Scientists based at The Rockefeller University have created an experimental system that models the implantation of a human embryo. The new system, an adaptation of one used to recapitulate the implantation of a mouse embryo, provides an attachment substrate, surrounds the blastocyst with just the right chemical environment, and provides scaffolding that accommodates the morphological movements that are particular to human embryos. For example, a human blastocyst undergoing implantation assumes a disk-like shape, whereas the mouse blastocyst is oblong.
The in vitro system has been used to show molecular and cellular processes in human development that occur up to day 14 after fertilization. The system, which has experimentally replicated implantation outside of the uterus for the first time, promises to expand scientists’ ability to answer basic questions about our own development, as well as to understand early pregnancy loss.
Details of the work appeared May 4 in the journal Nature, in an article entitled, “Self-Organization of the In Vitro Attached Human Embryo.” The article paid particular attention to postimplantation development of the human embryo, a process that remains mysterious.
“We unveil the self-organizing abilities and autonomy of in vitro attached human embryos,” wrote the authors. “We find human-specific molecular signatures of early cell lineage, timing, and architecture. Embryos display key landmarks of normal development, including epiblast expansion, lineage segregation, bi-laminar disc formation, amniotic and yolk sac cavitation, and trophoblast diversification.”
Viewing the implantation of the human embryo in such detail led the Rockefeller-led team, which included scientists from the University of Cambridge, to uncover some surprises. For example, the scientists originally hypothesized that implantation induced molecular crosstalk necessary for development. They continue to believe this dialogue happens, but their findings indicate that this is not required up to day 12.
Also unexpected was a phenomenon they observed known as self-organization. “We had seen self-organization using this system in the mouse embryo, and also in human embryonic stem cells, but we did not anticipate we'd see self-organization in the context of a whole human embryo,” said Rockefeller’s Ali Brivanlou. “Amazingly, at least up to the first 12 days, development occurred normally in our system in the complete absence of maternal input.”
In addition to insights into molecular details of this process, the findings from Brivanlou and colleagues have several clinical implications. In the near future, the ability to study implantation in culture is likely to shed light on why some early miscarriages occur and why in vitro fertilization has a high failure rate.
Over the longer term, the work could advance the treatment of a variety of diseases with human embryonic stem cells. “In order for that approach to be effective, we have to understand where these cells are coming from, and what decisions they've made and are about to make at the molecular level,” Rockefeller research associate Gist Croft says. “Only with that knowledge, specifically from human cells, can we control their ability to become cell types that are useful for drug screening or transplantation.”
Perhaps most importantly, this new method opens the door to a wide variety of studies, never before possible, on the molecular events that occur during the very earliest stages of human development.
“We're going to take a step back to the first day and systematically move forward,” says Brivanlou. “We'd like to get the complete molecular signature, and then move on to how these cells communicate with one another to figure out what cell type they are supposed to become. There is a lot more to be studied during this stage and we look forward to shedding more light on this vital step in human development.”
In accordance with internationally recognized bioethical guidelines, the group's experiments were concluded on day 14 postfertilization, well before even the earliest signs of nervous system development are observed.
An accompanying Nature commentary, however, suggests that the current 14-day limitation should be reappraised. Rockefeller's Amy Wilkerson, corresponding author Insoo Hyun of Case Western Reserve University School of Medicine, and Josephine Johnston of the Hastings Center argue that it is crucial to understand how the guideline applies to different types of embryo research in different jurisdictions and to re-evaluate its pros and cons.
“Now that it has become possible to culture human embryos to the 14-day limit and perhaps beyond, the time is right for the scientific community to educate the public about the potential benefits and to work with regulators on ethical consensus to guide this important research,” says Wilkerson, associate vice president of research support at Rockefeller.
While Brivanlou plans to focus on understanding initial implantation in more detail in the near term, the commentary authors suggest that revisiting the 14-day rule in a way that can both support research and accommodate diverse moral concerns could allow scientists to model additional aspects of early human development, and potentially shed light on the disorders that result in early pregnancy losses and birth defects.