Stem Cells from the Ground Floor

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Stem Cells from the Ground Floor
Jonathan Golob Medical Scientist Training
Program University of Washington Center for
Cardiovascular Biology and Regenerative
Medicine Department of Pathology Doctoral
Candidate
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What happens when we get injured, or something
just wears out?
Immune cells come in and clear away the debris
and any infection.
Regeneration is the complete restoration of the
original tissue. Damaged tissue is replaced by
new functional cells.
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Injured tissues heal by a blend of repair and
regeneration.
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Tissues regenerate new functional cells by
either dividing the existing functional cells
A stem cell must make more copies of itself
(self-renew) and give rise to more capable
offspring (differentiate).
or by activating an adult stem cell population.
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Adult stem cells can give rise to all the cells
in their tissue.
The more capable the cell becomes, the fewer
types of cells it can become. During
differentiation, cells progress down increasingly
restrictive lineages.
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Our bodies have many adult stem cell niches
Blood
Gut
Skin
Bone, Skin, Tendon, cartilage
Liver
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Early Moments in Mammalian Development
Morula
Blastocyst
Zygote
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Day 5 Human EmbryoBlastocyst Stage, 100 cells
Trophoectoderm (placenta and amnion)
Inner cell mass (all tissues in the body)
1/100 inch
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The inner cell mass gives rise to all the cells
in the body.
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During development, the daughters of the inner
cell mass differentiate into the cell types of
the body.
Gut
Endoderm
Blood
Inner Cell Mass
Mesoderm
Heart
Ectoderm
Skin
Brain
Germ
Sperm Or Eggs
Time of Gestation
After Birth
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Human Embryonic Stem Cells
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The embryonic stem cell is the stem cell of stem
cells
Embryonic Stem Cell
Gut
Endoderm
Scientists have figured out how to make inner
cell mass cells self-renew in plastic dishes. A
few hundred cells from one embryo can be grown
into at least 1.3 1031 cells creating a stem
cell line.
Blood
Mesoderm
Heart
Ectoderm
Skin
Brain
Germ
Sperm Or Eggs
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Embryonic stem cells can be differentiated in
plastic dishes into useful cell types.
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Discarded in-vitro fertilization clinic embryos
or somatic cell nuclear transfer embryos are used
to create human embryonic stem cells.
Eggs collected for in-vitro fertility treatment
cannot be easily frozen and stored. Early embryos
created after the combination of sperm and eggs
can be frozen. An excess of embryos are created
as the process of egg collection is painful,
dangerous and expensive. For most couples, more
embryos are created than are needed to have a
desired number of children.
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Somatic cell nuclear transfer is an alternate
source of embryonic stem cells
Unfertilized egg
Fusion with patients cell
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Somatic Cell Nuclear Transfer derived embryonic
stem cells avoid immune rejection problems and
allow the study of complex genetic diseases.
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The majority of embryonic stem cell research does
not create new embryonic stem cell lines.
Active areas of research include Directing the
differentiation into useful cell types. Studying
cell types that are difficult to acquire from
other sources. Studying the effect of drugs on
human development. What makes embryonic stem
cells different from other stem cells and
functional adult cells. Developing new treatments
for common diseases using embryonic stem cell
derived cells.
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Review of Embryonic Stem Cell Properties

• Derived from 4-5 day old embryos (Prior to
  implantation in uterus)
• Indefinite proliferative capacity (immortal)
  making a stem cell line
• Can become any cell type in the body
• The only cells that definitely can become heart
  muscle cells and other clinically important cell
  types.
• Allows experiments that would be otherwise
  impossible.

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A comparison between adult and embryonic stem
cells.
Adult stem cells
Embryonic stem cells
Typically reside in or near their tissue
Created from inner cell mass cells that exist
only in very early embryos
Are capable of giving rise to functional cells in
their tissue (but not other tissue types) Are
typically found only in tissues that undergo
regular turnover.
Are capable of giving rise to all of the cell
types in the body including non-regenerative
Can be divided many times (possibly indefinitely)
in culture to make many cells.
Decrease in both number and activity as one ages.
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The Problems We Face
Leading Causes of Death in the US (2001)
CDC NCHS
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The heart is an example of a non-regenerative
organ frequently injured.
Approximately one billion heart cells are lost
during a serious heart attack. If one survives
the initial event, a progressive chronic heart
failure often occurs due to the replacement of
functional beating heart cells with a tough
fibrous scar.
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Transplantation is the current standard treatment
for severe heart disease.
2,016 heart transplants were performed in
2004. About 2,500 Americans die of
cardiovascular disease each day. If all major
forms of cardiovascular disease were eliminated,
life expectancy would increase by about 7 years.
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Instead of replacing the whole organ, why not
just replace the lost cells?
For tissues incapable of regenerating, we look
towards stem cells as a source of functional
replacement cells.
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Can other tissues adult stem cells become heart
cells by transdifferentation?
Blood
Inner Cell Mass
Lateral Mesoderm
Mesoderm
Heart
Despite some early non-reproducable results,
adult bone marrow cells cannot become heart,
liver or brain cells.
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There may be adult stem cells in the heart.
Various labs around the world have described four
non-overlapping stem cell populations in the
heart. The data is still very incomplete for
each of these cell types. It is unclear what
role, if any, is played by these cells. An
eventual goal is to activate these cells after a
heart attack, or somehow augment their function.
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Human embryonic stem cells have reproducibly
differentiated into heart cells that can survive
grafting into a heart.
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Stem cells therapies promise to tip the balance
of healing more towards regeneration.
Tissues resort to non-functional repair
mechanisms when there is a lack of functional
replacement cells either due to the properties of
the tissue or the endogenous regeneration
pathways being overwhelmed. Embryonic stem cells
have an unmatched and undisputed ability to
become any cell type found within the body.
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Adult stem cells from the bone marrow cannot
transdifferentiate into heart cells
Early attempts, using a flawed experimental
approach, falsely indicated that bone marrow
derived stem cells could become heart cells,
against their lineage commitment.
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Hwang Wu-suk