Cell Differentiation Cmtut - 6305

Cell Differentiation: Cell
interactions in Development
Patricia Zuk, PhD
Research Director
Regenerative Biogengineering and Repair (REBAR) Lab
Department of Surgery
David Geffen School of Medicine at UCLA
so cells can interact with each other and
with their environment
this interaction turns specific signaling
paths ON or OFF
these pathways become important for
mediating proliferation, differentiation and
apoptosis
all three are crucial to development
Differentiation: Stem
cells
so fertilization of the egg
takes place in the oviduct
the fertilizes zygote travels
to the uterus for implantation
along the way the zygote
begins to divide (mitosis)
2-cell, 4-cell, 8-cell
embryonic stages etc.
the embryo reaches a stage
called the morula = ball of
small cells (embryo has not
enlargened)
by the end of the first week
the second embryonic stage
the blastocyst - forms
Differentiation: Embryonic Stem
cells
the blastocyst is a hollow
ball of cells containing an
outer rings of progenitor
cells = trophoblast and an
inner mass of cells at one
end of the embryo = inner
cell mass
it is these ICM cells that are
the source for the derivation
of embryonic stem (ES)
cells
the ES cells are said to be totipotent have the ability to specialize or differentiate
into ALL cells of the embryo
the blastocyst then begins a process of differentiation and these ES cells form
populations of stem cells with more restricted potentials
the ES cells first differentiate into two layers called the embryonic disc divides the
blastocyst cavity into an amniotic cavity and a yolk sac (primitive hematopoietic
organ)
these two layers then continue to differentiate into the three germ layers of the
embyro
ectoderm, mesoderm and endoderm
the formation of these germ layers marks the gastrula embryonic stage
Germ Layers
the ectoderm, mesoderm and endoderm are thought to
be made up of stem cells with a more restricted
phenotype when compared to ES cells BUT still capable
of forming multiple cell types within that lineage
e.g. pluripotent stem cells
interactions between signaling molecules produced by
these germ layers and with the developing ECM around
these tissues results in specific developmental events =
patterning
patterning requires the exposure of cells to a succession
of signals and subsequent activation of their associated
pathways
Cellular interactions in
development: Induction
interactions between the cells of the germ
layers influence the fate of the stem cells
within these layers
can affect their differentiation paths
induction = mechanism where one cell
population influences the development of
neighbouring cells
e.g. mesoderm induces the overlying
ectoderm to form neural tissue
embryonic development is a series of
inductive events
binary have a choice between one fate
or another (presence of one signal
development down one path, absence of
signal development down another path
gradient multiple fates may result
dependent upon the level or threshold of
the signaling molecule (these signaling
molecules are called morphogens)
relay a signal induces a cascade which
determines the fate of cells in proximity
these cells than produce additional signals
which affect the fate of their neighbours
Cellular Interactions: Patterning and TGF superfamily
signaling
a number of extracellular signaling molecules play roles in determining the fates
of developing cells and where these cells will develop
TGF superfamily: TGF , BMPs, activin (BMP2 and BMP4)
wide role in development
mediate proliferation of stem cells
can determine stem cell fate e.g. BMP4 = mesoderm
also mediate the production of CAMs, growth factors, ECM molecules all
which play roles in cell signaling and resulting differentiation responses
homologs found in multiple vertebrates
binding of these homologs to their receptors results in their activation
this activation phosphorylates/activates downstream adaptors called Smads
a cascade of Smads are activated resulting in eventual nuclear translocation
and regulation of gene expression
these Smads are specific to the TGF superfamily growth factor (Smad 1 =
BMP2, Smad 2 = TGF)
this signaling path is fine-tuned by the action of several adaptor proteins
(chordin, xolloid, noggin)
this fine tuning can result in the induction of neural tissue as opposed
to mesodermal tissue and results in the patterning of tissues within
the embryo
Other Patterning Signal Paths
numerous other patterning pathways comprised
of multiple signaling proteins
e.g. hedgehog pathway patterning of local tissues
and determination of cell fates
initial studies in Drosophila
homologs now characterized in vertebrates
hedgehog (sonic and indian hh in vertebrates), wingless
(Wnt in vertebrates), patched, smoothened, dishevelled
limb patterning FGF, sonic hedghog,
neural tube differentiation sonic hedgehog gradients
Want to know how ridiculous this
gets??
other signaling molecules in cell
differentiation/tissue fate determination
brachyury mesoderm
goosecoid
toll, spaetzle, cactus & dorsal
dorsal targets: snail, twist, rhomboid
delta, notch, jagged, suppressor of hairless
hunchback, Kruppel
even-skipped, fushi-tarazu

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