biology 624 - developmental genetics lecture #5 - stem cells
TRANSCRIPT
Biology 624 - Developmental Genetics
Lecture #5 - Stem Cells
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
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
Sources of Pluripotent Stem Cells
Adult somatic cells + 4 genes
Mouse Embryonic Cells and Derivation of ES Cells
From Keller, 2005
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
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
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?
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
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
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
Alternate cancer stem cell hypothesis:
1. Niche requirementschange
2. Progenitors mutateto self-renew
From Lobo et al, 2007
Raaijmakers et al, 2010
Myeloid Dysplasia/Leukemia via a Mutation in the
Niche…
Can we make stem cells fromcells 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
Cloned Mammals, Whose Nuclei Came From Adult
Somatic Cells
Embryonic Stem Cell Therapeutics
Blood VesselPrecursors
Embryonic Stem Cell Therapeutics
From Nishikawa et al, 2008
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
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
Wu and Hochedlinger, 2011
The Hematopoietic Stem Cell
Cell Fusion
From Vassilopoulos and Russell, 2003
A Clone of Xenopus laevis Frogs
The Cancer Stem Cell Hypothesis
From Donnenberg and Donnenberg, 2005
Hematopoietic stem cells – first identified
adult stem cells