Two teams of scientists independently created the first clusters of cells that behave like human embryos days after fertilization, known as blastocysts. Dubbed "human blastoids," the models could be a boon for research into early human development and pregnancy and fertility issues, but also raise questions on the ethical status of these cell groups.

Derived from either skin or stem cells, the human blastoids were similar in size, shape and cell number to blastocysts, and they included cell lineages that mimicked all three of their initial cell types.

The papers of both groups — one led by researchers from Monash University in Australia and another by a team from the University of Texas Southwestern Medical Center — were published March 17 in Nature.

"The two studies provide an exciting advance by describing conditions to engineer human blastocyst-like structures in the laboratory," said Peter Rugg-Gun, a group leader at England's Babraham Institute who was not involved in either study. "The research provides an important new cell model to investigate human early development, which could lead to a better understanding of infertility and early pregnancy loss."

About five days after a human egg is fertilized, it enters the blastocyst stage and implants on the wall of the uterus within a few days. Blastocysts contain dozens of cells, with trophoblast cells in the outer layer that create a fluid-filled cavity inside; both epiblast and hypoblast cells form the inner cell mass within that cavity. 

Scientific research on this critical stage of embryo development has been limited by a relatively small number of human embryo donations and incomplete model alternatives. Mouse blastoids have been developed in the last couple of years, as have models of older post-implantation embryos that are missing at least one of the cell types.

The newly developed human blastoids can model blastocysts four to five days after fertilization, could be generated in the hundreds and allow for a wide range of testing, said Jose Polo, a professor studying epigenetics at Monash University and an author of the Monash-led paper. He said they could be used for investigations into infertility and miscarriages during early development as well as the effects of drugs, toxins and viruses on early-stage embryos. 

"This will open a big window into these initial weeks of human development," Polo said.

Polo and his coauthors created human blastoids by reprogramming adult skin cells known as fibroblasts into cells that express genes in a similar way as trophoblasts, epiblasts and hypoblasts, the three initial cell types in blastocysts. Placed in a 3D culture dish, the cells formed a structure similar to blastocysts, with an outer layer and an inner cavity. 

The study led by UT Southwestern Medical Center instead employed human stem cells that differentiated into lineages that also resembled the three blastocyst cell types and self-organized into similar structures.

Authors of both studies said that although the human blastoids have similar structures and behaviors as blastocysts, they are not equivalent; rather, they simply model some aspects of blastocysts effectively.

"We think this ball of cells is a good model, it can bypass many of the current potential problems of studying this stage of development, but that's it," said Jun Wu, an author of the second study and an assistant professor of molecular biology at UT Southwestern Medical Center.

Still, both teams played it safe and stuck to the ethical guidelines for human embryo research, as defined by the International Society for Stem Cell Research. This included ending their experiments before the blastoids developed to the embryo equivalent of 14 days after fertilization, when specialized cells begin to emerge.

Martin Johnson, a University of Cambridge emeritus professor of reproductive sciences who was not involved in either study, said the human blastoids from Polo's team are not categorized as human embryos by U.K. law and are unlikely to have "full development potential," based on a comparison with similar mouse blastoids.

"Clearly, the authors wished for public approval of their work before crossing this line," Johnson said.

As the blastoid models are improved and more closely resemble blastocysts, they will "inevitably lead to bioethical questions," such as whether the 14-day rule should apply to them, Yi Zheng and Jianping Fu, respectively an associate research scientist and associate professor of mechanical engineering at the University of Michigan, said in a Nature article. They said some researchers will find research on blastoids more ethical than on blastocysts, while others might see it leading to engineering of human embryos.

For now, both kinds of human blastoids also had shortcomings as blastocyst models. The three types of cells developed at slightly different rates in individual blastoids, and cells were found that didn't resemble any kind of blastocyst cell. The blastoids formed with a success rate of less than 20%, which is low, according to Wu, though it is on par with mouse-blastoid production.

"Despite some limitations, we think these blastoids represent an accessible and flexible model of early human development, early pregnancy loss and developmental defects while reducing the reliance on human embryos for this research," Wu said.

In another paper published the same day in Nature, Israeli researchers reported that they grew mouse embryos for six days in an artificial womb to about halfway through the gestation period, another significant advance in embryo research that points to the possibility of developing mammals outside of a living uterus.

The study, "Modelling human blastocysts by reprogramming fibroblasts into iBlastoids," published March 17 in Nature, was authored by Xiaodong Liu, Jia Ping Tan, Jan Schröder, Asma Aberkane, Monika Mohenska, Sue Mei Lim, Yu Sun, Joseph Chen, Guizhi Sun, Yichen Zhou, Jennifer Zenker and Jose Polo, Monash University; John Ouyang and Owen Rackham, Duke-National University of Singapore Medical School; Daniel Poppe and Ryan Lister, University of Western Australia; and Amander Clark, University of California, Los Angeles.

The study, "Blastocyst-like structures generated from human pluripotent stem cells," published March 17 in Nature, was authored by Leqian Yu, Daniel Schmitz, Masahiro Sakurai, Lei Wang, Kunhua Wang, Gary Hon and Jun Wu, University of Texas Southwestern Medical Center; Yulei Wei, University of Texas Southwestern Medical Center, Wuyi University and International Healthcare Innovation Institute; and Shuhua Zhao, Kunming Medical University.

This story has been updated to include information about an additional study.