The experimental model makes cells behave like they do in the womb

HOUSTON – (May 8, 2023) – Many birth defects and spontaneous abortions occur during a stage of embryonic development known as neurulation, but we have little insight into how this critical developmental process occurs in humans.

HOUSTON – (May 8, 2023) – Many birth defects and spontaneous abortions occur during a stage of embryonic development known as neurulation, but we have little insight into how this critical developmental process occurs in humans.

The Rice University of Aryeh Warmflash Laboratory has received a $1.9 million five-year grant from the National Institutes of Health to optimize and develop experimental cell models that can explain the self-organizing process by which ectodermal cells give rise to the central nervous system. systems, skin and sensory organs.

The Warmflash lab will use a technique called micropatterning to make colonies of ectodermal cells self-organize and differentiate in ways that reflect embryonic development. By engineering cells to express different fluorescent signals based on the type of protein signal they use to communicate, scientists will be able to track and measure cells’ self-regulatory behavior.

This research may inform ways to prevent or counteract central nervous system birth defects originating from anomalous neurulation.

“The most fundamental question we are interested in is what guides the behavior of cells to assemble into embryonic tissue,” said Warmflash, a professor of biosciences and Texas Institute of Cancer Research and Prevention scholar.

To study this question, Warmflash and collaborators used micropatterning and cultured human pluripotent stem cells to develop self-organizing systems that model key cellular processes involved in embryogenesis.

“Micropatterning technology is just a way to control very precisely the geometry in which these cell colonies grow,” said Warmflash. “Micropatterning allows us to pattern surfaces with different chemical modifications so we can say, ‘OK, we want the cells to stay here and not there.’”

In standard stem cell culture, cells will grow into clumps of different sizes and differentiate randomly into a disordered and highly heterogeneous mass. But if micropatterning is used to curb random growth, cells behave in an organized manner that mirrors the behavior of cells in the actual embryo.

“Mammal development is a self-regulating process,” says Warmflash. “That means, at first, you grow a ball of cells that has a perfectly symmetrical structure because all the cells in it are basically the same.

“Then there are organisms whose symmetry has been broken. For example, when a mother fly lays fly eggs, they are asymmetrical: Just by looking at them, you can tell where the heads are, etc.

“In a mammalian or human embryo, the symmetry is initially unbroken. But in the end, the embryo has to figure out ‘this side will be the head and this will be the back’ and so on. The cells have to break that symmetry themselves. We want to understand how they do it.”

In the embryo, ectodermal cells sort themselves into one of four cellular “destinies” as the nervous system, nervous system, skin, or sensory organs. By micropatterning, Warmflash and his team were able to manipulate intracellular signals to achieve a distribution of cellular fates in a bull’s-eye pattern that mimics ectodermal patterns along the embryo’s medial-lateral axis.

“We induce cells to differentiate with pattern signals, and then they figure out how to regulate themselves,” says Warmflash. “They said, ‘Okay, we have to make these four different fates — the neurons will be in the middle and the skin will be at the edges, with another fate in between.’ That is the midline axis to the side, but there is another axis that is formed simultaneously, namely the head to toe axis.

“Right now, there really isn’t a good model of how the head-to-foot axis of the nervous system forms in humans, which shapes the nervous system into very broad regions: the forebrain, midbrain, hindbrain, and then the spinal cord. behind. .”

Warmflash hopes to refine the system to model the head to toe developmental axis, “where instead of neurons versus skin at the edge of the colony, the center of the colony will be the forebrain neurons and to the edges of the colony will be the neurons of the spinal cord.

“Instead of representing different types of ectoderm arranged along a medial-lateral axis, colonies would represent nervous systems arranged along the longitudinal axis of embryonic structures. We’re interested in how cells communicate to do that.”

In addition to these 2D maps of self-organizing cellular patterns, Warmflash hopes to use the micropatterning modeling system to study morphogenesis, which refers to how tissues or organs occupy space and develop their specific shapes.

“In this ectoderm model, you can encourage cells to fold in the third dimension,” says Warmflash. “And they would actually close from the top in a very similar way to how the neural tube closes during development. We’re interested in this because you have signaling between cells that changes their cell type and also affects the way they move and are sculpted to actually make functioning tissue.

“This may be very relevant clinically because many birth defects are actually neural tube closure defects.”

Modeling systems can be used to study mutations that cause defects in neural tube closure, opening up the possibility of knowing how to prevent or ameliorate such events.

“It is not yet known how certain mutations cause certain defects,” said Warmflash. “But those are things that we can study in these models with the aim of, first, understanding how things break and, then, hopefully figuring out how to prevent those things from happening.”


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DESCRIPTION: Aryeh Warmflash is a professor of biosciences at Rice University and the Texas Institute of Research and Undergraduate Cancer Prevention. (Photo by Jeff Fitlow/Rice University)
DESCRIPTION: The images generated by Rice scientists illustrate changes in the composition of ectodermal “fate” as a result of the control of cellular signaling. Depending on which signals are inhibited versus boosted, colonies form radial patterns of neural (cyan), surface (magenta) and placodal (red) fates (all represented in the left column), or rings of neural crests (yellow) at the expense of placodal fates (represented in the right column). (Image courtesy of Warmflash lab/Rice University)
DESCRIPTION: In this neural tube closure stem cell model figure, cell colony development from day 5 to day 7 is represented on the two axes, where “XY:bottom” indicates the distribution of differentiated cells at the bottom of the colony and “XZ” indicates the view side of the cell colony, with the neural tube cells (light blue) closing to form a tube covered by a continuous layer of future skin cells (magenta). (Image courtesy of Warmflash lab/Rice University)
DESCRIPTION: Stem cell model image of nervous system pattern with colors representing forebrain (magenta), midbrain (light blue), and hindbrain and spinal cord cells (yellow). (Image courtesy of Warmflash lab/Rice University)

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