Scientists release a new role for the nervous system in regeneration

Tufts University biologists have developed a computer model of planar regeneration (flatworm) that explains how planar fragments determine which end should form a tail and which should form the head. Development begins to answer an important question in regenerative research: what are the signals that determine the reconstruction of specific anatomical structures? By combining modeling and experiment, the researchers determined that the direction of the nerve fibers defined the redistribution of chemical signals by establishing the direction of the axis head-to-tail. The model was also able to predict the results of many genetic, pharmacological and surgical manipulations, such as two-headed or two-tailed worms.

The results published in the journal PLOS Computational Biology go beyond planning by showing how computer modeling of physiological and genetic signals can help understand and control regeneration. The discovery that directionality helps guide organ structure could have many applications in biomedical contexts, such as mammalian regeneration, congenital anomalies, organo-bioengineering, and cancer.

The computer model, which uses a new open-source simulation platform called the Planarian Interface for Modeling Body Organization (PLIMBO), incorporates many biological mechanisms at the core of regeneration – some previously published and others discovered in this study. This computing environment creates a realistic quantitative simulation of events occurring at the molecular, cellular, tissue and whole organism levels. The model has identified the important role that neurons play in regeneration by providing active transport of morphogens, molecules that help guide the growth and organization of cells in different tissues and anatomical structures. Researchers have found that neurons play a critical role in rebuilding the polarity of the body plan (head-to-tail), as well as in the ability to rapidly distribute morphogens to allow the regeneration process to function effectively at different scales ( tiny fragments to complete body.

The model is essentially a 2-dimensional map of a planar body, in which important signaling molecules such as Hh, NRF, ERK, Wnt, cAMP, beta-Cat, Ptc and APC, respect their own rules of production, distribution and transportation. along the cell paths, and interact with each other. To better understand the regeneration process, the authors examined the calculated results of cutting out portions of the map, inhibiting the transport of virtual morphogens, and / or disrupting the production of specific morphogens. The results of these interventions were then examined experimentally by physical excision of the worm and exposure to RNAi or pharmacological treatments, which may decrease or increase the biological production of specific morphogens.

While it has been known for decades that neurons play an important role in regenerative capacity, this is the first study that reveals that it is the neural directionality that specifically controls redistribution. subsequent biochemical substances that determines the anatomical polarity of a major axis of the body. This shows how an ordered pattern appears at the scale of a cell and spreads to tissues and organs.

"The model has been remarkably successful in predicting the true biological outcomes of the worm," said Michael Levin, Ph.D., professor of biology at Vannevar Bush at the School of Arts and Sciences and director of Tufts' Allen Discovery Center. "This allowed us to visualize how structuring information can propagate from the cell level to the organism level, and how the directionality of specific cells (such as neurons) determines the downstream biochemical gradients and the Organ Determination The model allowed us to accurately predict new experiments that had never been performed before, revealing that neural directionality takes it (and restores) pre-existing biochemical gradients. "

The neuronal direction guides the polarity in regeneration by serving as a rapid conduit to certain morphogens. Neurons contain in them a system of "tracks" called microtubules and molecular "motors" that carry molecules along these tracks. Dynein and kinesin are among the driving forces, and the inhibition of one of these molecules can lead to regeneration anomalies predicted by the model. New experiments have shown, as predicted by the model, that pre-existing gradients of chemical fragments do not fix the direction of the head and tail axes, but rather are rewritten by the directionality of the neuron fibers.

"PLIMBO allows us to examine regeneration in a rigorously quantitative way," said lead author Alexis Pietak, the biophysicist who designed the model and a member of the Allen Discovery Center. "We can fill gaps in knowledge by simulating the role of neurons and new morphogens, and whether they improve the ability to predict experimental results, which may not only allow us to better understand the process of regeneration, formation of tissues and organs, also indications of how body patterns might be disturbed in other animals during gestation, resulting in birth defects. "