SKIP & I, My achievement

SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate

Dr. Naoko Irie
Research associate of Azim Surani laboratory,
The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge

Research Outline

with Dr. Azim Surani
with Dr. Azim Surani

Collaborative work from the research groups of professor Azim Surani, Dr. Naoko Irie et al., from the university of Cambridge, UK, and Dr. Jacob Hanna et al. from the Weizmann institute in Israel has established a robust cell culture system for human germ cell development, which led to the identification of factors crucial for human primordial germ cell (hPGC) specification. Surprisingly, the key factors important for human PGC specification were found to be distinct from the ones in mouse, a well studied mammalian model for germ cell development. Since the in vitro hPGC-like cells (hPGCLCs) can be induced not only from human embryonic stem cells (hESCs) but also from induced pluripotent stem cells (iPSCs), it enables to isolate hPGCLC population from any human ESC/iPSC line including patient-specific iPSCs using newly identified cell surface markers. This hPGCLC induction system would contribute to research on fundamental germ cell development, epigenetic dynamics, as well as increase our understanding of germ cell related diseases.

in vitro differentiation of PGC
in vitro differentiation of PGC

Germ cells, egg and sperm, are unique cell types that are able to inherit genomic and epigenetic information by producing next generation upon fertilization. Misregulation of the development process may cause germ cell disorders such as infertility, testicular tumors or mitochondrial disease, as well influencing epigenetic inheritance through germ cells. Since early human embryos are not accessible for research, the mechanism of hPGC specification was largely unknown. However, we are able to culture hESCs which are derived from human pre-implantation embryos and hiPSCs which can be derived from adult cells and resemble hESCs. Establishment of an hPGC induction system from cultured hESCs/hiPSCs would open up opportunities for studying germ cell disorders as well as the fundamentals of germ cell development including epigenetic dynamics. Previous attempts for hPGC induction from hESCs/hiPSCs by others showed low differentiation efficiency and the resulting cells were not fully characterized. Therefore, we hypothesized that the hESCs/iPSCs in the conventional culture condition acquire low competency to differentiate into the germ cell lineage. Following some attempts for PGC inductions from different culture conditions of hESCs/iPSCs, we found out that medium containing four inhibitors for GSK3β, MEK, p38 and JNK called “4i” induces great competency for germ cell differentiation. 20-50% of 4i hESCs/iPSCs can differentiate into hPGCLCs in the presence of PGC induction cytokines. The PGCLCs exhibit a global gene expression profile similar to in vivo gonadal PGCs from 7 week old human embryos, and human seminoma, which is known to show characteristic features of PGCs. Moreover, we identified a critical human germ cell specifier, the previously known endoderm regulator SOX17, which, together with BLIMP1, acts as a conserved PGC regulator. The distinct molecular mechanism of PGC fate decision between human and mouse may indicate important aspects of mammalian diversity and evolution. Moreover, we have uncovered TNAP and CD38 as specific cell surface markers for the human germ cell lineage, which greatly enhances the successful isolation of the hPGCLC population following induction from any ESC/iPSC, including disease models. The hPGC development system will serve as a robust model for understanding germ cell disorders, germ cell biology as well as the potential impact of environmentally induced epigenetic modifications, their inheritance, and consequences for subsequent generations.

Irie, N., Weinberger, L., Tang, W.W.C., Kobayashi, T., Viukov, S., Manor, Y.S., Dietmann, S., Hanna, J.H., and Surani, M.A.
"SOX17 is a critical specifier of human primordial germ cell fate." (Best of Cell 2015)

Cell 160, 253–268. 2015

Comments from First author, Dr. Naoko Irie

with Dr. Jacob Hanna
with Dr. Jacob Hanna

Our PGC specific NANOS3-mCherry reporter hESC line and the BLIMP1 knockout and SOX17 knockout cell lines are deposited into the SKIP database. SKIP is equipped with a searching system which enables researchers to quickly and efficiently browse and retrieve information of many kind of published stem cells. It is very useful to be able to search disease model stem cells by ICD(International Statistical Classification of Diseases and Related Health Problems). I believe that it enhances interactions between researchers ultimately giving rise to new and effective collaborations with the purpose to broaden research opportunities and refine knowledge in the field.

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