Our aims
The HipGametes consortium addresses the topic of human IVG and derived non-viable embryos from several different, but complementary and interconnected approaches. Together, we hypothesize that, in the future, the generation of gametes from (edited) hiPSCs may provide a paradigm shift to the study of human egg and sperm cells, as well as human embryos at pre- and peri-implantation stages.
Successful protocols for female and male IVG may contribute to developing disease models that improve our understanding of infertility and the transmission of hereditary diseases.
Some of our main questions are: How do hiPSCs differentiate step-by-step in vitro into male and female gametes? What are the molecular characteristics of the male and female somatic compartments and, how do these characteristics change to support the different steps of gametogenesis? Can we replace the somatic compartment with iPSC-derived cells to have a standardized in vitro assay to promote male and female IVG? Can we develop edited hiPSC lines that are robust enough to guarantee normal gamete formation, while ensuring normal early development of the derived non-viable embryos? Do societal perspectives and attitudes towards the development of iPSC-gametes and their use in bringing about non-viable embryos differ from the attitudes towards the use of ‘natural’ embryos for scientific research and, if so, how? What are the legal and ethical ramifications of IVG and its use for the creation of non-viable human embryos?
Modeling human gametogenesis with stem cells
Gamete formation is a long and complex process, involving significant remodeling of the cytoplasm and nucleus of germ cells in a sex-specific manner. After fertilization, a totipotent cell (or zygote) is optimally prepared to enter the developmental program from which new individuals eventually emerge. We still know very little about the first steps of human development, as in the Netherlands and many other countries the generation of human embryos for scientific research is prohibited by law. This project has two main aims (in blue and purple):
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- to develop methods to generate male and female gametes in vitro (WP1, WP2 & WP3) from edited human induced pluripotent stem cells (WP4), and
- to explore ethical, legal, and societal aspects of this approach, providing insight into whether, and under what conditions, the use of such alternative embryo models could be considered acceptable or preferable (WP5 & WP6).
This multidisciplinary project contributes to the development of suitable and acceptable alternative human embryo models to study early human embryogenesis and the transmission of hereditary diseases.
Background
Human pluripotent stem cells (hPSCs) isolated from early embryos (embryonic stem cells, hESCs) or (patient-specific) induced pluripotent stem cells (hiPSCs), constitute an unparalleled resource to create scalable and renewable supplies of human cells with the potential to transform our understanding, diagnosis, and treatment of diseases for which there are currently no cures. A unique characteristic of hPSCs is their ability to differentiate into all cell types of the human body, making patient-specific hiPSCs an excellent tool for studying a broad range of organ-specific diseases and drug discovery strategies.
In recent years, the potential of hPSCs to develop into a whole embryo, as opposed to a specific cell type or organ (organoid), has attracted much scientific interest. Research in the Netherlands is at the forefront of this field, having provided international breakthroughs in the application of PSC-derived embryo models to study the peri-implantation period (blastoids, see: Beyond the Blastocyst), and early organogenesis (gastruloids, see: GREAT). Still, these models are inadequate to study the pre-implantation period (from fertilization until blastocyst formation), as they do not model the first days of embryonic development.
Generating a model from hiPSC-derived gametes can provide a way to recapitulate the pre-implantation period. A prerequisite is to realize a multi-step protocol to differentiate PSCs into gamete-like cells, via in vitro gametogenesis (IVG). In mice, it has been shown that it is possible to generate functional (male and female) gametes that, when fertilized in vitro, can develop from pre-implantation embryos to viable fertile mice. These promising results provide a (theoretical) foundation for the development of a human embryo model that can recapitulate the period from fertilization until blastocyst formation.
Human development timeline and developmental period mimicked by different stem cell-derived embryo models.