Biology 624 - Developmental Genetics Lecture #5 - Stem Cells
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
TYPES OF STEM CELLS: Embryonic stem cells Adult stem cells Cancer stem cell Germline stem cell iPS – induced pluripotent stem cells
Sources of Pluripotent Stem Cells Figures\Chapter21\DevBio7e21221.jpg Adult somatic cells + 4 genes
Mouse Embryonic Cells and Derivation of ES Cells From Keller, 2005
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
Hematopoietic stem cells – first identified adult stem cells
Some types and sources of adult stem cells From Jordan et al, 2006
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)
The stem cell niche concept From He et al, 2009
Blood vessels may provide a neural stem cell niche Kokovay et al (2010) Cell Stem Cell
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?
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
The Cancer Stem Cell Hypothesis From Dick, 2008
Scenarios of how cancer stem cells can affect tumor formation From Jordan et al, 2006
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
Alternate cancer stem cell hypothesis: 1. Niche requirements change 2 Alternate cancer stem cell hypothesis: 1. Niche requirements change 2. Progenitors mutate to self-renew From Lobo et al, 2007
Myeloid Dysplasia/Leukemia via a Mutation in the Niche… Raaijmakers et al, 2010
Can we make stem cells from cells that are NOT stem cells – i.e. “run the tape backwards”?
Successful Nuclear Transplants as a Function of the Developmental Age of the Donor Nucleus Figures\Chapter04\DevBio7e04060.jpg
Cloned Mammals, Whose Nuclei Came From Adult Somatic Cells Figures\Chapter04\DevBio7e04081.jpg
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Embryonic Stem Cell Therapeutics Blood Vessel Precursors Figures\Chapter21\DevBio7e21231.jpg
Embryonic Stem Cell Therapeutics Figures\Chapter21\DevBio7e21232.jpg
iPS suggest an alternative source of stem cells From Nishikawa et al, 2008
Comparison of protocols to derive pluripotent stem cells From Nishikawa et al, 2008
How iPS might help therapeutically From Nishikawa et al, 2008
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) Type I diabetes – differentiate into pancreatic b-cells (Maehr et al, 2009) Refs in Maehr et al, 2009
Wu and Hochedlinger, 2011
The Hematopoietic Stem Cell Figures\Chapter15\DevBio7e15211.jpg
From Vassilopoulos and Russell, 2003 Cell Fusion From Vassilopoulos and Russell, 2003
A Clone of Xenopus laevis Frogs Figures\Chapter04\DevBio7e04070.jpg
The Cancer Stem Cell Hypothesis From Donnenberg and Donnenberg, 2005
Hematopoietic stem cells – first identified adult stem cells Figures\Chapter15\DevBio7e15212.jpg