Researchers Edge Closer to Growing Human and Mice Embryos

Three articles published in Nature describe studies of human prenatal development outside the body. The techniques employed in the studies may illuminate events that unfurl as the beginnings of organs take form.

A group from the Weizmann Institute of Science, Rehovot, Israel, cultured mouse embryos halfway through their prenatal development, to the point at which hind limbs formed. A group from the University of Texas Southwestern Medical Center, Dallas, Texas, and a group from Monash University, Melbourne, Austrlia, created human blastocyst-like “blastoids” from stem cells. The three projects move the field ahead substantially.

Understanding the choreography of early development requires an in vitro interface that models the complex connections between the developing embryo and the placenta. The studies, although involving different species, provide a view of the still somewhat mysterious period of embryogenesis.

Jacob H. Hanna, MD, PhD, and colleagues at the Weizmann Institute of Science conducted a study involving a novel, static, rotating bottle culture platform with human cord blood serum and pressurized oxygen in which they nurtured naturally conceived 5-day-old mouse embryos for a week. Heads, beating hearts, and hind limbs appeared in the glassware, as shown in a video posted on YouTube.

A variety of techniques ― molecular analysis, histology, and single-cell RNA-sequencing to assess gene expression ― confirm that the three layers of the “ex-utero” embryos, as the group is calling them, match those of natural in vivo growth. Testing is possible. The researchers used green fluorescent protein to mark neural cells of the ectoderm and a red fluorescent protein, called tomato, to mark cells of the endoderm. They added viruses, toxins, other chemicals, and human cells to the developing mice. Each of these compounds allowed the team to view and measure different aspects of early development.

The human blastoid studies focused on the earlier part of the embryonic period, when all that can be seen are layers of cells in a sphere. The tiny balls of cells resemble naturally formed blastocysts, the fluid-filled spheres whose outer cells (trophectoderm) give rise to extra-embryonic structures. A small collection of cells, called the epiblast, adhere to the inside of the sphere and give rise to the embryo. A blastocyst has only three cell types, but the cells rapidly divide and form layers that then interact and contort as the organism takes form, beginning during the third week.

In their study, senior author Jun Wu, PhD, and the University of Texas group constructed “human blastoids” from human embryonic stem cells and from human induced pluripotent stem (iPS) cells. The human embryonic stem cells were sanctioned by the National Institutes of Health.

In the third study, senior author Jose Polo, PhD, from Monash University, and co-workers used iPS cells to create their “iBlastoids.” Like the study conducted in mice, the human blastoids mimic the real deal.

“They resemble blastocysts in morphology, size, cell number, and have all three cell types that are organized in a manner similar to a blastocyst,” said Wu, from the Texas group, at a news conference.

Both research groups halted blastoid development at day 10, shy of the International Society for Stem Cell Research’s 14-day limit that respects formation of the primitive streak, which is thought to demarcate the beginning of nervous system development. The organization is considering dropping that limit.

Both variations on the blastoid theme aren’t exactly like bona fide human blastocysts, said Amander Clark, PhD, of the University of California, Los Angeles, who is part of the iBlastoids team. “They are organized, embryo-like structures modeled on human embryos, but I don’t consider them to be the equivalent of human blastocysts that come from IVF [in vitro fertilization] clinics.” Blastoids include some cells that aren’t in blastocysts and that could be cell culture contaminants.

“The blastoid technology will likely catalyze further research that provides a better understanding of early human development, which is somewhat of a black box,” Paul Knoepfler, PhD, a professor in the Department of Cell Biology and Human Anatomy at the University of California, Davis, School of Medicine, Sacramento, California, told Medscape Medical News.

The fact that the later embryos are of mice and the earlier ones are not exact replicas of their human counterparts may, for now, enable discussion of practical applications to outshine bioethical concerns.

“Although blastoids can only model these few early days in human development, these days are crucial to the entire development of us,” said Polo, from Monash University. “For example, we’d be able to understand infertility, because we know that a large proportion of miscarriages happen in the first weeks of pregnancy. We can study congenital problems and diseases from the beginning and study the effects of drugs, toxins, and viruses on the early stages of development, all without using human or animal embryos.”

Knoepfler connects the dots that the three studies lay out. “The new method for development of mouse embryos into mid-gestation in vials without a mother will boost our knowledge of mammalian development more generally. This technology could also in theory be used to grow human embryos made by IVF or human blastoids in vials in the lab.”

But those possibilities raise the bioethical questions.

“For example, would lab-produced human embryos have a different status than those made by IVF or standard reproduction? What about embryos started by IVF, but then grown in a vial in a lab instead of a mother?” asked Knoepfler.

Nature. Published online March 17, 2021. Study by Hanna and colleagues, Abstract; Study by Polo and colleagues, Abstract; Study by Wu and colleagues, Abstract

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