1,721,051 research outputs found
Hmga2 Promotes Neural Stem Cell Self-Renewal in Young but Not Old Mice by Reducing p16Ink4a and p19Arf Expression
No full textSummaryStem cells persist throughout life in diverse tissues by undergoing self-renewing divisions. Self-renewal capacity declines with age, partly because of increasing expression of the tumor suppressor p16Ink4a. We discovered that the Hmga2 transcriptional regulator is highly expressed in fetal neural stem cells but that expression declines with age. This decrease is partly caused by the increasing expression of let-7b microRNA, which is known to target HMGA2. Hmga2-deficient mice show reduced stem cell numbers and self-renewal throughout the central and peripheral nervous systems of fetal and young-adult mice but not old-adult mice. Furthermore, p16Ink4a and p19Arf expression were increased in Hmga2-deficient fetal and young-adult stem cells, and deletion of p16Ink4a and/or p19Arf partially restored self-renewal capacity. let-7b overexpression reduced Hmga2 and increased p16Ink4a/p19Arf expression. Hmga2 thus promotes fetal and young-adult stem cell self-renewal by decreasing p16Ink4a/p19Arf expression. Changes in let-7 and Hmga2 expression during aging contribute to the decline in neural stem cell function
Sox17 expression confers self-renewal potential and fetal stem cell characteristics upon adult hematopoietic progenitors
No full textA key question concerns the mechanisms that determine temporal identity in stem cells. Fetal hematopoietic stem cells (HSCs) differ from adult HSCs in terms of gene expression profile, surface marker expression, differentiation, and self-renewal capacity. We previously showed that the transcription factor SOX17 is expressed by fetal, but not adult, HSCs and is required for the maintenance of fetal and neonatal, but not adult, HSCs. In the current study, we show that ectopic expression of Sox17 in adult HSCs and transiently reconstituting multipotent progenitors was sufficient to confer increased self-renewal potential and the expression of fetal HSC genes, including fetal HSC surface markers. Sox17 expression enabled transiently reconstituting adult progenitors to give long-term multilineage reconstitution that resembled fetal hematopoiesis, including increased erythropoiesis, increased myelopoiesis, and decreased lymphopoiesis. Long-term ectopic expression of Sox17 eventually led to leukemogenesis. These data demonstrate that SOX17 is sufficient to confer fetal HSC characteristics to adult hematopoietic progenitors and is therefore a key determinant of fetal HSC identity
Sox17 Dependence Distinguishes the Transcriptional Regulation of Fetal from Adult Hematopoietic Stem Cells
No full textSummaryFetal stem cells differ phenotypically and functionally from adult stem cells in diverse tissues. However, little is known about how these differences are regulated. To address this we compared the gene expression profiles of fetal versus adult hematopoietic stem cells (HSCs) and discovered that the Sox17 transcriptional regulator is specifically expressed in fetal and neonatal but not adult HSCs. Germline deletion of Sox17 led to severe fetal hematopoietic defects, including a lack of detectable definitive HSCs. Conditional deletion of Sox17 from hematopoietic cells led to the loss of fetal and neonatal but not adult HSCs. HSCs stopped expressing Sox17 approximately 4 weeks after birth. During this transition, loss of Sox17 expression correlated with slower proliferation and the acquisition of an adult phenotype by individual HSCs. Sox17 is thus required for the maintenance of fetal and neonatal HSCs and distinguishes their transcriptional regulation from adult HSCs
Enhanced purification of fetal liver hematopoietic stem cells using SLAM family receptors
No full textAlthough adult mouse hematopoletic stem cells (HSCs) have been purified to near homogeneity, it remains impossible to achieve this with fetal HSCs. Adult HSC purity recently has been enhanced using the SLAM family receptors CD150, CD244, and CD48. These markers are expressed at different stages of the hematopolesis hierarchy, making it possible to highly purify adult HSCs as CD150(+)CD48(-)CD244(-) cells. We found that SLAM family receptors exhibited a similar expression pattern in fetal liver. Fetal liver HSCs were CD150(+)CD48(-)CD244(-), and the vast majority of colony-forming progenitors were CD48(+)CD244(-)CD150(-) or CD48(+)CD244(+)CD150(-), just as in adult bone marrow. SLAM family markers enhanced the purification of fetal liver HSCs. Whereas 1 (111%) of every 8.9 Thy(low)Sca-1(+) lineage-Mac-1(+) fetal liver cells gave long-term multilineage reconstitution in irradiated mice, 1 (18%) of every 5.7 CD150(+)CD48(-)CD41(-) cells and 1 (37%) of every 2.7 CD150(+)CD48(-)Sca-1(+)lineage(-)Mac-1(+) fetal liver cells gave long-term multilineage reconstitution. These data emphasize the robustness with which SLAM family markers distinguish progenitors at different stages of the hematopolesis hierarchy and enhance the purification of definitive HSCs from diverse contexts. Nonetheless, CD150, CD244, and CD48 are not pan-stem cell markers, as they were not detectably expressed by stem cells in the fetal or adult nervous system
Neural crest stem cells in development and disease.
No full textWe found neural crest stem cells (NCSCs), which give rise to the entire peripheral nervous system (PNS), persist into late gestation in many regions of the PNS and throughout adulthood in the gut. We developed techniques to prospectively identify these NCSCs by flow cytometry enabling the examination of stem cell properties as they exist in vivo. Diversity of mature cell types in the nervous system is assumed to arise in response to local environmental differences, but the contribution of cell-intrinsic differences between stem cells has been unclear. We found that when present in the same environment, NCSCs isolated from different regions of the PNS had differences in their sensitivity to lineage determination factors which directed fate choice. Regional differences in the types of cells generated in the nervous system arise, at least in part, from regional differences between stem cells. NCSCs also underwent developmental transitions in cell-intrinsic properties. Postnatal NCSCs had reduced cell cycle status and self-renewal potential compared to fetal gut NCSCs and underwent changes in their neuronal subtype potential. These perinatal changes paralleled changes previously observed in hematopoietic stem cells, suggesting that stem cells in different tissues undergo similar developmental transitions. To begin to understand NCSC regulation at the molecular level, we analyzed the gene expression profile of gut NCSCs. Surprisingly, genes associated with Hirschsprung disease, a relatively common congenital disorder in which the neural crest fails to form ganglia in the hindgut, were highly up-regulated in gut NCSCs relative to whole-fetus RNA. We selected two of these genes for functional analysis, the glial cell line-derived neurotrophic factor receptor Ret and the endothelin-3 receptor endothelin receptor B (EDNRB), which together account for the majority of familial cases of Hirschsprung disease. We found primary roles for both Ret and EDNRB-signaling in NCSC migration, and intact signaling was necessary for NCSC migration into the hindgut. The migratory defect could be bypassed by transplanting NCSCs into the aganglionic colon. Gene expression profiling, combined with reverse genetics and analyses of stem cell function, suggests that Hirschsprung disease is caused by defects in neural crest stem cell function.PhDBiological SciencesCellular biologyMolecular biologyNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125680/2/3208482.pd
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
The physiological function of neural stem cells.
No full textStem cells play an important role in tissue formation, maintenance, and disease. However, much of what we know about many stem cells is based upon their behavior in culture. To better understand the role of stem cells in tissue development/maintenance or in disease, it will be important to characterize progenitor function both in vivo and in vitro. To this end, I have examined the physiological significance of central and peripheral nervous system (CNS and PNS) stem cells in various contexts. Neural crest stem cells (NCSCs) are self-renewing, multipotent progenitors that give rise to all lineages of the PNS. Although NCSCs persist in peripheral nerves throughout late gestation, their physiological function was unknown. Cre-recombinase fate mapping revealed that within peripheral nerves, endoneurial fibroblasts, in addition to myelinating and non-myelinating Schwann cells, are neural crest-derived, whereas perineurial cells, pericytes, and endothelial cells are not. The multilineage differentiation of nerve NCSCs into glial and non-glial derivatives in developing nerves appeared to be regulated by Neuregulin, Notch ligands, and Bone Morphogenic Proteins. These factors are expressed in developing nerves, and in culture cause nerve NCSCs to generate Schwann cells and fibroblasts, but not neurons. Since neurofibromas (tumors of the PNS) contain mainly glia and fibroblasts, these findings raised the question of whether NCSCs can be transformed by neurofibromin deficiency. Neurofibromatosis Type I is one of the most prevalent disorders of the nervous system, and is caused by mutations in neurofibromin 1 (NF1), a gene encoding a RasGap protein. This disease is characterized by the development of neurofibromas, which contain most PNS cell types including glia, neurons, and fibroblasts. Since these cell types arise from multipotent NCSCs, we analyzed the function of NF1 in NCSCs isolated from all regions of the developing PNS. At E13, NF1 deficiency increased the frequency, colony size, and self-renewal potential of NCSCs in regions of the PNS where neurofibromas commonly occur. In contrast, NF1 deficiency had little effect on NCSCs from regions where neurofibromas rarely occur, despite equal levels of NF1 expression and Ras pathway activation in all regions. Consistent with the role of NF1 as a negative Ras regulator, Ras pathway inhibition also regionally affected NCSC function. The mechanism by which NF1 and the Ras pathway regionally regulate NCSC function remains to be determined. At later time points in development, NF1 deficiency did not increase the persistence or frequency of NCSCs, arguing against a NCSC origin for neurofibromas that arise postnatally. However, it remains possible that NF1-/- cells may de-differentiate postnatally to acquire stem cell characteristics in the presence of additional mutations. To test whether NF1-related tumors contained stem cells in the presence of additional mutations, we generated NF1+/- mice on a p16Ink4ap19Arf-deficient background, since p16Ink4a and p19 Arf are commonly mutated in human malignant peripheral nerve sheath tumors (MPNSTs). These mice developed MPNSTs that contained self-renewing, multipotent progenitors. These findings may improve our understanding of NF1-related tumor development, perhaps leading to new therapies. CNS stem cells persist throughout the lifespan and neurogenesis continues in the adult mammalian brain, though neurogenesis and neural progenitor function in the olfactory bulb and hippocampus are known to decline during mammalian aging. It has been proposed that this is partially caused by the senescence of progenitors with age, but whether known senescence-associated genes are responsible remains uncertain. We studied the age-related decline in forebrain neurogenesis and progenitor function in aging wild-type and p16 Ink4a-deficient mice. Aging p16Ink4a-deficient mice showed a significantly smaller decline in subventricular zone (SVZ) progenitor function and olfactory bulb neurogenesis than did their wildtype counterparts. Declining SVZ progenitor function and olfactory bulb neurogenesis during aging are thus caused partly by increasing p16Ink4a expression. NCSCs also persist throughout adult life, at least in the enteric nervous system, raising the question of whether neurogenesis continues throughout life in PNS. We were unable to detect neurogenesis in the adult PNS under most normal, diseased, and injured physiological conditions. Thus, the physiological role of adult gut NCSCs remains uncertain.PhDBiological SciencesCellular biologyNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/127147/2/3406310.pd
Variations on the Author
No full text“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
No full textWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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