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Stem cells Differential gene expression and cell fate Why manipulate stem cells?

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?

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  1. Stem cells Differential gene expression and cell fate Why manipulate stem cells? Potential sources of therapeutic cells Concluding thoughts

  2. pluripotent stem cell pluripotent stem cell committed cell

  3. pluripotent- having the potential to develop into any cell type of the body

  4. http://departments.weber.edu/chfam/prenatal/blastocyst.html

  5. Stem cells Differential gene expression and cell fate Why manipulate stem cells? Potential sources of therapeutic cells Concluding thoughts

  6. Genes are made of DNA

  7. DNA is within the nucleus of each of our cells.

  8. This DNA is identical in each of the cells of our bodies…

  9. …even though different cells have very different structures and functions

  10. Q: How do cells with identical genetic compositions become so different from one another?

  11. A: Different cells express different subsets of their genes. 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

  12. 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)

  13. In muscle cells, gene B is expressed because muscle cells have transcription factors that bind to gene B’s promoter. Gene B Gene A

  14. Stem cells Differential gene expression and cell fate Why manipulate stem cells? Potential sources of therapeutic cells Progress on stem cell therapeutics

  15. Stem cells • 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

  16. Bone marrow contains Hematopoetic Stem Cells

  17. irradiation

  18. (injection with bone marrow)

  19. Adult stem cell types that have been tested clinically Hematopoetic stem cells Mesenchymal stem cells Neural stem cellsAdipose stem cells Lin et al., 2013

  20. Most stem cell clinical trials have used adult stem cells Lin, et al., 2013

  21. Adult Stem Cell Therapies • 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

  22. Stem cells • 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

  23. http://departments.weber.edu/chfam/prenatal/blastocyst.html

  24. Animal Models in which hESC-Derived Cells have been Effective Deb and Sarda, 2008

  25. 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

  26. 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

  27. ESCs from IVF • source tissue plentiful • cells divide infinitely in culture • easily programmable cells pros • immune response problems • ethical controversy • tumor risks cons

  28. Stem cells • 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

  29. Stem cells • 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

  30. Takahashi and Yamanaka 2006

  31. 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.

  32. 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).

  33. With iPSCs, the pluripotency must be tested Stadtfield & Hochedlinger 2010

  34. Stem cells • 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

  35. 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)

  36. 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

  37. Grskovic, et al. 2011

  38. 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

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