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Stem cells Differential gene expression and cell fate Why manipulate stem cells? Potential sources of therapeutic cells Concluding thoughts. pluripotent stem cell. pluripotent stem cell. committed cell. pluripotent - having the potential to develop into any cell type of the body.

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Stem cells

Differential gene expression and cell fate

Why manipulate stem cells?

Potential sources of therapeutic cells

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


Stem cells

Differential gene expression and cell fate

Why manipulate stem cells?

Potential sources of therapeutic cells

Concluding thoughts







A: Different cells express different subsets of their genes. so different from one another?

In neurons, gene A is expressed but not gene B:

In muscle cells, gene B is expressed but not gene A:

Gene A

Gene A

Gene B

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 B

Gene A

(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 B

Gene A


Stem cells have transcription factors that bind to gene B’s promoter.

Differential gene expression and cell fate

Why manipulate stem cells?

Potential sources of therapeutic cells

Progress on stem cell therapeutics


  • Stem cells have transcription factors that bind to gene B’s promoter.

  • Differential gene expression and cell fate

  • Why manipulate stem cells?

  • Potential sources of therapeutic cells

    • Adult stem cells

    • Embryonic stem cells (IVF embryos)

    • Induced pluripotent stem cells

    • Embryonic stem cells (SCNT-derived)

    • Transdifferentiation

  • Concluding thoughts


Bone marrow contains have transcription factors that bind to gene B’s promoter.Hematopoetic Stem Cells


irradiation have transcription factors that bind to gene B’s promoter.


(injection with bone marrow) have transcription factors that bind to gene B’s promoter.


Adult stem cell types that have been tested clinically have transcription factors that bind to gene B’s promoter.

Hematopoetic stem cells

Mesenchymal stem cells

Neural stem cellsAdipose stem cells

Lin et al., 2013


Most stem cell clinical trials have used adult stem cells have transcription factors that bind to gene B’s promoter.

Lin, et al., 2013


Adult Stem Cell Therapies have transcription factors that bind to gene B’s promoter.

  • no ethical dilemmas

  • autologous (self) donations are possible

  • cells need not be manipulated or grown in culture

  • no risks of teratomas (tumors)

pros

  • 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

cons


  • Stem cells have transcription factors that bind to gene B’s promoter.

  • Differential gene expression and cell fate

  • Why manipulate stem cells?

  • Potential sources of therapeutic cells

    • Adult stem cells

    • Embryonic stem cells (IVF embryos)

    • Induced pluripotent stem cells

    • Embryonic stem cells (SCNT-derived)

    • Transdifferentiation

  • Concluding thoughts


http:// have transcription factors that bind to gene B’s promoter.departments.weber.edu/chfam/prenatal/blastocyst.html


Animal Models in which have transcription factors that bind to gene B’s promoter.hESC-Derived Cells have been Effective

Deb and Sarda, 2008


Clinical Trials using have transcription factors that bind to gene B’s promoter.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 have transcription factors that bind to gene B’s promoter.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 have transcription factors that bind to gene B’s promoter. from IVF

  • source tissue plentiful

  • cells divide infinitely in culture

  • easily programmable cells

pros

  • immune response problems

  • ethical controversy

  • tumor risks

cons


  • Stem cells have transcription factors that bind to gene B’s promoter.

  • Differential gene expression and cell fate

  • Why manipulate stem cells?

  • Potential sources of therapeutic cells

    • Adult stem cells

    • Embryonic stem cells (IVF embryos)

    • Induced pluripotent stem cells

    • Embryonic stem cells (SCNT-derived)

    • Transdifferentiation

  • Concluding thoughts


  • Stem cells have transcription factors that bind to gene B’s promoter.

  • Differential gene expression and cell fate

  • Why manipulate stem cells?

  • Potential sources of therapeutic cells

    • Adult stem cells

    • Embryonic stem cells (IVF embryos)

    • Induced pluripotent stem cells

      • issues with iPSCs

      • progress with iPSCs

    • Embryonic stem cells (SCNT-derived)

    • Transdifferentiation

  • Concluding thoughts


Takahashi and Yamanaka 2006 have transcription factors that bind to gene B’s promoter.



New DNA.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 DNA.iPSCs, the pluripotency must be tested

Stadtfield & Hochedlinger 2010


  • Stem cells DNA.

  • Differential gene expression and cell fate

  • Why manipulate stem cells?

  • Potential sources of therapeutic cells

    • Adult stem cells

    • Embryonic stem cells (IVF embryos)

    • Induced pluripotent stem cells

      • issues with iPSCs

      • progress with iPSCs

    • Embryonic stem cells (SCNT-derived)

    • Transdifferentiation

  • Concluding thoughts


Many cell types have been derived from human DNA.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
First DNA.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 DNA., et al. 2011


Successful disease in a dish models
Successful “disease in a dish” models DNA.

  • 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 DNA.

  • patient-derived pluripotent cells

  • once established, cells divide infinitely in culture

  • easily programmable cells

  • less ethical controversy than ESCs

  • produce excellent tools for studying disease

pros

  • cells require a lot of manipulation to become iSPC

  • evidence of immunogenicity of iPSCs (Fu, 2013)

  • low rate of induced pluripotency (~.2%)

  • tumor risks

cons


  • Stem cells DNA.

  • Differential gene expression and cell fate

  • Why manipulate stem cells?

  • Potential sources of therapeutic cells

    • Adult stem cells

    • Embryonic stem cells (IVF embryos)

    • Induced pluripotent stem cells

    • Embryonic stem cells (SCNT-derived)

    • Transdifferentiation

  • Concluding thoughts



ESCs DNA. from SCNT

  • cells divide infinitely

  • easily programmable cells

  • genetically identical to patient

  • great for disease modeling

pros

  • ethical controversy

  • will require oocyte donors

  • not tested much with human cells

cons


  • Stem cells DNA.

  • Differential gene expression and cell fate

  • Why manipulate stem cells?

  • Potential sources of therapeutic cells

    • Adult stem cells

    • Embryonic stem cells (IVF embryos)

    • Induced pluripotent stem cells

    • Embryonic stem cells (SCNT-derived)

    • Transdifferentiation

  • Concluding thoughts


Transdifferentiation DNA.

Graf, 2011



  • Stem cells DNA.

  • Differential gene expression and cell fate

  • Why manipulate stem cells?

  • Potential sources of therapeutic cells

    • Adult stem cells

    • Embryonic stem cells (IVF embryos)

    • Induced pluripotent stem cells

    • Embryonic stem cells (SCNT-derived)

    • Transdifferentiation

  • Concluding thoughts


ESCs DNA.

iPSCs

derivation

cancer risk

immunogenicity

growth in culture

ability to program

embryos

high

high

good

good

somatic cells

very high

some?

good

good


ESCs DNA. 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 stem-cell 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 transplantations (a partial list)

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 transplantations (a partial list) 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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