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Live Imaging of Adult Neural Stem Cells in Rodents REVIEW published: 07 March 2016 doi: 10.3389/fnins.2016.00078 Live Imaging of Adult Neural Stem Cells in Rodents Felipe Ortega 1* and Marcos R. Costa 2 1 Biochemistry and Molecular Biology Department, Faculty of Veterinary Medicine, Complutense University, Madrid, Spain, 2 Brain Institute, Federal University of Rio Grande do Norte, Natal, Brazil The generation of cells of the neural lineage within the brain is not restricted to early development. New neurons, oligodendrocytes, and astrocytes are produced in the adult brain throughout the entire murine life. However, despite the extensive research performed in the field of adult neurogenesis during the past years, fundamental questions regarding the cell biology of adult neural stem cells (aNSCs) remain to be uncovered. For instance, it is crucial to elucidate whether a single aNSC is capable of differentiating into all three different macroglial cell types in vivo or these distinct progenies constitute entirely separate lineages. Similarly, the cell cycle length, the time and mode of division (symmetric vs. asymmetric) that these cells undergo within their lineage progression are interesting questions under current investigation. In this sense, live imaging constitutes a valuable ally in the search of reliable answers to the previous questions. In spite of the Edited by: current limitations of technology new approaches are being developed and outstanding Laura López-Mascaraque, amount of knowledge is being piled up providing interesting insights in the behavior of Instituto Cajal- Consejo Superior de Investigaciones Científicas, Spain aNSCs. Here, we will review the state of the art of live imaging as well as the alternative Reviewed by: models that currently offer new answers to critical questions. Olivier Raineteau, Institut National de la Santé et de la Keywords: live imaging, aNSCs, neurogenic niches, timelapse videomicroscopy, lineage tracing Recherche Médicale - Université de Lyon, France Carlos Vicario-Abejón, INTRODUCTION Instituto Cajal, Consejo Superior de Investigaciones Científicas, Spain Current Knowledge of the Cytoarchitecture of the Adult *Correspondence: Neurogenic Niches; Subependymal Zone and Dentate Gyrus Felipe Ortega Stem Cells are defined by their ability to self-renew, giving rise to new stem cells, and their [email protected] capacity to generate diverse specialized cell types. In the adult nervous system, the term neural stem cells (NSCs) refers to cells that maintain the capacity to self-renew and generate neurons Specialty section: and macroglial cells both in vitro (Reynolds and Weiss, 1996; Costa et al., 2011) and in vivo This article was submitted to (Lois and Alvarez-Buylla, 1993; Gould and Cameron, 1996; Kempermann et al., 1997; Menn Neurogenesis, et al., 2006; Sohn et al., 2015). Adult neural stem cells (aNSCs) continuously generate neurons a section of the journal Frontiers in Neuroscience oligodendrocytes and astrocytes in discrete niches in the brain, although it is unclear whether multipotent or unipotent aNSCs contribute all these different lineages. Historically, the adult Received: 14 December 2015 neurogenesis has been associated, under physiological conditions, to two specific neurogenic Accepted: 18 February 2016 Published: 07 March 2016 niches: the subependymal zone (SEZ) in the lateral wall of the lateral ventricle, and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus reviewed by Gage (2000) and Kriegstein Citation: Ortega F and Costa MR (2016) Live and Alvarez-Buylla (2009). However, the presence of aNSCs in alternative domains of the adult Imaging of Adult Neural Stem Cells in brain should not be discarded. Indeed, multipotent progenitors have been isolated from the Rodents. Front. Neurosci. 10:78. postnatal mouse cerebral cortex (Marmur et al., 1998; Belachew et al., 2003; Seaberg et al., doi: 10.3389/fnins.2016.00078 2005; Costa et al., 2007) or adult mouse cerebral cortex after traumatic and ischemic lesion Frontiers in Neuroscience | www.frontiersin.org 1 March 2016 | Volume 10 | Article 78 Ortega and Costa Live-Imaging of aNSCs in Rodents (Buffo et al., 2008; Sirko et al., 2013). Another interesting adult transit amplifying progenitors (TAPs; Pastrana et al., 2009; Costa domain described to contain NSCs is the inner core of the et al., 2011). TAPs are more active in proliferation, undergoing olfactory bulb (OB) of both rodents and humans. Populations of several rounds of amplifying divisions (Costa et al., 2011; Ponti NSCs expressing GFAP, Nestin, Sox2, and RC2 are located within et al., 2013) before giving rise to neuroblasts or Type A cells. the adult OB giving rise to neurons in vivo. Likewise they can Subsequently, neuroblasts form a chain migrating along the be expanded in vitro as neurospheres, giving rise to astrocytes, rostral migratory stream toward the olfactory bulb (Lois et al., oligodendrocytes and neurons. (Pagano et al., 2000; Gritti et al., 1996). After reaching the olfactory bulb neuroblasts differentiate 2002; Liu and Martin, 2003; Giachino and Taylor, 2009; Vergano- into different subtypes of neurons (Lledo et al., 2006; Fiorelli Vera et al., 2009; Moreno-Estelles et al., 2012). The same is et al., 2015). The majority becomes GABAergic granule neurons applied for human temporal and frontal cortex, amygdala and and a minority becomes GABAergic periglomerular neurons. hippocampus after resection due to a drug-resistant epilepsy, In addition, a small percentage of neuroblasts, generated in dysplasia, trauma, or brain edema (Arsenijevic et al., 2001). the dorsal wall of the SEZ, turn into short-axon glutamatergic, More recent evidence indicate that lesions may activate those or GABAergic juxtaglomerular neurons (Kosaka and Kosaka, “dormant” aNSCs through release of signaling molecules such 2008; Brill et al., 2009; Kiyokage et al., 2010) Moreover, at least as vascular endothelial growth factor (VEGF), basic fibroblast four subtypes of OB interneurons are generated at the anterior growth factor (bGFG), and sonic hedgehog (SHH; Sirko et al., ventral SEZ, arising from microdomains that correlate with the 2013; Luo et al., 2015). Contribution of these quiescent aNSCs expression domains of the Nkx6.2 and Zic family of transcription to a possible periodical and so far unnoticed turnover of their factors (Merkle et al., 2014). associated neuronal populations remains to be demonstrated Specific molecular markers to identify type B cells population Figure 1. have not been available for a long time. However recent Focusing on the two main neurogenic niches of the adult publications employed interesting combinations of markers brain, the SEZ harbors a population of aNSCs, known as type to differentiate between quiescent and activated type B cells, B cells, located beneath the ependymal cell layer of the lateral allowing for their isolation. Vascular cell adhesion molecule 1 (V- ventricles (Doetsch et al., 1999a,b). Type B has been proposed CAM1) has been recently described as a marker for quiescent to share a common lineage with embryonic radial glia (RG) type B cells (Kokovay et al., 2012). Likewise, combination of (Merkle et al., 2004). However, whether type B cells constitute the GFAP, prominin1 and the absence or presence of Epidermal endpoint or RG lineage progression or whether the divergence growth factor (EGF) receptors has been suggested as a valid arrives earlier is a matter of debate. Recent research went into approach for isolation of quiescent and activated type B cells, detail about the relationship between RG and aNSCs (Fuentealba respectively (Beckervordersandforth et al., 2010; Codega et al., et al., 2015; Furutachi et al., 2015). Interestingly, evidences 2014). The use of EGF fluorescent ligands, combined with the suggest that RG give rise to a subset of progenitors named CD24 (Calaora et al., 1996) and GFAP expression has also been pre-B1 cells at early stages of embryonic neural development employed to successfully isolate aNSCs and their progeny from (E 13.5-E 15.5). Pre-B1 cells remain quiescent until adulthood the SEZ (Pastrana et al., 2009). Along the same line, Daynac et al. when they become reactivated. Furutachi and colleagues, points (2015) employed a triple staining based on the stem cell marker to the slowing down of the cell cycle of a subset of RG as the Lewis X (LeX/ssea 1) (Capela and Temple, 2002), EGFR and responsible for the origin to the adult pool of NSCs. Moreover, the neuroblast marker CD24 to isolate the different populations the cyclin-dependent kinase inhibitor p57 is proposed as the key comprised within the lineage progression. regulator of the RG cell cycle. Selective deletion of p57 blocked Adult SEZ does not only provide the olfactory bulb with the deceleration of the cell cycle, impairing the emergence of new neurons. In this region, astrocytes and oligodendrocytes are adult NSCs. These evidences are also supported by long-term also generated and migrate toward the corpus callosum, rostral in vivo experiments that described, using the STARTRACK migratory stream, white matter tracts of the striatum and the tracing system, the presence of adult progenitors with embryonic fimbria fornix, under both physiological conditions (Hack et al., origins (E-14), remaining as small, round and quiescent cells 2005; Menn et al., 2006; Gonzalez-Perez and Alvarez-Buylla, on the SEZ (Garcia-Marques and Lopez-Mascaraque, 2013). 2011; Sohn et al., 2015; Tong et al., 2015), and demyelinating Type B cells are characterized by the expression of astroglial pathologies (Picard-Riera et al.,
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