Cell Differentiation: Cell interactions in Development

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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

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• 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

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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

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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

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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

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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

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Cellular Interactions Patterning and TGFb
superfamily signaling

• a number of extracellular signaling molecules
  play roles in determining the fates of developing
  cells and where these cells will develop
• TGFb superfamily TGFb, 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 TGFb superfamily
  growth factor (Smad 1 BMP2, Smad 2 TGFb)
• 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

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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

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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