Science & Technology

How-to guide for creating mouse-human chimeric embryos

The human stem cells in the glass needle are injected into the mouse embryo held by the left pipette.Credits: Image by Aimee Stablewski and Dawn Barnas at Gene Targeting and Transgenic Resources at Roswell Park Comprehensive Cancer Center

This study enables a much more accurate model of human development and disease and may help solve the shortage of organs for transplantation.

One year later Buffalo University Scientists have demonstrated that mouse embryos can produce millions of mature human cells, and have published detailed instructions on how to do so in other laboratories. did.

The ability to produce millions of mature human cells in vivo, including two types of cells, called chimeras, is critical to fulfilling the ultimate promise of stem cells to treat or treat human disease. However, to produce these mature cells, human primed stem cells must be returned to an early, underdeveloped, naive state so that they can co-develop with the inner cell mass of mouse blastocysts. I have.

Protocols that outline how to do that are currently Nature protocol According to UB scientists. They were invited to publish it because of the great interest it received from the team’s first publication explaining a milestone in May last year.

“This treatise will allow many scientists to use this new platform to study human illnesses of interest,” said UB’s Jacobs Medical College professor of physiology and biophysics and senior author. Said Dr. Jian Feng. “Over time, biomedical research shifts towards more effective use of human model systems to directly study almost all innate states of an individual. It is in human biology and medicine. It will stimulate unexpected discoveries and applications that may radically change our understanding. “

This protocol allows scientists to create animal models that Feng has stated to provide far more realistic images of embryonic development than previously possible. These more realistic animal models also have the potential to uncover the mechanisms behind many illnesses, especially those that afflict individuals from birth.

Better mouse model

“This step-by-step protocol benefits the entire field by allowing other scientists to use our methods to generate chimeras and study the human illnesses they specialize in. “Feng said. “It leads to the generation of better mouse models for various human diseases such as sickle cell anemia. COVID-19 (New Coronavirus Infection) And many other or various human developmental disorders. This paper describes a method for producing naive human pluripotent stem cells from existing induced pluripotent stem cells that may be derived from patients with various diseases, and uses these cells to generate mouse-human chimeras. It shows the method and how to quantify the amount of human cells in the chimera.

“Our method has enabled us to track the development of naive human pluripotent stem cells in mouse and human chimeric embryos in real time,” Feng said. These stem cells can be genetically or pharmacologically manipulated to provide valuable information about human development and disease.

“For example, we can label naive human pluripotent stem cells by inserting green fluorescent protein into the hemoglobin gene and studying the development of human erythrocytes in mouse-human chimeras,” Feng said. I am.

Another application is to generate a humanized mouse model to study many human diseases.

“These mice contain important human cells, tissues, and even organs to more accurately reflect human condition,” Feng said. “Our method produces human cells with the mouse during mouse embryogenesis. Better matching and rejection because there is a way to produce human cells where there is no competition with the mouse counterpart. there is no.”

Organs for future transplants

This protocol is a human organ to address a serious shortage of organs available for transplantation by allowing others to improve and adapt this method to eventually produce chimeras in large animals. Feng said it could also lead to the generation of.

“If naive human pluripotent stem cells can produce significant amounts of mature human cells in other larger species, it may be possible to make human tissues or even human organs in chimeric animals.” Explained Feng.

This is possible using blastocyst complementation, where Feng is a blastocyst of another species that has been genetically engineered so that one type of normal pluripotent stem cell does not grow a particular organ. He explained that such organs can be reconstructed.

Feng added: “Ultimately, a better understanding of how human cells develop and grow in chimeras will generate human cells, tissues and organs in a completely artificial system and treat many human diseases. The method can be radically changed. Chimera-based research is a bridge that must be crossed to reach that potential. “

Reference: “Generation of Chimeric Mouse and Human Embryos”, Boyang Zhang, Hanqin Li, Zhixing Hu, Houbo Jiang, Aimee B. Stablewski, Brandon J. Marzullo, Donald A. Yergeau, Jian Feng, July 2, 2021 Nature protocol..
DOI: 10.1038 / s41596-021-00565-7

The co-author with Feng is Dr. Boyang Zhang. Dr. Hankin Lee; Zhixing Hu, PhD; Dr. Houbo Jiang, All Departments of Biophysics and Physiology at Jacobs School. Aimee B, co-director of gene targeting and transgenic resources at the Roswell Park Comprehensive Care Center. Stablewski; Dr. Donald A. Jergo; Brandon J. Marzullo, Genomics and Bioinformatics Core at UB’s Center for Bioinformatics and Life Sciences, NY.

This work was supported by NYSTEM and the Buffalo Blue Sky Initiative.

How-to guide for creating mouse-human chimeric embryos How-to guide for creating mouse-human chimeric embryos

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