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Interspecific blastocyst complementation (IBC) provides a unique platform for research development and has the potential to overcome the global organ shortage. Despite recent successes, brain tissue has not yet been obtained through IBC.
On April 25, 2024, Jun Wu's team from Southwest Medical Center in Texas, Hui Yang/Haibo Zhou's team from the Center for Excellence in Brain Science and Intelligent Technology, Chinese Academy of Sciences, and Fan's team from the Institute of Zoology, Chinese Academy of Sciences published a paper titled "Generation of rat forebrain tissues in mice" online at Cell The research paper developed an optimized IBC strategy based on C-CRISPR that facilitated the rapid screening of candidate genes and found that Hesx1 deficiency supported the generation of rat forebrain tissue by IBC in mice.
The structure and function of the forebrain tissue of adult mice in xenogeneic rats are intact. Cross-species comparative analysis revealed that rat forebrain tissue developed at the same rate as the mouse host, but maintained a rat-like transcriptome profile. With the progression of development, the mosaic rate of cells gradually decreased, suggesting the existence of xenologous barriers during prenatal middle and late development. Interspecies forebrain complementation opens the door to the study of evolutionarily conserved and distinct mechanisms of brain development and cognitive function. The C-CRISPR-based IBC strategy has great potential to expand the research and application of interspecific organogenesis.
Advances in interspecies chimerism and blastocyst complementarity offer hope for addressing the global shortage of donor organs and expanding understanding of the molecular and cellular mechanisms involved in organogenesis. Blastocyst complementation involves injecting chimeric donor pluripotent stem cells (PSCs) into mutant host blastocysts that lack the necessary genes required for the development of one or more specific organs. Through the formation of intraspecific or interspecific chimeras, donor PSCs can fill the vacant developmental organ niche and generate organs derived from donor PSCs within the host body. Previous studies have successfully demonstrated intraspecific blastocyst complementation in a variety of mouse tissues, including pancreas, thymus, kidney, heart, liver, lung, germ cells, and forebrain. Although limited in scope, some studies have attempted interspecific blastocyst complementation (IBC) to produce rat pancreas, thymus, blood endothelial tissue, and germ cells in mice, and mouse pancreas, kidneys, and germ cells in rats. However, to date, no interspecific blastocyst complementation of any brain tissue has been achieved. There is a great deal of interest in generating brain tissue from one species to another, not only for in vivo studies of brain development and function in an evolutionary context, but also for providing an important basis for addressing ethical questions surrounding the contribution of human PSCs to animal brains. Traditional blastocyst complementation methods typically involve generating and reproducing sexually mature gene-edited mice, which is labor-intensive and can require significant time to determine the feasibility of selected candidate genes for target organ complementation. So far, no genes have been found suitable for interspecific neuroblastocyst complementation. Even for species with short gestation periods and rapid sexual maturation (e.g., 10-26 months in mice), screening candidate genes by targeted gene destruction of germline-capable PSCs can be a lengthy process. This approach is even more impractical for large livestock and non-human primates.
模式图（Credit: Cell）
The study introduces an optimized blastocyst complementation technique that allows for efficient screening of candidate genes and streamlines the generation of mouse functional rat embryonic stem cell (rESC)-derived forebrain tissue. This study shows that rESC-derived neurons are not only capable of functional integration but also enrichment in the mouse forebrain. This discovery represents a critical first step in realizing the potential of interspecies neuroblastocyst complementarity as a transformative approach to studying brain development and disease. With the further development of interspecies chimerism, interspecific neuroblastocyst complementation will pave the way for exploring gene regulatory networks, cell-to-cell communication, and brain function and behavior in an evolutionary context.
Original link https://www.cell.com/cell/abstract/S0092-8674 (24) 00308-8
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文章来源|“ iNature”
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