Gametes from Stem Cells The New Frontier in Human Reproduction

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1 Gametes from Stem Cells The New Frontier in Human Reproduction Professor Gerald Schatten Pittsburgh Development Center Magee-Womens Research Institute Professor, Vice-Chair and Division Director of Obstetrics, Gynecology & Reproductive Sciences, and Professor of Cell Biology & Physiology, & of Bioengineering University of Pittsburgh School of Medicine

2 al-kimiaالكیمیاء J. B. Gurdon et al., Science 322, (2008)

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4 Clark et al. Nat. Med. 2011

5 Direct Differentiation of Human Pluripotent Stem Cells into Haploid Spermatogenic Cells Cell Reports 2, , Chas Easley, B Phillips, M McGuire, J Barringer, H Valli, B Hermann, Cal Simerly, Alek Rajkovic, Toshio Miki, Kyle Orwig, Gerald P. Schatten ============================================================== Spermatogonial stem cell transplantation into Rhesus testes regenerates spermatogenesis producing functional sperm. CELL STEM CELL 11, , 2012 Hermann, B, Sukhwani, M, Winkler, F Pascarella, J, Peters, K, Sheng, Y, Valli, H Rodriguez, M, Ezzelarab, M, Dargo, K, Peterson, K, Masterson, K, Ramsey, C, Ward, T, Lienesch, M Volk, M, Cooper, D, Thomson, A, Kiss, J, Penedo, M, Schatten, G, Mitalipov, S and Orwig, K.

6 Direct Differentiation of Human Pluripotent Stem Cells into Haploid Spermatogenic Cells Cell Reports 2, , September 27, Chas Easley, B Phillips, M McGuire, J Barringer, H Valli, B Hermann, Cal Simerly, Alek Rajkovic, Toshio Miki, Kyle Orwig, Gerald P. Schatten

7 Haploid Cells are Generated from hpscs Cultured in SSC Conditions

8 Haploid Cells from hpscs Differentiated in SSC Conditions are Acrosin-positive

9 Haploid Spermatids from Pluripotent Stem Cells Show Similar Imprint Patterns to Human Sperm

10 NOT YET!

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13 Spermatogonial stem cell transplantation into Rhesus testes regenerates spermatogenesis producing functional sperm. Hermann, B Schatten, G, Mitalipov, S, Orwig, K. Cell Stem Cell (2012)

14 Figure 1 Source: Cell Stem Cell, Volume 11, Issue 5, Pages (DOI: /j.stem ) Copyright 2012 Elsevier Inc. Terms and Conditions

15 Figure 3 Source: Cell Stem Cell, Volume 11, Issue 5, Pages (DOI: /j.stem ) Copyright 2012 Elsevier Inc. Terms and Conditions

16 Figure 5 Source: Cell Stem Cell, Volume 11, Issue 5, Pages (DOI: /j.stem ) Copyright 2012 Elsevier Inc. Terms and Conditions

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18 Fig. 3 Oogenesis, embryonic development, and offspring from female ipsc-derived PGCLCs. (A) Oogenesis and embryonic development from ipsc-derived PGCLCs. (i) Bright-field image of the recipient and reconstituted (arrows) ovary complex. K Hayashi et al. Science 2012;science Published by AAAS

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21 C.F. Waddington, 1940

22 EMBO Rep. 2013;14(1):4. doi: /embor

23 Cancer stem cells: are we missing the target? Jones et al. JNCI 96:583, 2004

24 NATURE 23 August 2012

25 Why Should We Care About the Cancer Stem Cell Hypothesis? Courtesy Jerry Shay, UT-Dallas

26 Paternal Age at Childbearing and Offspring Psychiatri and Academic Morbidity B M. D Onofrio; M E. Rickert;E. Frans; R Kuja- Halkola, C Almqvist; A. Sjölander; H Larsson; P Lichtenstein JAMA Psychiatry. February 26, doi: /jamapsychiatry Conclusions and Relevance Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity.

27 Cell Divisions for Sperm 15 yr= = = = = 840

28 Cellular evidence for selfish spermatogonial selection in aged human testes Andrology 19 DEC 2013 DOI: /j x

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31 Spermatogonial stem cell transplantation into Rhesus testes regenerates spermatogenesis producing functional sperm. Hermann, B Schatten, G, Mitalipov, S, Orwig, K. Cell Stem Cell (2012)

32 1. Save SSCs 2. Render Infertile 3. Recover 4. Transplant Viable SSCs 5. Spermatogenesis 6. Natural or A.I. Spermatogonial stem cell transplantation into Rhesus testes regenerates spermatogenesis producing functional sperm. Hermann, B Schatten, G, Mitalipov, S, Orwig, K. Cell Stem Cell (2012)

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34 TESTICULAR

35 Spermatogonial stem cell transplantation into Rhesus testes regenerates spermatogenesis producing functional sperm. Hermann, B Schatten, G, Mitalipov, S, Orwig, K. Cell Stem Cell (2012)

36 1. Save SON s SSCs 2. SON Recovers 3. Render DAD Infertile 4. DAD Recovers 5. Transplant SON s SSCs TO DAD 6. SON s Spermatogenesis IN DAD 7. Natural Cryo, then A.I. After Spermatogonial Vasectomy stem cell transplantation into Rhesus testes regenerates spermatogenesis producing functional sperm. Hermann, B Schatten, G, Mitalipov, S, Orwig, K. Cell Stem Cell (2012)

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38 Frontiers in Stem Cells & Regeneration Intensive hands-on training course September 29-October 6, 2014 MBL, Woods Hole, Massachusetts, USA World class training featuring: Current biological concepts & topics and related ethics and regulatory issues Over 40 expert international faculty members Newest lab technologies & equipment Total immersion scientific inquiry Competitive admissions deadline: July 1, 2014 More info at