Cell Res: A new type of organoid with regenerative ability

Cell Res: A new type of organoid with regenerative ability.  Peking University Deng Hongkui and others have constructed a new type of organoid with regenerative ability.

This work provides a new in vitro model for studying organ regeneration, and also reveals the important role of epigenetic regulation based on chemical small molecules in organ regeneration.
Organoids can simulate the three-dimensional structure and function of internal organs in vitro, and have been widely used in research on functional tissue induction, disease model establishment, and drug screening. They have become one of the most important breakthroughs in the field of regenerative medicine in the past decade.

However, the current organoid preparation technology has obvious defects: although it simulates the interaction of stem cells and their differentiated cells in a homeostatic environment, they cannot show changes in the state of organ tissue damage and regeneration. In the process of injury-induced regeneration in vivo, damaged stem cells will appear to lead the process of tissue damage repair. How to establish an organoid culture method that can capture damaged stem cells in vitro is an important challenge for organoid research and application.

On January 8, 2021, Deng Hongkui, Xu Jun, and Li Cheng of Peking University, as co-corresponding authors, published a research paper titled: Establishment of intestinal organoid cultures modeling injury-associated epithelial regeneration in Cell Research.

This study constructed a new type of small intestine organoids with characteristics of injury and regeneration in vitro. Organoids are organ-like tissues derived from stem cells and are considered to be the next generation technology for constructing artificial organs or developing new drugs. Based on this new organoid model, Deng Hongkui’s research group has developed a set of epigenetic controlled chemical small molecules that can promote the repair of intestinal epithelial tissue damage in mice.

This work provides a new in vitro model for studying organ regeneration, and also reveals the important role of epigenetic regulation based on chemical small molecules in organ regeneration.

In order to solve the shortcomings of organoid preparation technology, Deng Hongkui’s research group used small intestinal organoids widely used in organoid research as a model, carried out functional screening, and established a new culture condition (referred to as 8C) to induce expression damage in small intestinal organoids Regenerate related genes and grow more complex three-dimensional structures.

These features are very similar to the “enhanced ecology” crypts that appear in the process of intestinal injury and regeneration (the crypts are located at the base of the villi and are the proliferation area composed of stem cells and their offspring). For this reason, they are called “enhanced ecology” small intestinal organoids. Referred to as Hyper organs. Compared with traditional organoids, the expansion ability of Hyper organoids has been greatly enhanced: After 5 consecutive generations of culture, the number of intestinal stem cells has increased by about 10,000 times compared with traditional organoids. In addition, Hyper organoids can be passaged and amplified for a long time and maintain the stability of the genome.

The author analyzed the cell population in Hyper organoids through single-cell transcriptome sequencing technology and found that the intestinal stem cell population and repair stem cell population were significantly enriched in Hyper organoids. These stem cell populations are the same as the intestinal damaged stem cells found in the body. Have similar molecular characteristics. Through lineage tracing and single-cell reconstruction of organoids experiments, it was confirmed that the cells in Hyper organoids function as intestinal stem cells. Further analysis found that the two epigenetic regulatory small molecules VPA and EPZ6438 in the 8C culture conditions play a key regulatory role in the regeneration of organoids by activating the downstream genes of the YAP pathway.

The author further studied the effect of the combined treatment of epigenetic regulation small molecules VPA and EPZ6438 on the repair of intestinal tissue damage in vivo. Studies have found that in a mouse model of radiation-induced small intestine injury, combined treatment of small molecules can increase the expression of downstream target genes of YAP and enhance the regeneration ability of small intestinal crypt tissue. In addition to the small intestine system, the combination can also promote the repair of colon tissue and reduce the pathological symptoms of acute colitis animal models.

This study established a new type of organoid model in vitro, which solved the problem that organoid technology could not simulate changes in organs and tissues under conditions of injury and regeneration in vitro. This model can capture and maintain damaged stem cell subsets in organ regeneration, and at the same time has the ability to efficiently expand and maintain in vitro, providing a new way for the use of organoid technology to study organ regeneration, establish disease damage models and drug screening .

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