Biology 624 - Developmental Genetics

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Biology 624 - Developmental Genetics
Lecture 5 - Stem Cells
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• DEFINITION OF A STEM CELL
• Self-renewing - can give rise to daughter cells
  that are stem cells
• Give rise to differentiated progeny - daughter
  cells can also differentiate, usually into
  multiple lineages

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• TYPES OF STEM CELLS
• Embryonic stem cells
• Adult stem cells
• Cancer stem cell
• Germline stem cell
• 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 by Inhibiting
Differentiation --Oct4/Sox2/Nanog PcG genes
block diff genes -- LIF and BMP block diff 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

• How are niches set up and maintained?
• Mechanism(s) of age-related loss of
• stem cells used up vs. niche loss
• 3. Role in cancer do they mutate to cancer
• stem cells?

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The Cancer Stem Cell Hypothesis

• Cancers are heterogeneous not all cells
• have the same markers, behaviors how arise?
• Does this reflect potential? Do some
• cells maintain or acquire stem cell properties
• and populate the rest of the tumor with non-
• tumorigenic cells?
• 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

• Can clonal evolution explain the data?
• Is it a global model (ie all cancers) or
• restricted? If restricted, how?
• Genetic vs. epigenetic if cancer stem
• cells contribute to a tumor, how labile?
• 3. The role of the stem cell niche in cancer
• stem cell biology

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Alternate cancer stem cell hypothesis1. Niche
requirementschange2. Progenitors mutateto
self-renew
From Lobo et al, 2007
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Myeloid Dysplasia/Leukemia via a Mutation in the
Niche
Raaijmakers et al, 2010
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Can we make stem cells from cells that are NOT
stem cells i.e. run the tape backwards?
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Successful Nuclear Transplants as a Function of
theDevelopmental 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 Vessel Precursors
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Embryonic Stem Cell Therapeutics
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iPS suggest an alternative source of stem cells
From Nishikawa et al, 2008
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Comparison of protocols to derive pluripotent
stem cells
From Nishikawa et al, 2008
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How iPS might help therapeutically
From Nishikawa et al, 2008
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iPS from patients with diseases have been
generated

• 1. ALS differentiate to motor neurons (Dimos
  et al, 2008)
• 2. Parkinsons disease (Soldner et al, 2009)
• Type I diabetes differentiate into pancreatic
  b-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