MedicalResearch: Could this be helpful for any individual with infertility problems?
Dr Hanna: Our research is focused on taking skin cell samples and converting them into embryonic-like stem cells (iPS cells) via direct reprogramming and without using embryo derived stem cell lines. Then we are focusing in differentiating these male or female iPS lines into sperm cells or oocytes, respectively. We have succeeded in the first and most important step of the process, where we succeed in reaching the progenitor cell state for sperm and egg (we have not achieved mature sperm and eggs ….Very important to emphasize!). So we are now focusing on completing the second half of this process. Once that is achieved this may become useful for any individual with fertility problems.
MedicalResearch: Could this be a viable option ALSO for same-sex couples? What are the prospects for letting gay or lesbian couples produce progenitor cell state cells from their skin cells? For example, is it conceivable that the “second half” of the protocol could some day also be done in vitro (making fully mature sperm and eggs), so that men could produce egg cells and women sperm cells?
Dr Hanna: In my opinion, It will be misleading to say that this scenario is impossible for male donor iPSCs. However, it is really important to emphasize that while this scenario might be technically possible and feasible, it is remote at this stage and many challenges need to be overcome. Further, there are very serious ethical and safety issues to be considered when and if such scenarios become considered in the distant future. Kevin Eggan (Harvard University) has previously shown that he can take Male mouse ES line, and induce loss of the Y chromosome (they become X0 instead of XY), and he generated female mice from those previously XY male lines (loss of Y chromosome is sufficient to result in differentiation of female germ cells by default (one X chromosome is sufficient). (http://www.ncbi.nlm.nih.gov/pubmed/11981557 -).
Once scientists are able to reconstitute the Second half of the germ cell induction protocol in the petri dish with human cells (it is not feasible in mice even currently), it will be likely possible to induce loss of Y chromosome from human male iPSCs lines and then generate oocytes (the opposite is rather unlikely, because it is very hard to introduce an entire Y chromosome in female cell lines – the technology is not there yet).
MedicalResearch: Could you walk me through the general process of creating sperm and egg from skin cells? (Also what chemical growth factors did you use to encourage the development of the PGCs?)
Dr Hanna: We use either embryonic stem cell (ESC) or induced pluripotent stem cells reprogrammed from adult skin cells via the Yamanaka approach (termed iPS cells).
In our paper we grow these ESCs/iPSCs in growth condition that make them correspond to earlier developmental stage become more naive state, and it turns out these cells in response to defined cytokines, known to be important for germ cell generation, are very robust in generating pre-cursors for human sperm and egg, termed PGCs (primordial germ cells). Conventional human iPSCs/ESCs grown in conventional non-naive conditions, are not efficient in differentiating into this crucial pathway.
So in addition to putting the 4 Yamanaka factors, we include in the media 4 small molecule inhibitors (Gafni et al nature 2013 – published by our group last year) to make the ipsc correspond to even more early developmental stage. The ipscs and escs are maintained in this naive-like state, and then when we give them the proper cytokines they make progenitor cell state cells very efficiently, by providing BMP4 cytokine.
MedicalResearch: How long would it take for the progenitor cell state cells to develop into fully fledged eggs/sperm?
Dr Hanna: it hard to predict at this moment, and we and other groups are trying to have these cells complete the process of turning into sperm or eggs after injecting them into host mouse testis/ovary, or completely do this in a plastic dish an a defined environment. This is going to be a very active area of research, and I am optimistic.
I cannot predict timeframes, but we and other groups are following up very hard and thoroughly on this.
SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate
Irie, Naoko et al.
Cell , Volume 160 , Issue 1 , 253 – 268
MedicalResearch.com Interview with:, & Jacob (Yaqub) Hanna M.D. Ph.D. (2015). Scientists Complete First Steps Toward Making Sperm and Eggs From Skin Stem Cells MedicalResearch.com