Researchers from the University of Cambridge and Caltech have created model mouse embryos from stem cells—the body’s master cells, which can develop into almost any cell type in the body—that have beating hearts, as well as the foundations for a brain and all of the other organs in the mouse body.
The results are the culmination of more
than a decade of research, and they could help researchers understand why some
embryos fail while others go on to develop into a fetus as part of a healthy
pregnancy. Additionally, the results could be used to guide repair and
development of synthetic human organs for transplantation.
The embryo model was developed without
eggs or sperm. Instead, the researchers mimicked natural processes in the lab
by guiding the three types of stem cells found in early mammalian development
to the point where they start interacting. By inducing the expression of a
particular set of genes and establishing a unique environment for their
interactions, the researchers were able to get the stem cells to “talk” to each
other.
The stem cells self-organized into
structures that progressed through the successive developmental stages until
the synthetic embryos had beating hearts and the foundations for a brain, as
well as the yolk sac where the embryo develops and from which it receives
nutrients in its first weeks. This is the most advanced stage of development
achieved to date in a stem cell-derived model.
A major advance in this study is the
ability to generate the entire brain, in particular the anterior region, which
has been a “holy grail” in the development of synthetic embryos.
“This opens new possibilities to study
the mechanisms of neurodevelopment in an experimental model,” Zernicka-Goetz
says. “In fact, we demonstrate the proof of this principle in the paper by
knocking out a gene already known to be essential for formation of the neural
tube, precursor of the nervous system, and for brain and eye development. In
the absence of this gene, the synthetic embryos show exactly the known defects
in brain development as in an animal carrying this mutation. This means we can
begin to apply this kind of approach to the many genes with unknown function in
brain development.”
“Our mouse embryo model not only
develops a brain, but also a beating heart, all the components that go on to
make up the body,” she explains. “It’s just unbelievable that we’ve gotten this
far. This has been the dream of our community for years, and the major focus of
our work for a decade, and finally we’ve done it.”
For a human embryo to develop
successfully, there needs to be a “dialogue” between the tissues that will
become the embryo and the tissues that will connect the embryo to the mother.
In the first week after fertilization, three types of stem cells develop: one
will eventually become the tissues of the body, and the other two will support
the embryo’s development. One of these latter two types, known as
extraembryonic stem cells, will become the placenta, which connects the fetus
to the mother and provides oxygen and nutrients. The other will become the yolk
sac, where the embryo grows and from which it receives nutrients in early
development.
Many pregnancies fail at the point when
the three types of stem cells begin to send mechanical and chemical signals to
each other, which tell the embryo how to develop properly.
“This early period is the foundation for
everything else that follows in pregnancy,” Zernicka-Goetz says. “If it goes
wrong, the pregnancy will fail.”
Over the past decade, Zernicka-Goetz’s
team has been studying these earliest stages of pregnancy to understand why
some pregnancies fail and some succeed.
“The stem cell embryo model is important
because it gives us accessibility to the developing structure at a stage that
is normally hidden from us due to the implantation of the tiny embryo into the
mother’s womb,” Zernicka-Goetz says. “This accessibility allows us to
manipulate genes to understand their developmental roles in a model
experimental system.”
To guide the development of their
synthetic embryo, the researchers put together cultured stem cells representing
each of the three types of tissue and allowed them to develop
in proportions and an environment conducive to their growth and
communication with each other, leading to their eventual self-assembly into an
embryo.
The researchers found that the
extraembryonic cells signal to embryonic cells through chemical signals but
also mechanistically, or through touch, guiding the embryo’s development.
“This period of human life is so
mysterious, so to be able to see how it happens in a dish—to have access to
these individual stem cells, to understand why so many pregnancies fail and how
we might be able to prevent that from happening—is quite special,”
Zernicka-Goetz says. “We looked at the dialogue that has to happen between the
different types of stem cells at that time—we’ve shown how it occurs and how it
can go wrong.”
While the current research was carried
out in mouse models, the researchers are developing an analogous model for
human embryo development to understand mechanisms behind crucial processes that
would be otherwise impossible to study in real embryos.
If these methods are shown to be
successful with human stem cells in future, they could also be used to guide
development of synthetic organs for patients awaiting transplants. “There are
so many people around the world who wait for years for organ transplants,”
Zernicka-Goetz says. “What makes our work so exciting is that the knowledge
coming out of it could be used to grow correct synthetic human organs to save
lives that are currently lost. It should also be possible to affect and heal
adult organs by using the knowledge we have on how they are made.”
Source: https://www.eurekalert.org/news-releases/962771
Journal article: https://www.nature.com/articles/s41586-022-05246-3
Image: Natural (top) and synthetic
(bottom) embryos side by side to show comparable brain and heart formation.
Image credit: Amadei and Handford
No comments:
Post a Comment