SEAN MORRISON

..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...

..The facultative use of symmetric or asymmetric divisions by stem cells may be a key adaptation that is crucial for adult regenerative capacity...

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..Mechanisms of stem cell maintenance are key to the regulation of homeostasis and likely contribute to aging and tumorigenesis when altered during adulthood...

..Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation...

..Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16INK4a expression...

..Upon transplantation of uncultured NCSCs into developing peripheral nerves in vivo, sciatic nerve NCSCs gave rise only to glia, while gut NCSCs gave rise primarily to neurons. Thus, cell fate in the nerve was stem cell determined...

..Tumors appeared to arise from differentiated glia, not NCSCs...

..Hmga2 thus promotes fetal and young-adult stem cell self-renewal by decreasing p16(Ink4a)/p19(Arf) expression. Changes in let-7 and Hmga2 expression during aging contribute to the decline in neural stem cell function...

..The persistence of NCSCs in the adult PNS opens up new possibilities for regeneration after injury or disease...

..Finally, Aldh1a1 deficiency did not affect the function of stem cells from the adult central or peripheral nervous systems. Aldh1a1 is not a critical regulator of adult stem cell function or Aldefluor staining in mice...

..Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues...

..Reduced stem cell function and tissue regenerative capacity during aging are caused by changes in self-renewal programs that augment tumor suppression. Cancer arises from mutations that inappropriately activate self-renewal programs...

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..Modifications to xenotransplantation assays can therefore dramatically increase the detectable frequency of tumorigenic cells, demonstrating that they are common in some human cancers...

..Bmi-1 over-expression therefore has more pronounced effects in culture and does not appear to be sufficient to induce tumorigenesis in vivo...

..This raises the possibility that drugs targeting this pathway could be more effective at eliminating cancer stem cells while being less toxic against normal stem cells...

..Thus, HSCs cannot be identified on the basis of BrdU-label retention and do not retain older DNA strands during division, indicating that these are not general properties of stem cells...

..Prdm16 therefore promotes stem cell maintenance in multiple tissues, partly by modulating oxidative stress...

..Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells...

..SLAM family receptor expression is conserved among HSCs from diverse contexts, and HSCs from old, reconstituted, and mobilized mice engraft relatively efficiently after transplantation when contaminating cells are eliminated...

..Coupled with recent insights into the mechanism by which Nogo inhibits axonal regeneration, this discovery may inspire new treatments for central nervous system injuries and neurodegenerative diseases...

..Expression of p16Ink4a and p19Arf in normal HSCs resulted in proliferative arrest and p53-dependent cell death, respectively. Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs...

..This migratory defect could be bypassed by transplanting wild-type NCSCs directly into the aganglionic region of the Ednrb(sl/sl) gut, where they engrafted and formed neurons as efficiently as in the wild-type gut...

..Therefore, senescence of stem cells must be prevented. Bmi1 is required for the maintenance of adult stem cells in some tissues partly because it represses genes that induce cellular senescence and cell death...

..Nerve development is thus more complex than was previously thought, involving NCSC self-renewal, lineage commitment and multilineage differentiation...

..By understanding these similarities and differences we may come to a molecular understanding of how stem cells replicate themselves and why aspects of this process differ between stem cells...

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..Many HSCs were associated with sinusoidal endothelium in spleen and bone marrow, though some HSCs were associated with endosteum. HSCs thus occupy multiple niches, including sinusoidal endothelium in diverse tissues...

..However, to understand tissue development/maintenance or the role of stem cells in disease, it is important to characterize progenitor function in vivo to evaluate physiological significance...

..These observations provide the first in vivo evidence for cell fusion of BMDCs with neurons and cardiomyocytes, raising the possibility that cell fusion may contribute to the development or maintenance of these key cell types...

..Thus, Delta-mediated feedback interactions between NCSCs, coupled with positive feedback control of Notch sensitivity within individual cells, may underlie developmental changes in the ligand-sensitivity of these cells...

..By better understanding these mechanisms we will gain new insights into how the PNS forms and what goes wrong in the context of disease. ..

..The discovery of NCSCs in postnatal tissues might fundamentally alter approaches to regeneration in the PNS. Answers to these questions could change the way we think about PNS development, injury, and disease. ..

..These studies will test whether NCSCs with specific regional characteristics can be derived from hES cells and whether these cells engraft in the gut of an animal model of Hirschsprung disease. ..

..By better understanding these mechanisms we will gain new insights into how the PNS forms and what goes wrong in the context of disease. ..

..Such information is critical to understand how blood cell formation is regulated and how stem cells are sustained in this tissue throughout life. ..

..These studies will test whether NCSCs with specific regional characteristics can be derived from hES cells and whether these cells engraft in the gut of an animal model of Hirschsprung disease. ..

..Answers to these questions would have fundamental implications for understanding the regulation of stem cell aging, and for generating new strategies for treating age-related morbidity. ..

..The discovery of NCSCs in postnatal tissues might fundamentally alter approaches to regeneration in the PNS. Answers to these questions could change the way we think about PNS development, injury, and disease. ..

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