Download DEFINITION OF A STEM CELL

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 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
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 cancer
stem cells?
The Cancer Stem Cell Hypothesis
1. Cancers are heterogeneous – not all cells
have the same markers, behaviors – how arise?
2. Does this reflect “potential”? Do some
cells maintain or acquire stem cell properties
and populate the rest of the tumor with nontumorigenic 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 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. 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
Cloned Mammals, Whose Nuclei Came
From Adult Somatic Cells
Embryonic Stem Cell Therapeutics
Blood Vessel
Precursors
Embryonic Stem Cell Therapeutics
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)
3. 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
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