Neural Stem Cell Institute

Rensselaer, NY, United States

Neural Stem Cell Institute

Rensselaer, NY, United States
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News Article | April 18, 2017

Researchers have found a protein in the blood of human umbilical cords that improves memory and learning in old mice. The provocative finding joins a flurry of other recent, sometimes controversial work attempting to find factors that explain the apparent antiaging properties of young blood. “These are exciting results,” says Sally Temple, scientific director of the Neural Stem Cell Institute in Rensselaer, New York, who was not involved with the work. She and others say the new finding suggests that this and other factors in young blood may have different, complementary effects on the aging brain. Decades ago in somewhat grisly experiments, researchers found that sewing together the circulatory systems of an old and young mouse so that they shared the same blood supply rejuvenated the old animals. In 2014, as part of renewed interest in this unusual procedure, known as parabiosis, neuroscientist Tony Wyss-Coray’s lab at Stanford University in Palo Alto, California, reported that it could mimic some of the brain-boosting effects of parabiosis with injections of young mouse plasma, the cell-free part of blood. Identifying the responsible factors in such blood is a challenge, however. Because mice are so tiny, it’s hard to collect enough mouse plasma to do biochemical and other analyses. As an alternative, Wyss-Coray’s lab recently tested the youngest human blood available—umbilical cord blood, which is traditionally thrown away after a birth but has become increasingly prized as physicians explore its therapeutic uses. In the new work, Wyss-Coray’s group gave human cord blood plasma to mice of varying ages that had defective immune systems and so did not reject the foreign human tissue. Like young mouse plasma, human cord plasma injected every 4 days for 2 weeks into the circulation activated neurons in old mice’s hippocampi, where memories are made and stored. (This activation did not happen in the hippocampi of young mice treated with cord blood.) After the injections, the aging animals also navigated a maze more quickly and performed better on other tests of learning and memory, Wyss-Coray’s team reports today in  . The team then looked for blood proteins that are abundant in human cords but decline in the general circulation with age. They ultimately homed in one called TIMP2, which was previously known to control the production of enzymes that chop up the matrix around cells and play a role in wound healing as well as the spread of cancer. (Its full name is tissue metallopeptidase inhibitor 2.) Old mice injected with mouse TIMP2 scored almost as well on memory tests as those given cord plasma, although they still didn’t match the cognitive skills of young mice, Wyss-Coray says. To help clinch its case for TIMP2, the Stanford group also showed that cord blood depleted of TIMP2 did nothing for old mice, and blocking TIMP2 in young mice impaired their memory. The researchers’ search for antiaging factors did not point to another protein, GDF11, which some scientists have reported stimulates the growth of new blood vessels and neural stem cells in the brain. (Another claim—that GDF11 rejuvenates muscle—has been hotly contested by several labs, partly because their studies suggest GDF11 levels rise with age.) But Wyss-Coray says the new study does not rule out a role for GDF11 in the brain. Harvard University neuroscientist Lee Rubin, who co-led the GDF11 brain study, says the new findings suggest “it isn’t just one thing. A lot of individual factors in blood can improve function.” Indeed, one might want to combine GDF11 and TIMP2 treatments to both generate new neurons and “get the most out of the cells that are there,” Temple suggests. Some experts are less impressed by the study. Parabiosis researcher Irina Conboy of the University of California, Berkeley, notes that the paper doesn’t put the modest memory and learning improvements from TIMP2 in context by comparing them to, say, putting an old mouse on an exercise wheel, which can also improve cognitive function. Her own work suggests that the apparent antiaging effects of young blood may reflect the fact that it contains less of certain factors in old blood that her lab and others have reported contribute to aging. Stanford has filed for patents on using TIMP2 to treat aging-associated conditions, and Alkahest, a company in San Carlos, California, that Wyss-Coray co-founded, plans to develop it. An Alkahest-sponsored trial at Stanford testing young human plasma as a treatment in 18 Alzheimer’s disease patients ended in January; results will be presented at a meeting in November, says Alkahest CEO Karoly Nikolich. (Rubin serves on Alkahest’s advisory board.) Meanwhile, some clinics are already offering young blood injections to reverse aging in people. But Wyss-Coray and others say such treatments are premature.

Gay L.,University of Oregon | Gay L.,Howard Hughes Medical Institute | Miller M.R.,University of Oregon | Miller M.R.,Howard Hughes Medical Institute | And 9 more authors.
Genes and Development | Year: 2013

Transcriptional profiling is a powerful approach for understanding development and disease. Current celltype-specific RNA purification methods have limitations, including cell dissociation trauma or inability to identify all RNA species. Here, we describe "mouse thiouracil (TU) tagging" a genetic and chemical intersectional method for covalent labeling and purification of cell type-specific RNA in vivo. Cre-induced expression of uracil phosphoribosyltransferase (UPRT) provides spatial specificity; injection of 4-thiouracil (4TU) provides temporal specificity. Only UPRT+ cells exposed to 4TU produce thio-RNA, which is then purified for RNA sequencing (RNA-seq). This method can purify transcripts from spatially complex and rare (<5%) cells, such as Tie2:Cre+ brain endothelia/microglia (76% validated by expression pattern), or temporally dynamic transcripts, such as those acutely induced by lipopolysaccharide (LPS) injection. Moreover, generating chimeric mice via UPRT+ bone marrow transplants identifies immune versus niche spleen RNA. TU tagging provides a novel method for identifying actively transcribed genes in specific cells at specific times within intact mice. © 2013 by Cold Spring Harbor Laboratory Press.

Bjornsson C.S.,Neural Stem Cell Institute | Apostolopoulou M.,Neural Stem Cell Institute | Tian Y.,University at Albany | Temple S.,Neural Stem Cell Institute
Developmental Cell | Year: 2015

Although many features of neurogenesis during development and in the adult are intrinsic to the neurogenic cells themselves, the role of the microenvironment is irrefutable. The neurogenic niche is a melting pot of cells and factors that influence CNS development. How do the diverse elements assemble and when? How does the niche change structurally and functionally during embryogenesis and in adulthood? In this review, we focus on the impact of non-neural cells that participate in the neurogenic niche, highlighting how cells of different embryonic origins influence this critical germinal space. © 2015 Elsevier Inc.

Stern J.H.,Neural Stem Cell Institute | Temple S.,Neural Stem Cell Institute
Neurotherapeutics | Year: 2011

Retinal degenerative disease has limited therapeutic options and the possibility of stem cell-mediated regenerative treatments is being actively explored for these blinding retinal conditions. The relative accessibility of this central nervous system tissue and the ability to visually monitor changes after transplantation make the retina and adjacent retinal pigment epithelium prime targets for pioneering stem cell therapeutics. Prior work conducted for several decades indicated the promise of cell transplantation for retinal disease, and new strategies that combine these established surgical approaches with stem cell-derived donor cells is ongoing. A variety of tissue-specific and pluripotent-derived donor cells are being advanced to replace lost or damaged retinal cells and/or to slow the disease processes by providing neuroprotective factors, with the ultimate aim of long-term improvement in visual function. Clinical trials are in the early stages, and data on safety and efficacy are widely anticipated. Positive outcomes from these stem cell-based clinical studies would radically change the way that blinding disorders are approached in the clinic. © 2011 The American Society for Experimental NeuroTherapeutics, Inc.

Winter M.,University of Wisconsin - Milwaukee | Wait E.,University of Wisconsin - Milwaukee | Roysam B.,University of Houston | Goderie S.K.,Neural Stem Cell Institute | And 4 more authors.
Nature Protocols | Year: 2011

This protocol and the accompanying software program called LEVER (lineage editing and validation) enable quantitative automated analysis of phase-contrast time-lapse images of cultured neural stem cells. Images are captured at 5-min intervals over a period of 5-15 d as the cells proliferate and differentiate. LEVER automatically segments, tracks and generates lineage trees of the stem cells from the image sequence. In addition to generating lineage trees capturing the population dynamics of clonal development, LEVER extracts quantitative phenotypic measurements of cell location, shape, movement and size. When available, the system can include biomolecular markers imaged using fluorescence. It then displays the results to the user for highly efficient inspection and editing to correct any errors in the segmentation, tracking or lineaging. To enable high-throughput inspection, LEVER incorporates features for rapid identification of errors and for learning from user-supplied corrections to automatically identify and correct related errors. © 2011 Nature America, Inc. All rights reserved.

De Genst E.,University of Cambridge | Messer A.,Neural Stem Cell Institute | Messer A.,University at Albany | Dobson C.M.,University of Cambridge
Biochimica et Biophysica Acta - Proteins and Proteomics | Year: 2014

Protein misfolding disorders, including the neurodegenerative conditions Alzheimer's disease (AD) and Parkinson's disease (PD) represent one of the major medical challenges or our time. The underlying molecular mechanisms that govern protein misfolding and its links with disease are very complex processes, involving the formation of transiently populated but highly toxic molecular species within the crowded environment of the cell and tissue. Nevertheless, much progress has been made in understanding these events in recent years through innovative experiments and therapeutic strategies, and in this review we present an overview of the key roles of antibodies and antibody fragments in these endeavors. We discuss in particular how these species are being used in combination with a variety of powerful biochemical and biophysical methodologies, including a range of spectroscopic and microscopic techniques applied not just in vitro but also in situ and in vivo, both to gain a better understanding of the mechanistic nature of protein misfolding and aggregation and also to design novel therapeutic strategies to combat the family of diseases with which they are associated. This article is part of a Special Issue entitled: Recent advances in molecular engineering of antibody.

Stern J.,Neural Stem Cell Institute | Temple S.,Neural Stem Cell Institute
Developments in Ophthalmology | Year: 2014

Remarkable progress over the past decade has led to the first clinical studies of stem cell therapy for retinal disease. The unique access retina offers for implantation, monitoring, and ablation is well suited for stem cell trials, and retinal applications have now moved to the forefront of the field of regenerative medicine. Retinal progeny derived from either pluripotent stem cells or tissue-specific retinal and retinal pigment epithelium (RPE) stem cells have the capacity both to replace damaged retina and to provide trophic support that slows disease progression. In contrast, bone marrow and neural stem cells produce nonretinal progeny that provide trophic support but with limited integration and capacity to differentiate into retinal progeny that can replace damaged retinal tissue. Embryonic and induced pluripotent stem cells differentiated into neural retinal and RPE progeny provide an unlimited supply of human cells for transplantation and disease modeling but raise the risks of aberrant differentiation and over proliferation. Tissue-specific stem cells isolated from neural retina or RPE that are naturally committed to retinal fates have a restricted lineage potential that improves the margin of safety. This improved safety of retina and RPE stem cells is balanced, however, by a restricted proliferative potential, which limits the quantity of progeny produced. In this chapter, we review the types of stem cells under development for retinal therapy. © 2014 S. Karger AG, Basel.

Rabin D.M.,Albany Medical College | Rabin D.M.,Neural Stem Cell Institute | Rabin R.L.,Albany Medical College | Blenkinsop T.A.,Neural Stem Cell Institute | And 2 more authors.
Aging | Year: 2013

Purpose: The goal of this study was to examine changes in the expression of transcripts and proteins associated with drusen in Age-related Macular Degeneration (AMD) after exposing human retinal pigment epithelium (hRPE) cells to chronic oxidative stress. Methods: Primary adult human RPE cells were isolated from cadaveric donor eyes. The subpopulation of RPE stem cells (RPESCs) was activated, expanded, and then differentiated into RPE progeny. Confluent cultures of RPESC-derived hRPE and ARPE-19 cells were exposed to a regimen of tert-butylhydroperoxide (TBHP) for 1-5 days. After treatment, gene expression was measured by quantitative PCR (qPCR), protein expression was assessed by immunocytochemistry and transepithelial resistance and cell toxicity were measured. Results: hRPE cells exposed to a regimen of TBHP for 5 days upregulate expression of several molecules identified in drusen, including molecular chaperones and pro-angiogenic factors. 5-day TBHP treatment was significantly more effective than 1-day treatment at eliciting these effects. The extent of hRPE response to 5-day treatment varied significantly between individual donors, nevertheless, 6 transcripts were reliably significantly upregulated. ARPE-19 cells treated with the same 5-day stress regime did not show the same pattern of response and did not upregulate this group of transcripts. Conclusions: RPESC-derived hRPE cells change significantly when exposed to repeated oxidative stress conditions, upregulating expression of several drusen-related proteins and transcripts. This is consistent with the hypothesis that hRPE cells are competent to be a source of proteins found in drusen deposits. Our results suggest that donor-specific genetic and environmental factors influence the RPE stress response. ARPE-19 cells appear to be less representative of AMD-like changes than RPESC-derived hRPE. This adult stem cell-based system using chronic TBHP treatment of hRPE represents a novel in vitro model useful for the study of drusen formation and dry AMD pathophysiology. © Rabin et al.

Wang Q.,Neural Stem Cell Institute | Wang Q.,Albany Medical College | Yang L.,Neural Stem Cell Institute | Alexander C.,University of Wisconsin - Madison | Temple S.,Neural Stem Cell Institute
PLoS ONE | Year: 2012

Neural progenitor cells (NPCs) divide and differentiate in a precisely regulated manner over time to achieve the remarkable expansion and assembly of the layered mammalian cerebral cortex. Both intrinsic signaling pathways and environmental factors control the behavior of NPCs during cortical development. Heparan sulphate proteoglycans (HSPG) are critical environmental regulators that help modulate and integrate environmental cues and downstream intracellular signals. Syndecan-1 (Sdc1), a major transmembrane HSPG, is highly enriched in the early neural germinal zone, but its function in modulating NPC behavior and cortical development has not been explored. In this study we investigate the expression pattern and function of Sdc1 in the developing mouse cerebral cortex. We found that Sdc1 is highly expressed by cortical NPCs. Knockdown of Sdc1 in vivo by in utero electroporation reduces NPC proliferation and causes their premature differentiation, corroborated in isolated cells in vitro. We found that Sdc1 knockdown leads to reduced levels of β-catenin, indicating reduced canonical Wnt signaling. Consistent with this, GSK3β inhibition helps rescue the Sdc1 knockdown phenotype, partially restoring NPC number and proliferation. Moreover, exogenous Wnt protein promotes cortical NPC proliferation, but this is prevented by Sdc1 knockdown. Thus, Sdc1 in the germinal niche is a key HSPG regulating the maintenance and proliferation of NPCs during cortical neurogenesis, in part by modulating the ability of NPCs to respond to Wnt ligands. © 2012 Wang et al.

Blenkinsop T.A.,Neural Stem Cell Institute | Salero E.,Neural Stem Cell Institute | Stern J.H.,Neural Stem Cell Institute | Temple S.,Neural Stem Cell Institute
Methods in Molecular Biology | Year: 2013

The retinal pigment epithelium (RPE) is implicated in many eye diseases, including age-related macular degeneration, and therefore isolating and culturing these cells from recently deceased adult human donors is the ideal source for disease studies. Adult RPE could also be used as a cell source for transplantation therapy for RPE degenerative disease, likely requiring first in vitro expansion of the cells obtained from a patient. Previous protocols have successfully extracted RPE from adult donors; however improvements in yield, cell survival, and functionality are needed. We describe here a protocol optimized for adult human tissue that yields expanded cultures of RPE with morphological, phenotypic, and functional characteristics similar to freshly isolated RPE. These cells can be expanded and cultured for several months without senescence, gross cell death, or undergoing morphological changes. The protocol takes around a month to obtain functional RPE monolayers with accurate morphological characteristics and normal protein expression, as shown through immunohistochemistry analysis, RNA expression profiles via quantitative PCR (qPCR), and transepithelial resistance (TER) measurements. Included in this chapter are steps used to extract RPE from human adult globes, cell culture, cell splitting, cell bleaching, immunohistochemistry, and qPCR for RPE markers, and TER measurements as functional test. © 2013 Springer Science+Business Media, LLC.

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