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Induced pluripotent stem cells by datha

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ipscs generation nuclear regprogrammaing, their therapeutic applications

ipscs generation nuclear regprogrammaing, their therapeutic applications

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  • 1. Induced Pluripotent Stem Cells Generation and their Therapeutic Applications B.DEVADATHA M.Sc IInd YEAR BMB DEPT. OF BIOCHEMISTRY & MOLECULAR BIOLOGY PONDICHERRY UNIVERSITY GUIDED BY: Dr K.JEEVARATNAM PROFESSOR DEPT. OF BMB
  • 2. INTRODUCTION • Induced pluripotent stem cells (iPS cells) are somatic cells that have been reprogrammed to a pluripotent state by the introduction of specific factors. • iPS cells are similar to embryonic stem (ES) cells in several aspects such as morphology, expression of pluripotency markers and the capacity to develop teratomas. • Yamanaka and Sir John Gurdon (2012) were awarded the Nobel Prize in Physiology or Medicine "for the discovery that mature cells can be reprogrammed to become pluripotent."
  • 3. Somatic Cell Nuclear Reprogramming
  • 4. DISCOVERY OF iPS CELLS • The human ES cells derived from human blastocysts were first established by Thomson et al. • The iPS cells were first established in 2006 by Takahashi and Yamanaka by the retrovirus-mediated transduction of four transcription factors (c-Myc, Oct3/4, SOX2, & Klf4) into mouse fibroblasts. • Human iPS cells were established in 2007, by the transduction of either the same set of transcription factors or another set of transcription factors (Oct3/4, SOX2, Nanog, Lin28) into human fibroblast. • Human iPS cells have been reported to be established from skin fibroblasts, keratinocytes, and mobilized CD34+ hematopoietic stem/progenitor cells and differentiated T cells from peripheral blood.
  • 5. Reprogramming Factors Oct4 • Expression is essential for the development of the inner cell mass (ICM) in vivo, the derivation of ES cells and the maintenance of a pluripotent state. Sox2 • Transcription factor involved in the self-renewal of ES cells. It has an important role in maintaining ES-cell pluripotency and heterodimerizes in a complex with Oct4. c-Myc • Pleiotropic transcription factor that has been linked to several cellular functions, including cell cycle regulation, proliferation, growth, differentiation and metabolism.
  • 6. Reprogramming Factors Klf4 • Expressed in a variety of tissues, including the epithelium of the intestine, kidney and the skin. • Forced overexpression of Klf4 in ES cells inhibits differentiation in erythroid progenitors, suggesting a role for this factor in ES-cell function. Nanog • Transcription factor that was involved in maintaining EScell self-renewal and pluripotency. • Nanog-deficient ES cells completely lose their selfrenewal capability, differentiating into extra-embryonic cell lineages. Lin-28 • Expressed in ES cells and during early embryogenesis but its expression becomes restricted to several tissues during late embryogenesis and adult life.
  • 7. iPSC has been generated from Mouse (Yamanaka et al., 2006) Humans (Yamanaka et al., 2007) Rhesus monkey (Liu et al., 2008) Rats (Liao et al., 2009; Li et al., 2009) Canine (Shimada, H. et al, 2010) Porcine ( Esteban, M. A. et al., 2009) Marmoset (Wu, Y. et al., 2010) Rabbit (Honda, A. et al., 2010) Equine (Kristina Nagy et al., 2011 ) Avian (Lu et al., 2011)
  • 8. iPSC Therapeutic Applications
  • 9. iPSC Therapeutic Applications (Cont) Monogenic and Polygenic Diseases • Generation of iPS cells from patients with a variety of genetic diseases with either Mendelian or complex inheritance has been described. • Include ADA-SCID, Gaucher disease type III, Huntington disease, juvenile-onset type 1 diabetes mellitus , Down syndrome. Neurodegenerative Disorders • Patient-specific fibroblasts offer a unique opportunity for studying and modeling the effects of specific gene defects on human neuronal development in vitro and other potential therapies for the relevant neurogenetic disorders. • Patient-derived iPS cells could be subsequently differentiated in vitro into dopaminergic neurons for treatment of Parkinson's disease.
  • 10. iPSC Therapeutic Applications (Cont) Degenerative Cardiac Diseases • iPS cell based cell replacement therapy is currently generating a great deal of interest in the treatment of ischemic heart diseases since iPS cells are capable of differentiating into patient-specific functional cardiomyocytes. Obstacles in therapeutic application of iPSCs in humans (i) Use of harmful oncogenes as part of the reprogramming factors . (ii) Use of viral vectors for gene delivery that carry the risk of insertional mutagenesis. (iii) Low efficiency and slow kinetics of reprogramming. (iv) Lack of robust and reliable differentiation protocols for human iPS cells.
  • 11. Generation of iPSC Derived Cardiomyocytes
  • 12. iPSC in Modelling Cardiac & Neural diseases
  • 13. Conclusion • With an aging population, ever-increasing costs of healthcare and a decrease in new drug discoveries, new and innovative ways of accelerating and streamlining human disease study and treatment are required. • Human iPSC technology offers an unprecedented opportunity to develop patient-specific and diseasespecific iPSC lines to be used for regenerative therapies, disease study, drug safety and discovery. • The potential of iPS cell technology is tremendous, but this technology is still in its infancy. • To realize the full application of iPS cells, it will be essential to improve the methodologies for iPS cell generation and to precisely evaluate each clone and sub clone of iPS cells for their safety and efficacy .
  • 14. Reference • Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–676. • Shinya Yamanaka & Helen M. Blau. Nuclear reprogramming to a pluripotent state by three approaches iPS cells: A source of cardiac regeneration Yoshinori Yoshida, Shinya Yamanaka • Giovanni Amabile and Alexander Meissner .Induced pluripotent stem cells: current progress and potential for regenerative medicine • Yingzi Oh,Heming Wei, Dongrui Ma, Xiaoming Sun,Reginald Liew. Clinical applications of patient-specific induced pluripotent stem cells in cardiovascular medicine • Yoshida Y, Yamanaka S. iPS cells: a source of cardiac regeneration. J Mol Cell Cardiol 2011;50:327e32 • Alejandra M. Vitalea, Ernst Wolvetangb, Alan MackaySima.Induced pluripotent stem cells: A new technology to study human diseases
  • 15. Thank you

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