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The use of human stem/progenitor cells in reproductive medicine: Where are we now?

The use of human stem/progenitor cells in reproductive medicine: Where are we now?. Necati FINDIKLI. Michael Faraday (1791-1867).

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The use of human stem/progenitor cells in reproductive medicine: Where are we now?

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  1. The use of human stem/progenitor cells in reproductive medicine: Where are we now? Necati FINDIKLI

  2. Michael Faraday (1791-1867) British Prime Minister William Gladstone, observing Faraday performing a particularly unlikely experiment one day, pointedly asked him how useful such a 'discovery' could possibly be. "Why," Faraday smartly replied, "you will soon be able to tax it!"

  3. 33 Years...

  4. Scientific and Medical Developments • Ovulation Induction • CVS • ICSI • Cryopreservation of gametes/embryos • Preimplantation Genetic Diagnosis • Stem Cell Technologies

  5. Stem Cell Resources Embryonic Stem Cells Amniotic Stem Cells Placenta-derived Stem Cells Fetal Stem Cells Cord Blood Stem Cells Adult Stem Cells Reproductive Medicine

  6. Stem Cells in Reproductive Medicine • Reproductive Organ Tumors • Urinary Insufficency • Endometriosis • Infertility • Fertility Preservation • Infertility Treatment • Germline Gene Therapy

  7. Endometrial Stem Cells “Endometrial regeneration is established with the help of the cells in basalis, not functionalis” (Prianishnikov, 1978; Padykulaet al., 1984; Padykula,1991) Gargett, 2007

  8. Endometrial Stem Cells • In sex-mismatched transplantation patients chimerism was observed in several tissues including liver, intestines and endometrium. Kleeberger et al., 2002; Okamoto et al. 2002; Taylor, 2004

  9. Endometrial Stem Cells Gargett and Masuda, 2010

  10. Endometriosis Gargett and Guo, 2010

  11. Stem Cells Three main Characteristics • Unspecialized cells • Can renew themselves for a long periods of time • Can be induced to form other specialized cells in a body.

  12. Stem Cells “Self-renewal” “Stem Cell” Differentiation Pluripotency “Progenitor Cell” “Transiently Amplified Cells” “Differentiated Cells”

  13. Stem Cell Niche

  14. Production of Gametes Nagano. 2007

  15. Production of Gametes from Primordial Germ Cells (PGCs) or Gamete Stem Cells

  16. Potential Use of PGCs in Reprod. Medicine Cell/Tissue Freezing Chemotherapy/ Radiotherapy Germline Gene Therapy Stem Cells Cell/Tissue Freezing In vitro Culture Transplantation In vitro Gamete Production In vivo gamete production Oocyte Sperm Fertility Preservation Gene Therapy Infertility Therapy

  17. Fertility Preservation Kubota andBrinster,2005; Geens et al., 2008

  18. Gamete Stem Cells -In vitro Culture- In vitro growth of murine spermatogonial stem cells. Kubota et al.,2003;2004

  19. GSC- In vitro Culture 2005

  20. Hayashi et al. 2011

  21. Propagation of human spermatogonial stem cells in vitro Sadri-Adrekani et al. 2009, 2011

  22. In vitro production of fertile sperm from murine spermatogonial stem cell lines “The system can induce spermatogenesis from SSCs that show spermatogenic failure due to a micro-environmental defect in their original testes. Thus, an in vitro system is established that can be used to correct or manipulate the micro-environmental conditions required for proper spermatogenesis from murine SSC lines.” Sato et al. 2011

  23. Production of Gametes from Embryonic Stem Cells (ESCs) And induced Pluripotent Stem Cells (iPSCs)

  24. Production of Gametes Nagano. 2007

  25. “Developmental Tree”

  26. Embryonic Stem Cells Trophectoderm ICM Evans andKaufman, 1981 (mESC) Thompson et al., 1998 (hESC)

  27. Somatic cells SCNT + Oocyte Sperm Donation Parthenogenetic activation of oocytes In Vitro Fertilization For ART purposes In Vitro Fertilization For research purposes 8-cell embryos Embryo biopsy for PGD Blastomeres (In vitro culture) Arrested embryos Morula Morula Affected embryos Coculture with genetically-labelled cells Blastocysts ICM Human embryonic stem (hES) cells (Findikli and Vemuri. 2009)

  28. Sperm cells from embryonic stem cells

  29. Oocytes from Stem Cells Derivation of oocytesfrommouseembryonicstemcells Hubner et al. 2003 Testicularcellconditionedmediumsupportsdifferentiation of embryonicstem(ES) cellsintoovarianstructurescontainingoocytes Lacham-Kaplan et al. 2005

  30. Sperm cells from embryonic stem cells Nayernia et al. 2006 • ICSI was applied on 210 oocytes • 65 oocytes were fertilized • 7 transgenic live birth

  31. Human Embryonic Stem Cells Findikli et al. 2006

  32. Somatic cells SCNT + Oocyte Sperm Donation Parthenogenetic activation of oocytes In Vitro Fertilization For ART purposes In Vitro Fertilization For research purposes 8-cell embryos Embryo biopsy for PGD Blastomeres (In vitro culture) Arrested embryos Morula Morula Affected embryos Coculture with genetically-labelled cells Blastocysts ICM Somatic cell Reprogramming Human embryonic stem (hES) cells IPs (Findikli and Vemuri. 2009)

  33. Patient-specific gamete production 1 Somatic cells Oocyte Parthenogenetic Activation SCNT 8-Cell Embryo Oocyte Sperm Morula Genetic Selection In Vitro Differentiation Blastocyst Embryonic Germ Cells Somatic Cell Reprogramming Genetic Modification 3 2 hES Cells iPSCs Adult Stem Cells

  34. Oocytes from Adult Stem Cells “Can bone marrow or peripheral blood-derived stem cells be sources of oocytes?” “Oocytegeneration in adultmammalianovariesbyputativegermcells in bone marrowandperipheralblood” Johnson et al. 2005 Mice were sterilized by chemotherapy. Oocyte production was observed after peripheral blood transfusion.

  35. Oocytes from Adult Stem Cells “Germlinestemcellsandfolicularrenewal in thepostnatalmammalianovary” Johnson et al. 2004 “Oogenesis in culturesderivedfromadulthumanovaries” Bukovsky et al. 2005 "Ovulatedoocytes in adultmicederivedfromnon-circulatinggermcells" Eggan et al. 2005

  36. Oocytes from Adult Stem Cells

  37. Oocytes from Adult Stem Cells

  38. More questions than answers? A B Reproducibility of the results?

  39. Clinical Translation ?

  40. Production of Gametes Erasure of genomic imprinting??? Cell-cycle control & Differentiation ??? Marques-Mari et al. 2009

  41. Conclusion Jules Verne (1828-1905) “Anything one man can imagine, other men can make real”!"

  42. Conclusion Studies show that gamete production from stem cells is now possible to some extent. On the other hand there are still numerous unresolved or unknown issues regarding the molecular pathways leading to the optimal production, maturation and functionality of the produced gametes. Nearly all studies have been performed on animal models. Therefore, whether similar success can be obtained in humans is still not clear. We are still couple of steps far from seeing their potentials in a clinical setting.

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