently needed (4). Although several methods have been used to pattern cells, limitations still exist for the demonstrated methods including those that make use of optical, electrical, magnetic, hydrodynamic, and contact printing technologies (5-9). Firstly, most of the methods require modification of the cell's native state. The magnetic assembly method, for example, requires cells to be labeled with magnetic probes. Dielectrophoresis typically requires the use of a special medium (e.g., nonconductive) which may lack essential nutrients or have biophysical properties (such as the osmolality) that may adversely affect cell growth or physiology (6). Optical tweezers provide a label-free and contactless approach, but typically require high laser power to manipulate cells, leading to a high risk of cell damage (5). Secondly, the working principles of the existing technologies mostly preclude the combination of high precision and high throughput into a single ...

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“…Ephrin-mediated cellular contact between NSCs and their neighboring cells has been proposed to modulate the signaling involved in neurogenesis and NSC self-renewal in the adult brain. Endothelial cells form a critical part of the vasculature niche and involve SC maintenance [21]. Although the direct interactions, through either adherence or gap junctions, between the SCs and adjacent cells are not understood completely, it is believed that such interactions are important to more directly convey information to the SCs or to feedback to the microenvironment cells to participate in repairs or signal regulation.…”

Section: Cell-cell Interactionsmentioning

confidence: 99%

The role of the microenvironment on the fate of adult stem cells

Dong

Hao

Han

et al. 2015

Sci. China Life Sci.

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Adult stem cells (SCs) exist in all tissues that promote tissue growth, regeneration, and healing throughout life. The SC niche in which they reside provides signals that direct them to proliferate, differentiate, or remain dormant; these factors include neighboring cells, the extracellular matrix, soluble molecules, and physical stimuli. In disease and aging states, stable or transitory changes in the microenvironment can directly cause SC activation or inhibition in tissue healing as well as functional regulation. Here, we discuss the microenvironmental regulation of the behavior of SC and focus on plasticity approaches by which various environmental factors can enhance the function of SCs and more effectively direct the fate of SCs.

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Direct cell–cell contact with the vascular niche maintains quiescent neural stem cells

Cited by 240 publications

References 53 publications

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

Controlling cell–cell interactions using surface acoustic waves

The role of the microenvironment on the fate of adult stem cells

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