Violeta Vargas | Columbia University (original) (raw)

Papers by Violeta Vargas

Science, 2020

Human organoid cultures can be used to probe secretion and drug permeability into and out of the ... more Human organoid cultures can be used to probe secretion and drug permeability into and out of the brain

Quiescent neural stem cells (NSCs) in the adult ventricular-subventricular zone (V-SVZ) have a re... more Quiescent neural stem cells (NSCs) in the adult ventricular-subventricular zone (V-SVZ) have a regional identity and undergo activation to generate neurons. The domains for gliogenesis are less explored. Here we show that Platelet-Derived Growth Factor Receptor beta (PDGFRβ) is expressed by adult V-SVZ NSCs that generate olfactory bulb interneurons and glia with slow baseline kinetics. Selective deletion of PDGFRβ in adult V-SVZ NSCs leads to their release from quiescence uncovering multiple domains in the septal wall for oligodendrocyte and astrocyte formation. Unexpectedly, we identify a novel intraventricular oligodendrocyte progenitor inside the brain ventricles. Together our findings reveal different NSC spatial domains for gliogenesis in the adult V-SVZ that are largely quiescent under homeostasis and may have key functions for brain plasticity.

Cell Reports, 2019

The ventricular-subventricular zone (V-SVZ) harbors adult neural stem cells. V-SVZ neural stem ce... more The ventricular-subventricular zone (V-SVZ) harbors adult neural stem cells. V-SVZ neural stem cells exhibit features of astrocytes, have a regional identity, and depending on their location in the lateral or septal wall of the lateral ventricle, generate different types of neuronal and glial progeny. We performed large-scale single-cell RNA sequencing to provide a molecular atlas of cells from the lateral and septal adult V-SVZ of male and female mice. This revealed regional and sex differences among adult V-SVZ cells. We uncovered lineage potency bias at the single-cell level among lateral and septal wall astrocytes toward neurogenesis and oligodendrogenesis, respectively. Finally, we identified transcription factor co-expression modules marking key temporal steps in neurogenic and oligodendrocyte lineage progression. Our data suggest functionally important spatial diversity in neurogenesis and oligodendrogenesis in the adult brain and reveal molecular correlates of adult NSC dormancy and lineage specialization.

Acta Neuropathologica, 2018

The barrier between the blood and the ventricular cerebrospinal fluid (CSF) is located at the cho... more The barrier between the blood and the ventricular cerebrospinal fluid (CSF) is located at the choroid plexuses. At the interface between two circulating fluids, these richly vascularized veil-like structures display a peculiar morphology explained by their developmental origin, and fulfill several functions essential for CNS homeostasis. They form a neuroprotective barrier preventing the accumulation of noxious compounds into the CSF and brain, and secrete CSF, which participates in the maintenance of a stable CNS internal environment. The CSF circulation plays an important role in volume transmission within the developing and adult brain, and CSF compartments are key to the immune surveillance of the CNS. In these contexts, the choroid plexuses are an important source of biologically active molecules involved in brain development, stem cell proliferation and differentiation, and brain repair. By sensing both physiological changes in brain homeostasis and peripheral or central insults such as inflammation, they also act as sentinels for the CNS. Finally, their role in the control of immune cell traffic between the blood and the CSF confers on the choroid plexuses a function in neuroimmune regulation and implicates them in neuroinflammation. The choroid plexuses, therefore, deserve more attention while investigating the pathophysiology of CNS diseases and related comorbidities.

Neuron, Jan 18, 2018

Obernier et al. (2018) show that the primary mode of division of adult ventricular-subventricular... more Obernier et al. (2018) show that the primary mode of division of adult ventricular-subventricular zone (V-SVZ) neural stem cells is symmetric, with the majority generating two non-stem cell progeny, and a minority self-renewing. This discovery has important implications for understanding stem cell dynamics and adult neurogenesis.

Stem cell reports, May 19, 2017

Characterization of non-neoplastic and malignant human stem cell populations in their native stat... more Characterization of non-neoplastic and malignant human stem cell populations in their native state can provide new insights into gliomagenesis. Here we developed a purification strategy to directly isolate EGFR(+/-) populations from human germinal matrix (GM) and adult subventricular zone autopsy tissues, and from de novo glioblastoma (GBM) resections, enriching for cells capable of binding EGF ligand ((LB)EGFR(+)), and uniquely compared their functional and molecular properties. (LB)EGFR(+) populations in both GM and GBM encompassed all sphere-forming cells and displayed proliferative stem cell properties in vitro. In xenografts, (LB)EGFR(+) GBM cells showed robust tumor initiation and progression to high-grade, infiltrative gliomas. Whole-transcriptome sequencing analysis confirmed enrichment of proliferative pathways in both developing and neoplastic freshly isolated EGFR(+) populations, and identified both unique and shared sets of genes. The ability to prospectively isolate ste...

Cell Stem Cell, 2016

Highlights d The lateral ventricle choroid plexus is a novel component of the adult V-SVZ niche d... more Highlights d The lateral ventricle choroid plexus is a novel component of the adult V-SVZ niche d LVCP secretome supports the recruitment and proliferation of NSCs and their progeny d NSCs are especially sensitive to age-dependent changes in the LVCP secretome d Transcriptome analysis reveals novel facets of LVCP biology

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 18, 2015

Adult neural stem cells reside in specialized niches. In the ventricular-subventricular zone (V-S... more Adult neural stem cells reside in specialized niches. In the ventricular-subventricular zone (V-SVZ), quiescent neural stem cells (qNSCs) become activated (aNSCs), and generate transit amplifying cells (TACs), which give rise to neuroblasts that migrate to the olfactory bulb. The vasculature is an important component of the adult neural stem cell niche, but whether vascular cells in neurogenic areas are intrinsically different from those elsewhere in the brain is unknown. Moreover, the contribution of pericytes to the neural stem cell niche has not been defined. Here, we describe a rapid FACS purification strategy to simultaneously isolate primary endothelial cells and pericytes from brain microregions of nontransgenic mice using CD31 and CD13 as surface markers. We compared the effect of purified vascular cells from a neurogenic (V-SVZ) and non-neurogenic brain region (cortex) on the V-SVZ stem cell lineage in vitro. Endothelial and pericyte diffusible signals from both regions dif...

Neuron, 2014

A major question in studying adult neurogenesis is the source and identity of molecules that regu... more A major question in studying adult neurogenesis is the source and identity of molecules that regulate stem cells. In this issue of Neuron, Delgado et al. (2014) uncover that endothelial-derived NT-3 acts as a mediator of quiescence in the V-SVZ adult neural stem cell niche.

Current Opinion in Neurobiology, 2013

Stem cells persist in specialized niches in the adult mammalian brain. Emerging findings highligh... more Stem cells persist in specialized niches in the adult mammalian brain. Emerging findings highlight the complexity and heterogeneity of different compartments in the niche, as well as the presence of local signaling microdomains. Stem cell quiescence and activation are regulated not only by anchorage to the niche and diffusible signals, but also by biophysical properties, including fluid dynamics. Importantly, the adult neural stem cell niche integrates both local and systemic changes, reflecting the physiological state of the organism. Moreover niche signaling is bidirectional, with stem cells and their progeny and niche cells dynamically interacting with each other during homeostasis, regeneration and aging.

Cell Stem Cell, 2008

Stem cells reside in specialized niches that regulate their self-renewal and differentiation. The... more Stem cells reside in specialized niches that regulate their self-renewal and differentiation. The vasculature is emerging as an important component of stem cell niches. Here, we show that the adult subventricular zone (SVZ) neural stem cell niche contains an extensive planar vascular plexus that has specialized properties. Dividing stem cells and their transitamplifying progeny are tightly apposed to SVZ blood vessels both during homeostasis and regeneration. They frequently contact the vasculature at sites that lack astrocyte endfeet and pericyte coverage, a modification of the blood-brain barrier unique to the SVZ. Moreover, regeneration often occurs at these sites. Finally, we find that circulating small molecules in the blood enter the SVZ. Thus, the vasculature is a key component of the adult SVZ neural stem cell niche, with SVZ stem cells and transit-amplifying cells uniquely poised to receive spatial cues and regulatory signals from diverse elements of the vascular system.

Cell Stem Cell, 2011

A. (2005). Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol.... more A. (2005). Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol. 3, e283.

Journal of Investigative Dermatology, 2005

There are conflicting reports of the consequences of deleting b1 integrins from the epidermis of ... more There are conflicting reports of the consequences of deleting b1 integrins from the epidermis of transgenic mice. Epidermal thinning with normal differentiation and lack of inflammation has been observed; conversely, epidermal thickening, abnormal differentiation, and dermal fibrosis can occur. b1 integrin deletion results in decreased epidermal proliferation, yet on wounding the proliferative defect is overcome. To distinguish primary from secondary consequences of b1 integrin loss, we compared epidermal b1 deletion at E14.5 via K5Cre and 4-hydroxy-tamoxifen induced deletion in adulthood via K14CreER. As reported previously, there was dermo-epidermal splitting, inflammation, reduced proliferation, and hair follicle and sebaceous gland loss in 30-d-old K5Cre b1-null mice. These changes were not observed 30 d after b1 integrin deletion in adult epidermis, however, and there were no changes in the hair follicle stem cell compartment. Deletion in adult epidermis revealed a previously unreported correlation between the level of b1 integrins and proliferation in the interfollicular epidermis that was remarkably consistent with human epidermis. In addition, the number of melanocytes in interfollicular epidermis was greatly increased. Our results highlight the context-dependent effects of b1 integrin deletion and suggest that inflammation may be responsible for some of the K5Cre b1-null phenotype.

Developmental Cell, 2005

man, 2001), and it has been proposed that stem cells in a particular location normally feed a res... more man, 2001), and it has been proposed that stem cells in a particular location normally feed a restricted num-Keratinocyte Laboratory Cancer Research UK London Research Institute ber of lineages in response to local signals (Niemann and Watt, 2002). As in other tissues, it is the combina-44 Lincoln's Inn Fields London WC2A 3PX tion of the intrinsic characteristics of the stem cells and their microenvironment that shapes their properties and United Kingdom defines their fate (Fuchs et al., 2004; Wagers and Weissman, 2004). A range of Wnts, their receptors, and antagonists are Summary expressed dynamically within the epidermis (Millar, 2002). Epidermal expression of N-terminally truncated, Using K14⌬N␤-cateninER transgenic mice, we show activated β-catenin leads first to induction of hair that short-term, low-level ␤-catenin activation stimugrowth (anagen), then to de novo HF formation from the lates de novo hair follicle formation from sebaceous IFE, SG, and preexisting HF (Gat et al., 1998; Lo Celso glands and interfollicular epidermis, while only suset al., 2004; Van Mater et al., 2003). Conversely, when tained, high-level activation induces new follicles β-catenin signaling is inhibited, new HF formation is from preexisting follicles. The Hedgehog pathway is prevented, growth of existing HF is disturbed, and folliupregulated by ␤-catenin activation, and inhibition of cles develop cysts of IFE with associated sebocytes Hedgehog signaling converts the low ␤-catenin phe-(Niemann and Watt, 2002; Fuchs et al., 2004). These notype to wild-type epidermis and the high phenotype studies clearly show that β-catenin can control epiderto low. ␤-catenin-induced follicles contain clonogenic mal lineage commitment in the adult tissue. High levels keratinocytes that express bulge markers; the follistimulate HF formation, intermediate levels favor sebocles induce dermal papillae and provide a niche for cyte differentiation, and low levels convert HF into IFE melanocytes, and they undergo 4OHT-dependent cy-(Niemann and Watt, 2002). cles of growth and regression. New follicles induced In normal epidermis, Shh expression is restricted to in interfollicular epidermis are derived from that celluthe base of anagen hair follicles and inhibition of Shh lar compartment and not through bulge stem cell blocks anagen (Oro and Higgins, 2003). When activated migration or division. These results demonstrate the β-catenin is overexpressed in the epidermis, upregularemarkable capacity of adult epidermis to be reprotion of Shh and Ptc occurs where new follicles form grammed by titrating ␤-catenin and Hedgehog signal (Gat et al., 1998; Lo Celso et al., 2004). Whereas β-catstrength and establish that cells from interfollicular enin regulates lineage choice, Shh is primarily a prolifepidermis can acquire certain characteristics of bulge erative stimulus, mediated at least in part by direct instem cells. duction of cell-cycle regulators such as cyclin D and cyclin E (Duman-Scheel et al., 2002).

Development, 2003

Mammalian epidermis is maintained by stem cells that have the ability to self-renew and generate ... more Mammalian epidermis is maintained by stem cells that have the ability to self-renew and generate daughter cells that differentiate along the lineages of the hair follicles, interfollicular epidermis and sebaceous gland. As stem cells divide infrequently in adult mouse epidermis, they can be visualised as DNA label-retaining cells (LRC). With whole-mount labelling, we can examine large areas of interfollicular epidermis and many hair follicles simultaneously, enabling us to evaluate stem cell markers and examine the effects of different stimuli on the LRC population. LRC are not confined to the hair follicle, but also lie in sebaceous glands and interfollicular epidermis. LRC reside throughout the permanent region of the hair follicle,where they express keratin 15 and lie in a region of high α6β4 integrin expression. LRC are not significantly depleted by successive hair growth cycles. They can, nevertheless, be stimulated to divide by treatment with phorbol ester, resulting in near c...

Journal of Investigative Dermatology, 2004

Epidermal activation of Erk MAPK is observed in human psoriatic lesions and in a mouse model of p... more Epidermal activation of Erk MAPK is observed in human psoriatic lesions and in a mouse model of psoriasis in which b1 integrins are expressed in the suprabasal epidermal layers. Constitutive activation of the upstream kinase MEK1 causes hyperproliferation and perturbed differentiation of human keratinocytes in culture. It is not known, however, whether Erk activation in differentiating keratinocytes is sufficient to trigger hyperproliferation of basal keratinocytes and a skin inflammatory infiltrate. To investigate this, we expressed constitutively active MEK1 in the suprabasal epidermal layers of transgenic mice. Proliferation in the epidermal basal layer was stimulated and epidermal terminal differentiation was perturbed. Some older mice also developed papillomas. There was a large increase in T lymphocytes, dendritic cells, and neutrophils in the skin. The effects of suprabasal MEK1 on basal keratinocytes and leukocytes, cells that were transgene negative, suggested that MEK1 activity might stimulate cytokine release. Transgenic keratinocytes expressed elevated IL-1a and crossing the mice with mice overexpressing the IL-1 receptor in the epidermal basal layer led to exacerbated hyperproliferation and inflammation. These data suggest that activation of MEK1 downstream of b1 integrins plays an important role in epidermal hyperproliferation and skin inflammation.

Current Opinion in Genetics & Development, 2006

The mammalian epidermis is a highly accessible tissue in which to study the properties of adult s... more The mammalian epidermis is a highly accessible tissue in which to study the properties of adult stem cells. Global gene expression profiling has revealed new markers and regulators of the stem cell compartment. Although stem cells have the potential to differentiate into multiple lineages, their progeny follow a more restricted number of lineages in undamaged epidermis as a result of local microenvironmental cues. The response of the epidermis to a particular signal depends on signal strength and duration. Recent advances in the field have led to elucidation of the mechanisms by which stem cells are maintained and the pathways that interact with Wnt signalling to specify lineage choice as cells leave the stem cell compartment. This work has also yielded new insights into skin tumour development.

Science, 2021

Gliogenesis in the adult mouse brain Neural stem cells in the adult mouse brain can generate both... more Gliogenesis in the adult mouse brain Neural stem cells in the adult mouse brain can generate both neurons and glia. Exactly where each stem cell is positioned can determine what type of neurons it generates. Delgado et al. show that neural stem cells are also choosy about what sorts of glia they make and when (see the Perspective by Baldwin and Silver). Injury or selective deletion of platelet-derived growth factor receptor β (PDGFRβ) from the stem cells kicked them into overdrive and revealed their selectivity with respect to gliogenesis. An unusual type of glial progenitor cell, intraventricular oligodendrocyte progenitors, are found nestled between the cilia of ependymal cells derived from tight clusters of PDGFRβ-expressing stem cells. Science , abg8467, this issue p. 1205 ; see also abj1139, p. 1151