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Developmental Biology - Cell Signalling

Synthetic 'Morphogens' Guide Complex Tissue Growth

Human engineered developmental signals could assist regenerative medicine...


For a tiny embryo to develop into an adult organism, its cells must develop in precise patterns and interact with their neighbors in carefully orchestrated ways. To create complex tissues and organs from the pattern of rods and cones in the retina to the complex filtration systems of the kidney all these developing cells must constantly answer a fundamental but, surprisingly difficult question: Where am I?
"In the field of regenerative medicine, we can use stem cells to make organoids to study disease, but we can't yet put them into a person and have them repair a wound or heal sick tissue. A big part of the reason for this is - we don't know which signals tell cells (1) where to go and (2) what to do when they get there."

Wendell Lim, PhD, Byers Distinguished Professor and chair of the UCSF Department of Molecular and Cellular Pharmacology.

One of the ways cells in developing organisms keep track of where they are and what they are supposed to be doing next is through a chemical signal called a morphogen. Morphogen signals are produced by organizer cells and diffuse out through local tissue. As the signal is diffused through the cells, its concentration fades.

The amount of fade in a morphogen signal tells local cells exactly how far each cell is from the original source of that signal. With multiple organizer cells churning out different morphogen signals from key locations within a growing organism, cells can create a 3D spatial map to guide their development into complex tissues. In effect, a cellular GPS coordinated system.
Scientists are still working to understand how: (1) morphogen signals are broadcast over just the right distances and (2) how cells are calibrated to respond to the proper concentration at the appropriate time. These questions are difficult to investigate as natural morphogens interact with the environment in complex and hard to define ways.

Instead of deconstructing morphogens one interaction at a time, Lim's synthetic biology team at UCSF, along with a pair of research groups at the Francis Crick Institute in London - engineered a synthetic morphogen from the ground up. Their goals were reported in two papers. One published October, 2020, in the journal Science, studied what makes morphogens work aiming to create synthetic signals to control tissue regeneration or guide cellular therapies; or to heal wounds and/or fight cancers.

Lim's team, led by then postdoctoral fellow Satoshi Toda, started with an inert molecule called GFP to which cells are normally completely unresponsive. To give cells the ability to respond to this new signal, researchers used special types of antibodies to create GFP-responsive receptors. The team genetically inserted these receptors into cells in laboratory dishes and linked them up to a cellular control system called SynNotch, which the team had previously developed.

When the researchers instructed a subset of organizer cells at one end of the dish to produce GFP, clouds of the fluorescent protein diffusing away from these anointed organizers activated engineered receptors and imparted patterned gene activity in surrounding cells.
"I think it's pretty striking that a crude morphogen is not very hard to make. It gives us a sense of how much simpler signaling molecules might have evolved to become morphogens in the early days of multicellular evolution."

Wendell A. Lim PhD, Cell Design Institute, Department of Cellular and Molecular Pharmacology, and Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, USA.

At UCSF, researchers revealed how these engineered morphogens can signal the formation of novel, user-defined striped patterns. At the Crick Institute, scientists used a similar approach in living flies - to show how engineered morphogens could take the place of natural signals in successfully organizing the intricate patterns of the fly wing. Because all the interactions in these systems are engineered, their characteristics are understood and therefore amenable to mathematical modeling according to the researchers.
These studies open the way to a testable theory of pattern formation by morphogens, and one day could help scientists program cells like robots to follow molecular trails to find and regenerate injured or diseased tissues.

Abstract
In metazoan tissues, cells decide their fates by sensing positional information provided by specialized morphogen proteins. To explore what features are sufficient for positional encoding, we asked whether arbitrary molecules (e.g., green fluorescent protein or mCherry) could be converted into synthetic morphogens. Synthetic morphogens expressed from a localized source formed a gradient when trapped by surface-anchoring proteins, and they could be sensed by synthetic receptors. Despite their simplicity, these morphogen systems yielded patterns reminiscent of those observed in vivo. Gradients could be reshaped by altering anchor density or by providing a source of competing inhibitor. Gradient interpretation could be altered by adding feedback loops or morphogen cascades to receiver cell response circuits. Orthogonal cell-cell communication systems provide insight into morphogen evolution and a platform for engineering tissues.

Authors
Satoshi Toda, Wesley L. McKeithan, Teemu J. Hakkinen, Pilar Lopez, Ophir D. Klein and Wendell A. Lim.

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Oct 16 2020   Fetal Timeline   Maternal Timeline   News



Engineered morphogens can signal the formation of novel, user-defined patterns. At the Crick Institute, scientists used a similar approach in living flies - to show how engineered morphogens could take the place of natural signals and successfully organize intricate patterns on a fly's wing. CREDIT Science.


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