biology 624 - developmental genetics lecture #5 - stem cells
TRANSCRIPT
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Biology 624 - Developmental Genetics
Lecture #5 - Stem Cells
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DEFINITION OF A STEM CELL:
1.Self-renewing - can give rise to daughter cells that are stem cells
2.Give rise to differentiated progeny - daughter cells can also differentiate, usually into multiple lineages
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TYPES OF STEM CELLS:
1.Embryonic stem cells
2.Adult stem cells
3.Cancer stem cell
4.Germline stem cell
5.iPS – induced pluripotent stem cells
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Sources of Pluripotent Stem Cells
Adult somatic cells + 4 genes
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Mouse Embryonic Cells and Derivation of ES Cells
From Keller, 2005
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ES Cells Maintain Pluripotency byInhibiting Differentiation
--Oct4/Sox2/Nanog +PcG genes block diffgenes
-- LIF and BMP blockdiff via inhibit MAPK
--FGF promote diff
From He et al, 2009
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Hematopoietic stem cells – first identified
adult stem cells
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Some types and sources of adult stem cells
From Jordan et al, 2006
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ADULT STEM CELLS:
--HSC = Hematopoietic system--Neural stem cells = Neurons and glia--Gut stem cells = gut epithelium and
other cells--Breast stem cells = mammary glands
-- Mesenchymal stem cells? = numerous mesodermal derivatives
-- Satellite cells in muscle? = muscle-- Liver stem cells?--Vascular stem cells? (pericytes,
hemangiomas)
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The stem cell niche concept
From He et al, 2009
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Blood vessels may provide a neural stem cell niche
Kokovay et al (2010) Cell Stem Cell
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Adult Stem Cells - Outstanding Issues
1.How are niches set up and maintained?
2.Mechanism(s) of age-related loss of stem cells – “used up” vs. niche loss
3. Role in cancer – do they mutate to cancerstem cells?
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The Cancer Stem Cell Hypothesis
1.Cancers are heterogeneous – not all cellshave the same markers, behaviors – how arise?
2.Does this reflect “potential”? Do somecells maintain or acquire stem cell propertiesand populate the rest of the tumor with non-tumorigenic cells?
3.If so there should be a hierarchy of cells – and this has implications for therapy
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The Cancer Stem Cell Hypothesis
From Dick, 2008
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Scenarios of how cancer stem cells can affect tumor formation
From Jordan et al, 2006
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The Cancer Stem Cell Hypothesis –
Outstanding Issues
1.Can clonal evolution explain the data?
2.Is it a global model (ie all cancers) or restricted? If restricted, how?
2.Genetic vs. epigenetic – if cancer stemcells contribute to a tumor, how labile?
3. The role of the “stem cell niche” in cancerstem cell biology
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Alternate cancer stem cell hypothesis:
1. Niche requirementschange
2. Progenitors mutateto self-renew
From Lobo et al, 2007
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Raaijmakers et al, 2010
Myeloid Dysplasia/Leukemia via a Mutation in the
Niche…
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Can we make stem cells fromcells that are NOT stem
cells –i.e. “run the tape
backwards”?
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Successful Nuclear Transplants as a Function of the
Developmental Age of the Donor Nucleus
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Cloned Mammals, Whose Nuclei Came From Adult
Somatic Cells
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Embryonic Stem Cell Therapeutics
Blood VesselPrecursors
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Embryonic Stem Cell Therapeutics
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From Nishikawa et al, 2008
iPS suggest an alternative source of stem cells
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From Nishikawa et al, 2008
Comparison of protocols to derive
pluripotent stem cells
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From Nishikawa et al, 2008
How iPS might help therapeutically
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iPS from patients with diseases have been generated
1. ALS – differentiate to motor neurons (Dimos et al, 2008)
2. Parkinson’s disease (Soldner et al, 2009)
3. Type I diabetes – differentiate into pancreatic -cells (Maehr et al, 2009)
Refs in Maehr et al, 2009
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Wu and Hochedlinger, 2011
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The Hematopoietic Stem Cell
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Cell Fusion
From Vassilopoulos and Russell, 2003
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A Clone of Xenopus laevis Frogs
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The Cancer Stem Cell Hypothesis
From Donnenberg and Donnenberg, 2005
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Hematopoietic stem cells – first identified
adult stem cells