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Human embryos start with a tiny mass of cells that are all identical. The first step in growing a homogeneous cell ball into a complex individual with distinct organs and tissues is to divide them into different populations. Scientists at the Gladstone Institutes modeled this first stage of human development in the laboratory in order to better understand how organs are formed. With this knowledge, they hope to create more authentic organoids that can be used for drug testing, disease modeling and even potentially for transplantation.
The new study, published in eLife, is the fruit of a collaboration between Todd McDevitt, Ph.D., Principal Investigator at Gladstone, and Bruce Conklin, MD. The researchers published human pluripotent stem cell clusters, capable of transforming into any type of cell in the body, to silence genes important to cell mechanics. The modifications prompted the cells to move and self-organize until they are divided into two groups: those that were manipulated and those that did not. summer. This physical division ultimately influenced the type of cells that they would become.
"When you only modify a part of the cells, they organize in a very specific way, thus recalling different ways in which the cells organize in the early embryo to create a complex tissue." said Ashley Libby, first author of the study and graduate. Gladstone student supervised by McDevitt and Conklin. "In this study, we focused on mechanical changes, factors that influence how cells interact with each other."
The researchers used a variant of the CRISPR genome editing to temporarily silence, or disable, one of two different genes in the cells. The first gene, called CDH1, acts like velcro to help cells stick to each other. Cells with the CDH1 gene silenced clustered into small islands, surrounded by clusters of unmodified cells. This type of segregation occurs many times during development, including at the very beginning of the organization of cells in different layers that eventually become organic systems.
In another group of cells, the researchers inhibited the ROCK1 gene, which modifies the flexibility of the cell. Changing the flexibility of the cell affects its ability to physically attract its neighbors, with the stiffer cells exerting more force. Neighboring cells often have variable flexibility and influence over each other during tissue development. Upon recreation of this effect in the laboratory, cells carrying the intact ROCK1 gene were more rigid and fired in the center, while gentler cells lacking the gene were pushed outward, thus creating a ring. Several rings appear during development, including during limb training.
Interestingly, silencing the genes has not only changed the immediate behavior of the modified cells, but also their future identity as they mature. In addition, these changes also influenced unedited neighboring cells, predisposing them to become a different cell type.
"If the cells remain homogeneous, the tissues can not form," said McDevitt, also a professor in the Department of Bioengineering and Therapeutics at the University of San Francisco. "An event that breaks the symmetry must occur to create the various types of cells needed to form functioning tissues and organs." We had already observed it before, but we did not know how to control it in an experimental study until now. "
New insights into how the physical organization of cells influences their identity provide researchers with a more robust method for creating organoids, miniature and simplistic organs developed from stem cells.
"Most scientists and engineers use top-down approaches to impose constraints on the system and then see how cells respond," McDevitt said. "Instead, we disrupt something that is inside a cell, which is more true than the development of an organ."
Rather than pushing the cells in one direction or another with the help of molds or scaffolds, the research team found a way to mimic normal development through changes in the expression of genes that influence signaling and cell organization. This could enable them to eventually create better organoids to study embryo formation and the appearance of congenital anomalies, as well as the formation of more complex human tissues.
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