Tumors Produced from Human ESC Xenografted to Immunodeficient Mice

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Tumors Produced from Human ESC Xenografted to
Immunodeficient Mice

• Ivan Damjanov
• The University of Kansas
• School of Medicine,Kansas City,KS

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Analysis of Tumors Produced from Xenografted
hESC

• Are all hESC xenografts benign?
• Do all hESC after xenografting differentiate or
  can they remain undifferentiated?
• Can hESC transform into ECC ( embryonal
  carcinoma cells)?
• Are immature neural cells (neuroblasts)
  potentially malignant?

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Analysis of Tumors Produced from Xenografted ESC
in Nude Mice

• What to look for?
• Somatic tissues- ectoderm, endoderm, mesoderm
• Extraembryonic cells-yolk sac and trophoblastic
  elements
• Undifferentiated ESC
• Malignant somatic cells

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ISCI-1 Xenograft Histology

• Number of cell lines/xenograft tumors34
• Number of clones-could not determine
• Site of xenografts testis, muscle/subcutaneous
  tissue, kidney
• Duration of xenografting-not specified

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Ectodermal Tissues

• Simple epithelia (not further characterized)
• Neuroepithelium (mature and immaturefetal)
• Neuroepithelium related epithelia
  ( pigmented retinal epithelium, choroid
  plexus)
• Squamous epithelium
• Squamous metaplasia of glandular epithelium

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Neural tubes
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Neural tube-immunohistochemistry for
neurofilaments
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Cartilage
Choroid plexus
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Pigmented retinal epithelium
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Mesenchymal Tissues

• Loose connective tissue, not further specified
• Muscle cells-smooth muscle, striated muscle, ?
  Heart cells
• Cartilage and bone
• Fat cells
• Vessels

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Loose connective tissue
Cartilage
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Endodermal tissues

• Gastrointestinal epithelia
• Bronchial epithelium

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Mucus secreting goblet cells in intestinal
epithelium
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Intestinal differentiation-immunohistochemistry
for smooth muscle actin
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Complex glands
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Association of Cells and Tissues

• At random
• Organoid
• Neural tissue aggregates
• Intestinal epithelium and smooth muscle cells
• Bronchial epithelium and smooth muscle cells and
  cartilage
• Kidney

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Retinal epithelium
Neural tissue
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Persistence of Undifferentiated hESC

• How to recognize the undifferentiated ESC ?
• Can one use standard histopathology, or is it
  necessary to use immunohistochemistry, or
  electron microscopy?
• Do these cells differentiate into other tissues
  or are they developmentally nullipotent?
• Are these xenografts malignant?

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Final Conclusions

• Most xenografts of hESC are benign teratomas,
  composed of somatic tissues
• Some tissues are preferentially formed such as
  neural tissue and mesenchyme
• Differentiation has a limited scope and
  organogenesis occurs exceptionally
• Placental/yolk sac elements were not seen

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Final Conclusions (continued)

• Some xenografts (3) contain embryonal carcinoma
  like cells (EC-like cells)
• The developmental potential of these EC-like
  cells remains unknown
• The malignancy of these EC-like cells remains
  unknown

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Some Remaining Questions about Human ESC

• Are they truly pluripotent, i.e., capable of
  differentiating into somatic and extraembryonic
  tissues?
• Are they all benign?
• Comparison with human ECC- what are the
  significant similarities and/or differences?
• Are they changing during over time?

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Suggestions for Further Studies

• Xenograft cell lines that have in vitro shown
  extraembyonic (yolk sac and trophoblastic)
  differentiation
• Xenograft hESC derived cell lines that have a
  somatic phenotype ( e.g., cardiac, hepatic,
  insular phenotype)
• Xenograft cell lines that have? ECC

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