Specification of human germ cell fate with enhanced progression capability supported by hindgut organoids
João Pedro Alves-Lopes,
Frederick C.K. Wong,
Walfred W.C. Tang,
Wolfram H. Gruhn,
Navin B. Ramakrishna,
Geraldine M. Jowett,
Kirsi Jahnukainen,
M. Azim Surani
Affiliations
João Pedro Alves-Lopes
Wellcome/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK; NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, J9:30, Department of Women’s and Children’s Health, Karolinska Institutet and Karolinska University Hospital, Visionsgatan 4, Solna, 17164 Stockholm, Sweden; Corresponding author
Frederick C.K. Wong
Wellcome/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
Walfred W.C. Tang
Wellcome/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
Wolfram H. Gruhn
Wellcome/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
Navin B. Ramakrishna
Wellcome/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK; Genome Institute of Singapore, A∗STAR, Biopolis, Singapore 138672, Singapore
Geraldine M. Jowett
Wellcome/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
Kirsi Jahnukainen
NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, J9:30, Department of Women’s and Children’s Health, Karolinska Institutet and Karolinska University Hospital, Visionsgatan 4, Solna, 17164 Stockholm, Sweden; New Children’s Hospital, Paediatric Research Centre, University of Helsinki and Helsinki University Hospital, Pl 281, 00029 Helsinki, Finland
M. Azim Surani
Wellcome/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK; Corresponding author
Summary: Human primordial germ cells (hPGCs), the precursors of sperm and eggs, are specified during weeks 2−3 after fertilization. Few studies on ex vivo and in vitro cultured human embryos reported plausible hPGCs on embryonic day (E) 12−13 and in an E16−17 gastrulating embryo. In vitro, hPGC-like cells (hPGCLCs) can be specified from the intermediary pluripotent stage or peri-gastrulation precursors. Here, we explore the broad spectrum of hPGCLC precursors and how different precursors impact hPGCLC development. We show that resetting precursors can give rise to hPGCLCs (rhPGCLCs) in response to BMP. Strikingly, rhPGCLCs co-cultured with human hindgut organoids progress at a pace reminiscent of in vivo hPGC development, unlike those derived from peri-gastrulation precursors. Moreover, rhPGCLC specification depends on both EOMES and TBXT, not just on EOMES as for peri-gastrulation hPGCLCs. Importantly, our study provides the foundation for developing efficient in vitro models of human gametogenesis.
