On April 25, Yang Hui and Zhou Haibo from the Center for Excellence and Innovation in Brain Science and Intelligent Technology of the Chinese Academy of Sciences, Wu Jun from the Southwest Medical Center of the University of Texas in the United States and Guo Fan from the Institute of Zoology of the Chinese Academy of Sciences published a research paper entitled Generation of rat forebrain issues in rice online on Cell. This study proposes an efficient heterologous blastocyst complementary system, which for the first time generates functional rat forebrain tissue in mice, revealing the autonomous and non autonomous effects of cell development under the background of heterologous forebrain compensatory chimerism. This achievement is of great significance for exploring the mechanisms of brain evolution in the context of evolution.



The use of stem cells to generate functional organs or tissues is a hot topic in stem cell research. Heterologous blastocyst complementarity technology makes it possible to cultivate organs or tissues of another species within one species. This technology injects pluripotent stem cells into a host blastocyst that lacks key developmental genes, and donor cells compensate for the missing organs or tissues of the host, cultivating organs from another species. Previous studies have cultivated rat pancreas, thymus, vascular endothelial tissue, and germ cells in mice, as well as mouse pancreas, kidneys, and germ cells in rats. At present, brain tissue has not yet been cultivated in heterozygous blastocysts. Cultivating brain tissue from one species to another will help researchers study the development and function of the brain from an evolutionary perspective.

The traditional blastocyst complementarity method involves constructing heterozygous gene mutant mice that affect specific organ development. Breeding these mice to produce blastocysts with genetic mutations and injecting donor cells into these mutated blastocysts to form complementary chimeras of blastocysts is time-consuming, labor-intensive, and not suitable for heterozygous lethal genes. The use of traditional blastocyst complementarity methods to verify whether specific genes can support blastocyst complementarity in a certain organ is a lengthy process. To overcome these limitations, the study introduced C-CRISPR technology. C-CRISPR technology achieves almost 100% gene knockout efficiency by combining multiple gRNAs with Cas9, avoiding the need for gene editing animals. A new system called CCBC was created by combining C-CRISPR technology and blastocyst complementary technology. This system allows for rapid verification of whether the target gene is suitable for blastocyst complementarity and enables one-step generator reconstruction of chimeras.

This study compared the transcriptome differences of rat cells in chimeric and WT rats and identified some differentially expressed genes related to axonogenesis, forebrain development, and neurogenesis regulation. Through cell interaction analysis, this study observed multiple potential ligand receptor interactions. This may explain how host Hesx1-/- mouse cells affect donor rat cells and help them survive and differentiate in the forebrain.



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