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Stem Cells (STEM CELLS (What are they? (Totipotent: give rise to whole…
Stem Cells
STEM CELLS
Mesenchymal stem cells
Stromal potential in making bone, fat, muscle
Immunosuppressive and immunoprotective so clinical trials to use them in GVHD bc they only last a few hours
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Repair and homeostasis
One dividing SC in crypt base of villi of intestine for all cells. Paneth cells support formation of TA cells which form epithelium, goblet and enteroendocrine cells
SC for growth and repair and stimulated and inhibited as required i.e. quiescent unless injury or replacement
Multipotents found in most tissues e.g. lining of intestine replaced every 4 days OR one haematopoietic SC can give rise to new bone marrow system. Different proliferative rates
Liver conditionally renewing tissue bc bile epithelial cells become facultative stem cells if liver undergoes catastrophe
Pluripotent SC
ICM of blastocyst (day 5) by sacrificing human embryo surplus to need. Grow indefinitely in vitro and still maintain normal genetic makeup through division
Reprogrammed somatic cells using Yamanaka factors into iPS cells (via viral or protein transaction or plasmid transfection). Done by forcing the transcription of 4 genes
Grow indefinitely in vitro, unlike other SC, and maintain normal genetic makeup
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Similar sort of process can be used to change between two cells types like fibroblast to neuron. Don't need to go back up a tree to an intermediate and then back down TRANS-DIFFERENTIATION
What are they?
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Self replicate for indefinite periods and give rise to many of the differentiated cell types making up a tissue, by using differential gene expression via chromatin and epigenetic changes. Changes are permanent and heritable through replication. Each branching of lineages has more and more gene expression shutdowns
Multipotent: can give rise to several types of mature cells e.g. haematopoietic stem cells of bone marrow
Can know if a cell is stem if it can repopulate a tissue by giving rise to differentiated, functional progeny and self-renewal
Lack specialised organelles, high nucleus:cytoplasm
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SYSTEMS BIOLOGY
Molecular classification
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Check RNA? Easy to measure and is different in different types of cells, but there is a difference between protein and RNA level
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Protein? Different between cell types but would need lots of cells to see patterns or real differences
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Instead, can differentiate cells and group them by gauging their flow through the following: genome, epigenome, transcriptome, proteome, metabolite interaction (But how much is too much difference to safely say its a different cell type?)
Design new cells
Systems biology principles:
Emergence: properties that emerge are more important than each constituent
Modularity: what defines phenotype? Behaviour?
Robustness: reproducibility, predictability
Next step: not just replace cells and implant normal ones, but make new cells with extra features and functions
Stem cells: main problem is knowing how to trigger cells and activate and renew when we want i.e. microenvironment for multipotents
Cell identity
Multipotent cells don't have phenotypic features. However can transcription markers to see where new cells are originating
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Embryonic are the only pluripotent stem cells endogenously. However somatic cells can be made pluripotent
Stem cells differentiate into new cells in the future, so its hard to see if they are stem cells at a given time
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Each cell type is dependent on expression, the nucleus contains all the necessary information for every cell, as shown by Molly the sheep (also proven by somatic = iPS cells)
Surface molecular markers don't differentiate between cells, molecular signature does a better separation job
TISSUE ENGINEERING
Design criteria
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Thin or avascular structures don't need to consider blood supply bc they'll get nutrients through mass transfer
Tissues have cells, ECM and blood supply (not in cartilage)
The tissue won't be perfect, need to compromise and optimise
Biodegradable (once new cells are made around), suitable in vivo (no inflammation), good structure, cheap, sterilised, stable storage, works as desired
Limitations
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Regulatory: therapeutic goods administration, FDA. needs to be approved
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Foreign body reaction: proteins surround > denature > neutrophils come > neutrophil and macrophages fuse > giant cell > cytokines released and fibroblasts create collagenous bag around
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Biomaterial roles
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Generate new functional tissue to repair or replace due to disease, trauma or defect
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Create a scaffold, that mimic the native ECM, onto which new tissue can grow
ETHICS
Slow progression
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Using gametes and embryos: infertile couples and same sex. But how do we know the babies will be healthy?
Making organoids: model development of organs where pluripotent act as the primitive source of the organ (structure rarely the same unless a biopsy is used)
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Source
Can become endoderm, mess or ecto i.e. any somatic cell
PSC from the ICM of blastocyst (day 5) or from reprogramming somatic cells into iPS cells using 5 Yamanaka factors
Multipotent SC come from PSC or from foetal or adult tissue but are hard to isolate (low in number, no specific markers) and difficult to grow (microenvironment)
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ESC sourcing requires destroying the embryo (representation of life?) which is surplus to IVF needs and donated CONSENT
Funding for research is only granted after a proposal of research, since there needs to be regulation
Creating embryos or hybrids is illegal and also combining the genetic material of more than 2 people
iPS cells can be made form any cell from anyone and thus are easy to make, without the person's consent or knowledge
Unregulated
Sites offer stem cell therapy and use patient testimonials as evidence, but how do these patients feel 5 years later?
Also recommendations from "stem cell doctor" (not real) who say its like magic; but it is expensive and diverts from existing care
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In Australia, if stem cells are sold by a registered Australian doctor, then therapeutics administration don't intervene
Public expectation
Reality: only a few proven treatments: blood, skin (no nerves or sweat glands), cornea
Public thinks stem cells are a miracle cure, and thus sometimes doesn't accept the risks and thinks results will be amazing
Still a basic level of research, but there is a support rate of 70%