Lecture 18

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Human Biology
Maria Papaconstantinou

23 MAR 2011 HMB321 L18: Bret Pearson, Planarians a new model to disease and regeneration Big Question -How to establish new human disease models? The Beginning -Prebilateria (not bilaterally symmetric,e.g.Sponge and jellyfish) -Branches into ecdysozoa and deuterostomes (invertebrates;vertebrates) -As well as lophotrochozoa (diverse species,e.g.Annelids,snails,molluscs) How to bring new system into the lab? -Organism should have“special advantages” -Study adult stem cells -Develop tools and culture conditions Planarians and Adult Stem Cells -Adult stem cell -Large uncondensed nucleus is a key characteristic (how it was found) -Non-stem cells are differentiated and have condensed,small nuclei -Important for tissue homeostasis,injury regeneration => longevity? -E.g. C. Elegans have 0 divisions and live only 4 days, whereas mice have more divisions and live up to 3 years,whereas humans have more divisions than mice and live 80 years or so,BUT… -Planarians seem to be immortal,i.e.Their division rate seems infinite = immortal? -Stem cell is only as good as the lineage that it outputs -Maintenance of correct lineage is unknown process,especially in vertebrates -This maintenance goes awry in our 20s-30s => organismal senescence vs. Cancer (in developed countries,in about 1 in 3 humans;hyper-proliferative) -How stem cells accomplish their lineages? -Hierarchal => start with Non-stem cell (somatic cell) provides info for adult stem cell (ASC) -Cell-cell signalling occurs between Niche &ASC -Stem cells are defined by unique biology of self-renewal (multipotency) -Progenitor Cells => changes in gene expression for particular line starting -Post-mitotic progeny => differentiated cells (humans replace 10^10 cells per day; maintenance of homeostasis) -Last process = proliferation control? -Tumour suppressors => can you figure this out from stem cells to work around cancer?To figure out how things go awry? Challenges in studying adult stem cells -Unknown cellular lineages -Cells don’t divide well in culture -Manipulation of adults is difficult/time consuming (i.e.Decade-long streams in adult cells) -Accessibility in adults is almost impossible (i.e.Can’t watch the stem cells do anything) What are planarians? -Planarians are the garbage can of evolution? -TH Morgan,1911 -Got them into the laboratory;his early work was not fruitfly based,but Planarians -He tried to slice the Planarian in different ways to figure out if it would regenerate wrong -Found that each piece he could off => made an entirely proportionate worm (like reproduction);incredible regeneration,just takes time -Always thought that if you cut off the head => must have polarity => will grow back as a head or nothing at all -The Planarian just grew into a new worm -Using ISH => found that 10-20% of the worm are made of stem cells -A smaller proportion are the actively dividing cells -So,how do intact planarians regulate theirASC? -So,how do the stem cells change regulation during regeneration? -There are different domains of proliferation after injury -Hyperproliferation of cells at the anterior end to make brain tissue => need to decrease/down B-catenin,p53 -If you artificially KO B-catenin => will produce 2 heads -In tail tissue => B-cat up,p53 -KO B-cat,produces 2 fins Planarians in the lab -Cheap and easy maintain (small-scale management,eats liver,etc) -Increase pop’n through amputations => clones! Injury causes temporary stem cell hyper-proliferation -All regions can be cut to regenerate -How can injury cause hyper-proliferation?What are the processes (similar toASC?)? Stem cell numbers change with nutrient levels -Pro
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