KANAZAWA, Japan Nov. 5, 2020 / PRNewswire / – University researchers of Kanazawa report, in Science how concentration gradients of particular molecules ('synthetic morphogens') can be produced in biological systems. These gradients can be harnessed to program pattern formation, offering the promise of controlled tissue engineering.
Multicellular organisms can grow and develop thanks to so-called morphogens: molecules that provide positional information. They are produced in a source, from which they diffuse and form a concentration gradient in their surroundings. Nearby cells can "read" this gradient, thus "know" where they are in the body and "act" accordingly. Now Satoshi Toda from the University of Kanazawa and his colleagues report the successful engineering of a synthetic morphogen system that can be programmed. This achievement not only helps to understand how morphogens exactly encode positional information, but it also holds promise in the context of engineering tissue formation.
Toda, who is a principal investigator at the NanoLSI WPI at the University of Kanazawa, has become an expert in cellular pattern programming and tissue self-assembly in just a few years, and his team addressed the question of what a signaling system looks like. minimal synthetic morphogens, with the synthetic system operating 'orthogonally' to the biological (endogenous) morphogens, meaning that the endogenous and synthetic systems do not interfere.
The researchers adapted an existing synthetic receptor system called synNotch to work with soluble green fluorescent proteins (GFPs) as morphogen molecules. (The original synNotch system requires morphogen molecules to be attached to a cell membrane, that is, they are not soluble.) They did this by designing so-called anchor cells that can capture a GFP molecule in solution. An anchor cell carrying a trapped GFP molecule is then detected by a recipient cell (by chemical coupling). Toda and his colleagues demonstrated that this approach worked in vitro : a morphogen concentration gradient of GFP and activated cells formed in approximately 24 hours.
The scientists then investigated how the shape of the morphogen gradient can be regulated. They found that for different densities of anchor proteins, different gradient shapes were obtained. Furthermore, the spatial distribution of the gradient could be influenced by the use of inhibitors (molecules that block the anchor-receptor mechanism). Toda and his colleagues concluded that synthetic morphogen gradients can be adjusted so as to obtain shapes similar to those that occur in vivo .
Ultimately, Toda's research team showed that it is possible to alter the "interpretation" of the gradient. They designed different types of feedback loops, for example one in which detection of GFP leads to increased production of GFP, or one in which detection of GFP leads to production of GFP inhibitors. Through such circuit engineering combined with sources of morphogens and inhibitors, scientists were able to produce binary and ternary domain structures.
The results of Toda and his colleagues have promising potential for application. To quote the researchers: "These synthetic morphogen platforms can program positional information without interference with endogenous signaling pathways. Therefore, it may be possible to implement them in vivo as inert tools for probing or redirecting [tissue] development. "
Caption: Arbitrary proteins such as GFP can be converted to a synthetic morphogen that forms a gradient pattern of gene expression.
Research highlights NanoLSI Kanazawa University
Morphogens  they are molecules that are essential for the biological process of pattern formation. They are produced in a source, after which they diffuse through the surrounding tissue in an embryo, establishing concentration gradients in the process. These gradients drive the biochemical reactions that ultimately lead to the formation of all tissues and organs in an organism. Satoshi Toda of the University of Kanazawa a pioneer in programming multi-cellular self-organizing structures, and his colleagues have now shown that it is possible to design synthetic morphogen systems that have programming functionality but at the same time do not interfere with biological processes. (non-synthetic morphogenic systems).
Green fluorescent protein
Green fluorescent protein (GFP) is a molecule that shows green fluorescence after exposure to ultraviolet blue light. GFP is often used in biomedical protein expression experiments. For example, it has been shown that the GFP gene can be expressed in specific cells, particular organs, or whole organisms. Now Toda and his colleagues have shown that (soluble) GFP can be used as a synthetic morphogen.
Satoshi Toda Wesley L. McKeithan Teemu J. Hakkinen Pilar Lopez  Ophir D. Klein and Wendell A. Lim . Engineering synthetic morphogen systems that can program multicellular patterns, Science 370 327-331 (2020).
DOI: 10.1126 / science.abc0033
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About the Nano Life Science Institute (WPI-NanoLSI)
Nano Life Science Institute (NanoLSI) at Kanazawa University is a research center established in 2017 as part of the International Research Center Initiative World Premier of the Ministry of Education, Culture, Sports, Science and Technology. The objective of this initiative is to form world-class research centers. NanoLSI combines the most advanced knowledge of bio-scanning probe microscopy to establish 'nanoendoscopic techniques' to directly image, analyze and manipulate biomolecules to understand the mechanisms that govern life phenomena such as disease.
About Kanazawa University
As the leading comprehensive university on the sea coast from Japan Kanazawa University has contributed greatly to higher education and academic research in Japan since its founding in 1949. The University has three universities and 17 schools offering courses in subjects including medicine, computer engineering, and humanities.
The University is located on the coast of the Sea of Japan in Kanazawa – a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students, including 600 from abroad.
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