Stem Cell

Report
I. Stem cells
II. Differential gene expression and cell fate
III. Why manipulate stem cells?
IV. Potential sources of therapeutic cells
V. Concluding thoughts
pluripotent stem cell
pluripotent stem cell
committed cell
pluripotent- having the potential to develop into
any cell type of the body
http://departments.weber.edu/chfam/prenatal/blastocyst.html
I. Stem cells
II. Differential gene expression and cell fate
III. Why manipulate stem cells?
IV. Potential sources of therapeutic cells
V. Concluding thoughts
Genes are made of DNA
DNA is within the nucleus of each of our cells.
This DNA is identical in each of the cells of our
bodies…
…even though different cells have very different
structures and functions
Q: How do cells with identical genetic compositions
become so different from one another?
A: Different cells express different subsets of their genes.
In neurons, gene A is
expressed but not gene B:
Gene A
Gene B
In muscle cells, gene B is
expressed but not gene A:
Gene A
Gene B
In muscle cells, gene B is expressed because muscle cells have
transcription factors that bind to gene B’s promoter.
(muscle cell specific transcription factors)
Gene A
Gene B
(promoter of gene B)
In muscle cells, gene B is expressed because muscle cells have
transcription factors that bind to gene B’s promoter.
Gene A
Gene B
I. Stem cells
II. Differential gene expression and cell fate
III. Why manipulate stem cells?
IV. Potential sources of therapeutic cells
V. Progress on stem cell therapeutics
I. Stem cells
II. Differential gene expression and cell fate
III. Why manipulate stem cells?
IV. Potential sources of therapeutic cells
A. Adult stem cells
B. Embryonic stem cells (IVF embryos)
C. Induced pluripotent stem cells
D. Embryonic stem cells (SCNT-derived)
E. Transdifferentiation
V. Concluding thoughts
Bone marrow contains Hematopoetic Stem Cells
irradiation
(injection with bone marrow)
Adult stem cell types that have been tested
clinically
Hematopoetic stem cells
Mesenchymal stem cells
Neural stem cells
Adipose stem cells
Lin et al., 2013
Most stem cell clinical trials have used adult stem cells
Lin, et al., 2013
Adult Stem Cell Therapies
pros
cons
• no ethical dilemmas
• autologous (self) donations are possible
• cells need not be manipulated or grown in culture
• no risks of teratomas (tumors)
• few tissues are represented by adult stem cells
• those tissues that DO have them have very few
• if not autologous, MUST be tissue type matched
• evidence of clinical efficacy limited to HSCs
• cannot be amplified or maintained in culture
I. Stem cells
II. Differential gene expression and cell fate
III. Why manipulate stem cells?
IV. Potential sources of therapeutic cells
A. Adult stem cells
B. Embryonic stem cells (IVF embryos)
C. Induced pluripotent stem cells
D. Embryonic stem cells (SCNT-derived)
E. Transdifferentiation
V. Concluding thoughts
http://departments.weber.edu/chfam/prenatal/blastocyst.html
Animal Models in which hESC-Derived Cells have been Effective
Deb and Sarda, 2008
Clinical Trials using hESCs
2009-2011 Geron Corporation hESC-derived oligodendrocyte
progenitors for treatment of spinal cord injuries (Daley, 2012)
-in animal models, these cells car repair damaged neurons
-the first hESC clinical study to overcome FDA restrictions
-four patients enrolled
-no publications yet; no reported negative effects, but unclear if
treatments were effective
Clinical Trials using hESCs, cont.
2009-present Advanced Cell Technology (ACT) hESC-derived retinal
pigment epithelial cells are being used to treat macular
degeneration (Schwartz,et al. 2012)
-started with 2 patients, both showed vision improvement and
no signs of tumors after 4 months
-study is continuing with higher doses of cells and in more
patients
ESCs from IVF
pros
• source tissue plentiful
• cells divide infinitely in culture
• easily programmable cells
cons
• immune response problems
• ethical controversy
• tumor risks
I. Stem cells
II. Differential gene expression and cell fate
III. Why manipulate stem cells?
IV. Potential sources of therapeutic cells
A. Adult stem cells
B. Embryonic stem cells (IVF embryos)
C. Induced pluripotent stem cells
D. Embryonic stem cells (SCNT-derived)
E. Transdifferentiation
V. Concluding thoughts
I. Stem cells
II. Differential gene expression and cell fate
III. Why manipulate stem cells?
IV. Potential sources of therapeutic cells
A. Adult stem cells
B. Embryonic stem cells (IVF embryos)
C. Induced pluripotent stem cells
1. issues with iPSCs
2. progress with iPSCs
D. Embryonic stem cells (SCNT-derived)
E. Transdifferentiation
V. Concluding thoughts
Takahashi and Yamanaka 2006
• DNA inserted randomly could create problems with endogenous DNA.
• DNA insertions are inherited by all progeny of manipulated cell.
• The genes added could cause cells to be more prone to division.
New iPSC protocols do NOT require insertion of foreign DNA
• Exposure of differentiated cells to chemical treatments
caused them to become pluripotent (Masuda et al., 2013).
• Protein transduction of somatic cells can produce iPS cells
(Nemes et al., 2013).
• Mouse lymphocytes were induced to become pluripotent
via acid treatment (Obokata et al., 2014).
With iPSCs, the pluripotency must be tested
Stadtfield & Hochedlinger 2010
I. Stem cells
II. Differential gene expression and cell fate
III. Why manipulate stem cells?
IV. Potential sources of therapeutic cells
A. Adult stem cells
B. Embryonic stem cells (IVF embryos)
C. Induced pluripotent stem cells
1. issues with iPSCs
2. progress with iPSCs
D. Embryonic stem cells (SCNT-derived)
E. Transdifferentiation
V. Concluding thoughts
Many cell types have been derived from human iPS cells
• hepatocytes (Takebe et al., 2014)
• neurons (Prilutsky et al, 2014)
• folliculogenic stem cells (Yang et al., 2014)
• cardiomyocytes (Seki et al., 2014)
• pancreatic beta cells (Thatava et al, 2011)
First iPSC clinical trial to begin this year
• lab of Dr. Masayo Takahashi at Riken in Kobe, Japan
• 6 patients with macular degeneration in trial
• iPSCs will be reprogrammed in culture to become
retinal pigment epithelium
• once 50,000 cells per patient are produced, these
will be introduced back into the retinas
Grskovic, et al. 2011
Successful “disease in a dish” models
• Familial dysautonomia, a genetic disease of
autonomic nervous system
• Rett Syndrome, a disease within the autism
spectrum
• HGPS (progeria), premature aging
• Parkinson’s, degradation of midbrain dopaminergic
neurons leading to loss of motor activity
Grskovic, et al. 2011
iSPCs
• patient-derived pluripotent cells
pros
• once established, cells divide infinitely in culture
• easily programmable cells
• less ethical controversy than ESCs
• produce excellent tools for studying disease
cons • cells require a lot of manipulation to become iSPC
• evidence of immunogenicity of iPSCs (Fu, 2013)
• low rate of induced pluripotency (~.2%)
• tumor risks
I. Stem cells
II. Differential gene expression and cell fate
III. Why manipulate stem cells?
IV. Potential sources of therapeutic cells
A. Adult stem cells
B. Embryonic stem cells (IVF embryos)
C. Induced pluripotent stem cells
D. Embryonic stem cells (SCNT-derived)
E. Transdifferentiation
V. Concluding thoughts
Freeman, 2012
ESCs from SCNT
pros
• cells divide infinitely
• easily programmable cells
• genetically identical to patient
• great for disease modeling
cons
• ethical controversy
• will require oocyte donors
• not tested much with human cells
I. Stem cells
II. Differential gene expression and cell fate
III. Why manipulate stem cells?
IV. Potential sources of therapeutic cells
A. Adult stem cells
B. Embryonic stem cells (IVF embryos)
C. Induced pluripotent stem cells
D. Embryonic stem cells (SCNT-derived)
E. Transdifferentiation
V. Concluding thoughts
Transdifferentiation
Graf, 2011
Graf, 2011
I. Stem cells
II. Differential gene expression and cell fate
III. Why manipulate stem cells?
IV. Potential sources of therapeutic cells
A. Adult stem cells
B. Embryonic stem cells (IVF embryos)
C. Induced pluripotent stem cells
D. Embryonic stem cells (SCNT-derived)
E. Transdifferentiation
V. Concluding thoughts
ESCs
iPSCs
derivation
embryos
somatic cells
cancer risk
high
very high
immunogenicity
high
some?
growth in culture
good
good
ability to program
good
good
ESCs are currently considered the “gold standard” for
pluripotency.
Current research is investigating whether iPSCs are truly
equivalent to ESCs.
Many scientists developing iPSCs still must use ESCs for
comparison in their experiments.
Conditions that might be alleviated using stemcell derived transplantations (a partial list)
macular degeneration
Parkinson’s
Type II Diabetes
Altzheimer’s
heart disease
spinal cord injuries
burns
Huntington’s
Challenges to cell culture-derived transplantations
cancer risk from cultured cells
immune response from cultured cells
creating cultured cells to have all the functions of those
cells produced by the body
the necessity of producing a LOT of the target cells in
culture
creating cultured cells that integrate with host tissues
iPSCs are outstanding tools for disease modeling
useful as a way to test drugs without experimenting on
patients
a means to generate therapies specific to specific patients
can be used also to study diseased cells and figure out
what is wrong with them

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