The "most important moment" of the monkey's life, the embryonic primary intestinal motility, reappeared in vitro for the first time

Source: Science and Technology Daily

For the first time in a monkey's life, the "most important moment" was reproduced in vitro

Science published its research work online in the form of "research articles".

Reporter Lu Chengkuan

Louis Warbert, a famous British developmental biologist, once said: "The most important moments in a person's life are not birth, marriage and death, but the movement of the original intestine." ”

Researchers from the Institute of Zoology of the Chinese Academy of Sciences and other units, with the help of the team's in vitro culture system for non-human primate embryos established for many years, cultured the cynomolgus monkey blastocysts in vitro until the appearance of protonic motility, and further developed to 20 days after fertilization, reproducing the prosthetic motility of non-human primate embryos in vitro. The study laid an important research foundation for understanding the early embryonic development process of primates, recreating the "most important moments" in the monkeys' lives. The research results were recently published online in the journal Science.

An ancient field of study The mystery of the movement of the original intestine is gradually being unveiled

So, what exactly is prointestinal motility?

To make a long story short, early embryonic development is related to the origin of life and has always been a hot spot and difficult point in biological research. After the mammals mate, the sperm and egg combine to form a fertilized egg. The fertilized egg undergoes a series of ruptures and differentiation in the fallopian tubes to form a blastocyst. Subsequently, the blastocyst migrates to the uterus for implantation. Before and after the "home" of the blastocyst in the uterus, some of its cells begin to move, rearrange and differentiate, starting the movement of the intestinal tract, forming three germ layers of inner, middle and outer germs, that is, the prointestinal embryo. The process from blastocyst development to the protocellar is the movement of the prointestinal tract.

"The movement of the gastrulation is the most special stage of early embryonic development, and the number of cells will directly increase from a few hundred to thousands or tens of thousands." Zhou Qi, academician of the Chinese Academy of Sciences and director of the Institute of Zoology, said.

As one of the most important events in embryonic development, the movement of the primary intestine is an ancient and mysterious field of research. Early developmental biologists differed in their interpretation of the movement of the primary intestine, and it was not until the 1950s and 1960s that there was a more uniform definition of the movement of the prointestinal tract, that is, "cells differentiate into three germ layers after orderly migration."

Developmental biologists initially studied the movement of the original intestine in simple, low-grade invertebrates such as sponges, jellyfish, sea urchins, nematodes, and fruit flies, revealing basic cell biology events such as cell motility, cell polarization, cell junctions, and intercellular communication in this process; then using higher vertebrates such as fish (zebrafish), amphibians (Xenopus laevis), and mammals (mice) as models to explore the movement of the protointestinal tract, and the mystery of the mechanism of prointestinal motility was gradually unveiled.

In 2016, a research team from Cambridge established an in vitro culture system for mouse post-implantation embryos, and observed the formation of anterior and posterior axes and ovary cylindrical morphology of mouse embryos cultured in vitro, which provided an important experimental means for elucidating embryonic development and prointestinal embryogenesis after early implantation.

Despite great breakthroughs in the in vitro culture system of mouse embryos, even rodents that are also mammals have significantly different early embryos from primates. For example, the mesoderm forms a cup-like structure after implantation in mouse embryos, while primate embryos form a bilayer placenta-like structure. Therefore, it is difficult to deduce the results of the mouse study on the movement of the protointestinal tract directly to primates such as humans.

The "highlight moment" of embryonic development avoids the ethical limit of 14 days for human embryo culture

Prointestinal motility is a milestone event in the development of primates, including humans. "Abnormalities in early embryonic development and prointestinal motility often lead to major diseases such as pregnancy failure and postnatal organ defects." Wang Hongmei, corresponding author of the paper and a researcher at the Institute of Zoology of the Chinese Academy of Sciences, said.

However, due to ethical restrictions, in vitro human embryo culture cannot exceed 14 days after fertilization, but primate prointestinal motility mostly occurs 14 days after fertilization, so biologists have been ignorant of the "highlight moment" of human prointestinal motility.

Unveiling the mystery of the movement of the prointestinal tract, the application of model animals will play an irreplaceable and important role in human understanding of the movement of the prointestinal tract. Because of their proximity to human genetics and evolution, the cynosmophilic monkey was selected as a model animal by the researchers, avoiding the ethical limit of 14 days of human embryo culture.

During the project, the researchers established a new in vitro culture system that can support the embryos of cynomolgus monkeys to develop in vitro for up to 20 days after fertilization, demonstrate for the first time that primate embryos can develop into the prointestinal motility in vitro without maternal support, and reproduce several key events in the early embryonic development of primates.

The researchers provided sufficient evidence from multiple perspectives such as morphology, labeled molecular staining, and single-cell transcriptome that cynomolgus monkey embryos that developed in vitro highly reproduced embryonic development processes in vivo, including the formation of a clear amniotic cavity and yolk sac structure, followed by protointestinal motility, the formation of protostructure, and accompanied by differential differentiation of anteroposterior and posterior axis structures. Primitive germ cells can also be observed on the 12th to 16th days of embryonic development in vitro culture, characteristics that have not been observed in previous human embryos in vitro culture. Combined with single-cell transcriptome sequencing analysis, this study provides for the first time the gene expression characteristics of amniotic cells during early embryonic development in primates and redefines multiple cell types in early primate embryos.

A major breakthrough in reproductive medicine has helped to identify the causes of poor pregnancies and fetal malformations

In Wang Hongmei's view, the study has opened up a new research platform for exploring the early embryonic development and prointestinal motility of primates, provided potential new tools for clinical drug research and development and regenerative medicine development of major diseases such as early human embryonic development abnormalities, and provided important data for human beings to deeply understand the embryonic development mechanism and the exploration of in vitro gestational life (non-human).

Qiao Jie, academician of the Chinese Academy of Engineering and president of the Third Hospital of Peking University, commented on the study that monkeys are considered to be a reliable animal model for the study of human physiology and pathology, and the establishment of an in vitro culture system for postimplantation development provides a platform for studying the process of postimplanted embryonic development of primates, which will greatly improve our understanding of primate and early human embryonic development and related diseases, especially for the discussion of the causes of adverse pregnancies and fetal malformations.

Professor Sha Jiahao of the State Key Laboratory of Reproductive Medicine of Nanjing Medical University also believes: "The study uses embryonic in vitro culture technology to successfully analyze the important event of primate early prosthesis, which is a major scientific research breakthrough in the field of reproductive medicine, and the breakthrough of this technology is of great significance for the study of human development and disease occurrence mechanism." ”

This breakthrough helps to elucidate the regulatory mechanism of protoegodermal development in primates, and at the same time promotes the cognition of human embryonic development, such as: the molecular regulation mechanism of the process of trioderm formation, embryonic body axis formation, protogenesis, cell migration chemotaxis, etc., as well as the interaction between cells, revealing the differences between higher primates and lower animals, and filling the theoretical gaps in the embryonic development mechanism of higher animals.

At the same time, the establishment of the in vitro protopembry formation model system of this primate can screen for lethal and teratogenic factors derived from sperm, eggs and intrauterine; it can also help understand the differentiation of early embryonic cells, optimize and improve assisted reproductive technology, and provide basic theoretical guidance for clinical treatment of infertility and prevention of birth defects, and develop new treatment methods. Since the formation of protoegodermal embryos can differentiate into triodermal cells of various organs of the body, it is of great significance for regenerative medicine research, such as the study of pluripotent stem cell differentiation into specific cell types for disease simulation and stem cell therapy.