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CELLULAR REGENERATION AND SENESCENCE, healthy liver: cell death= Cell…

- - - - Vertebrates have a limited capacity for pure regeneration.
    - - Low capacity: Heart, Brain, Kidney
      - Medium dependant capctiy: Liver, Pancreas
      - High capacity: Skeletal muscle, hair, skin, blood, intestines (tissues that re metabolic active) i think.
    - - Background & knowlegde:
        
        Hepatocytes = parenchymal cells of the cell ( the cell responsible for the function if the tissues). Hepatocyte cell turnover is vry slow( 200-400 days) 1-2% at any one time are actucally in the cell cycle. the remainder of the cells are in G0( quiescent cells)
        
        The Cell cylce: M1(mitosists cell division), interphase( G1(cell is metabolically activty synthesis of new protiens), S(DNA replication) G2(prepare for M phase). G0 occurs in the G1 portion. the cells withdrawn from the cell cycle but they maintain the ability to re-enter the cell cylce stimulus dependant=quiescent ( needed to regulate growth etc)
        
        is that why they can regerate so quickly as 98% are in reserve
      - Malato et all 2011 J clin Invest (important papaer in the feild) Showing normal-mild stimulus of regernation
        
        (1)they showed how the liver regenerates. under different stimuli: they used cell fate tracing (cell labelled with fluorescent cell protein EYFP) acts a marker to track the fate of hepatocytes this allowed them to study the origin of new cells, as any cell that is derived from the a YFP expressing cell will also express YFP. they also marked matured hepatocyte
        
        (2) after study the cells for around 1/2 , they saw that all of the marked mature hepatocytes were also red (FYP) showing that all new hepatocytes are derived from existing hepatocytes all the cells were expressing YFP showing the linage of the new hepatocytes.
        
        (3) they also used CCL4 a hepatotoxin that damages' the liver, inducing cell death. the new cells were also YFP expressing, showing that in under acute injury or normal turnover, all new heptaocytes a derived from existing ones
        
        this is is an example of Cell regeneration differeation cell type A proliferates to make more hepatocytes
      - Extreme liver Regeneration
        
        Partial hepatomy ( where the liver has chopped off**) 2/3 PH removal of the liver. 21 days later the liver had regeneration
        
        Most of the cells were derived from a hepatocyte( a hepatocyte has entered the cell cylce from G0 and proliferated), but there were also areas where mature Heps. were not expressing FYP. indicating that they were not derived from an original hepatocyte. they have come from another cell type.
        
        2% of the cells were not dreived from the existing Heptaotcytes, using CK19 stainting ( a marker of bile duct). Where were the cells coming from
        
        it showed that under extreme injury hepatocytes alone cannot regenerate the liver. the Biliary epitheila cells(BEC) can de-differentiate to from a liver progenitor cell (LPC). the LPC can: (1) de-differentiate to become a BEC or (2) differentiate to form hepatocytes. an LPC is a Facultative Stem cell
        
        FACULTIVE REGNERATION Overview: different type of cell(differentiated cell type B) which then de-differentiates to form a Facultative stem cell which can then form a new hepatocyte cell or go back into a BEC
    - - Thorel et al. 2010 (Nature) **Extreme pancreas Regneration showing the process of Transdifferentiation
        
        aim: how do beta cells regenerate. if they do. they stained the Pancreas to oblate(kill) B-cells. B-cells release insulin= green stain. Alpha cells produce glucagon= red stain.
        
        after 15 days= low green as no insulin is being produced as B cells dead. overtime 10 months: you can see that more green= more B cells. so they do regenerate by where are they coming from
        
        they used fluorescent markers to trace the fate of the B cells. (YFP to track B-cell proliferation) . From tacking insulin they could see 4 cells expressing insulin) the YFP were tracking the B-cells from the start. out of the 4 insulin expressing cells only 1 of them expressing YFP. (meaning that they are beta cells but they are not derived from a beta cell)
        
        if you stain for glucagon a marker for alpha cells, they other 3 cells stained positive for glucagon. suggesting that they are coming from alpha cells.
        
        when the authors used YFP to track for alpha cell proliferation, they found that the insulin postive cells were also YFP and glucagon positive meaning that he insulin positive beta cells are derived from alpha cells.
        
        Transdifferentiation
        
        Differentiated cell type B( alpha cell) Differentiated to become a different type of a cell to become a beta cells
        
        Can we see what point in the cell cycle they have to be in to be able to differentitate and is there a point of no return.
    - - Background & K: they live in the the stem cell niche. there are high number in every active stem cells in tissues that continuously lost and replaced (skin, intestine, blood)
        
        there is a small population of Quiescent stem cells in cell types that are terminally differentiated (e.g. skeletal muscle and neurons) stem cells lie(live) in Quiesent (G0) until they are activated
        
        what is a stem cell: must have 2 defining features
        
        must have the capacity of self-renewal (the cell can proliferate, which must come back to being a stem cell)
        
        Must have the ability to differentiate into multiple cell type (adult tissue type)
        
        types of stem cells
        
        Haematopietic stem cell
        
        location : bone marrow
        
        Mesenchymal stem cell
        
        Bone marrow
        
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        Intestinal stem cell
        
        Cryts of the small intestine
        
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        Satellite Cell
        
        Periphery of skeletal muscle fibre
        
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        lie in G0 (quiesent) upon activation through stimulus they undergo proliferation ( once they under go proliferation they are labelled progenitor cells) some will self renwal and some be used in repair and regeneration
      - [adult stem cells]
        
        they live in the stem cell niche (near stromal cells) cells become active and proliferate away from the niche. as they start to proliferate they become committed to a certain linage.
        
        Cell that are active and proliferating are cells progenitor cells some of these progenitor cells form a differentiated cell and some will return back to the Quiescent state (G0) again
        
        *Asymmetric Cell division theories the daughter cells have aystrmety *(how does a cell decided to self renew or differentiate?)
        
        Extrinsic Regulation(more likely in adult stem cells, factors in the niche regulate self renwal or not.TO self renew or to not)
        
        stem cell is in niche which regulates through signals what the cell will/wont dont. half of the dividing cell receives (self renewal signals signals from the niche and the lower half does not receives the signals ( which causes the cell to differentiate, it will proliferate, become a progenitor cell etc )
        
        Intrinsic Regulation
        
        a stem cell has self renewal factors(protiens) present within the cell, (that promote self renwal) during mitosis, the factors are at the bottom part of the cell so the bottom part of the cell recieves those factors,
      - Small Intestine (key model for looking at stem cells
        
        B&K: lines the gut (1 cell thick), 4 cell types present: absorptive cell( take up nutrients) globlet cell, Paneth cell(kill bacteria), Enteroendocrine cell (hormone secretion) the villi increase surface area. has a fast cell turn over (3-5 days along the villi)
        
        BARKER et al 2007 nature How are stem cells in the small intestine constantly being replaced
        
        they used fate tracing technique to map cell division and origin of daughter cell. they lablled cells with heritable makre (blue) which showed: 1. the source of the cells is from a single cell in the crypts of the small intestine. 2. this cell gives rise to all types of cell in the intestine
        
        the cell from the crytt over 60 days, all the blue cells were derived from one singlar cell.
        
        conclusion the cells in the crypts of the small intestine are stem cells, as they can give rise to all of the different cell types that make up your intestine (the 4 cell types mentioned before) this explains the regerative capacity and quick turnover
- - - - Neurogenesis continues throughout life in the sub granular zone of the hippocampus this is due to neural stem cells (nestin+ve stem cell) imagine showed that throughout the life of a mouse there is a reduction in nestin+ve cells. conclusion= a reduction in neural stem cell number throughout the life course. this is true in alot of tissues throughout the body= smaller capacity for regeneration (we get more HSC as we age throughout hte body)
    - - study took away the satellite cells (muscle stem cells) and gave it back stem cells from a younger adult, old or geriatric mouse, then they injured the mouse, to stimulate stem cell rejenerat and the measured the rejearivte capctiy. the found that adult had the most new muscle fibre geriatic had the least( equal number of stem cell number were given to the mouse)
        
        shows that stem cell function declines with age ( is this the loss of the self renewal factors intrinsic or extrinsic from the niche or the cell)
  - - - Replicative senescence= where the cells stop dividing. Senescence= the irreversible loss of proliferative potential in somatic cells, occurs in the G1 phase of the cycle
        
        Implications of Cell cylce arrest in G1
        
        in the G1 phase of cell cycle, the cell is metabolically active, there is alot of protein synthesis occurring as the cell wants to grow. = Big cells
    - - As we age we get an increase in the number of senescent cells in the body(idda et al 2020 aging), the cells can no longer re-enter the cell cycle and proliferate and repair a damaged tissues.
        
        how does this happen? DNA BAckground and knowledge
        
        DNA Replication: helicase unwinds DNA creating replication bubble(Two replication forks, primers added to each strand, DNA polymerase add nulceotides to new DNA strand in a 5-3 direction (moving in the p[arent strand 3-5 prime direction)
        
        Leading strand of DNA= continues replication, lagging strand= discontinuous replication (with okazaki fragments. at the end Primers are reomved and DNA segments replace that place. HOWEVER, there is a gap at the end of the lagging strand as there is nothing to grab onto= 3 prime overhang. the end replication problem there is a region of DNA at the end of the chromosme, with a 3' prime overhange. this could be interpretd by the cell as a double strand break.
        
        Telomeres role preserving DNA & cell integratiy
        
        (1)telomeres= short repeating DNA sequences at the end of the end of a chromosome (TTAGGGo n the leading strand). used to solved the 3 overhang problem. they protect the genomic DNA. and stop the cell from thinking that there is a double strand break. the telomere forms a T LOOP to protect the DNA
        
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        Telomeres and cellular senesance link
        
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        Telomerase role in ageing and preserving telomere length
        
        a ribonuclear protien ( has its own RNA template) it binds to the parent strand of DNA and extend it which allows the lagging strand to also increase in size. so that the cell doesn't loose telemetric length with each cell division
        
        telomerase extends time to senescence if you express telomerase in cells then you can make the cell last longer before they reach senescence. in a study: it showed that the average amount of time it takes for a cell to become senescence is longer when cells were treated with ectopic expression of telomerase. = there is a strong relationship between telomerase and sensense which is telomerase plays a limiting factor in
        
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