TRACS exist in tissues during planarian whole-body regeneration

TRACS set the stage in flatworm regeneration.


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Planarians are flatworms, possess a fantastic ability to regenerate themselves. If you cut one planarian down the middle, each half would reform its missing parts. This would result in two different planarians within a couple of weeks.

How’s that possible? What cells types play a characteristic role in this process?

A new study at the Stowers Institute for Medical Research gives answers to these questions.

Scientists conducted the study on Schmidtea Mediterranea, an essential model for stem cell research and Regeneration. In the process of Regeneration, the wound-induced epidermis and the wound-induced muscle plays different but vital roles.

Scientists found that all three germ layers (muscle, epidermis, and intestine) of Schmidtea Mediterranea transcriptionally respond to amputation. Also, both tissues near the wound site and far away from the wound site contribute to regenerative capacity.

Blair Benham-Pyle, Ph.D., a postdoctoral scientist in the lab of Stowers Executive Director and Chief Scientific Officer, said, “Regeneration was a little bit of a black box before—we knew some important genes, and we could look at how some genes were altered globally in response to amputation and during Regeneration, but we didn’t know how individual cell types across the animal were changing their behavior or function. That’s what this experiment allowed us to characterize.”

“The dream experiment was to characterize gene expression on the single-cell level, across all of the different cell types of a regenerating animal, over time.”

Scientists experimented using a single-cell sequencing method named SplitSeq. Using the method, they captured almost 300,000 single-cell transcriptomes across eight different tissues and the stem cell compartment in animals that had lost the ability to regenerate, compared with those capable of regenerating.

Benham-Pyle said, “This allowed us to look at all of the different cell types across the entire animal to see which responded to amputation and what genes were marking these cells as they changed and responded to regeneration.”

“We found and characterized five different cell types, from all three germ layers, that transiently altered their transcriptional output after amputation. When genes enriched in these cell types were knocked down, all of them contribute to Regeneration in different ways, being activated at different times and in different parts of the body.”

Scientists were surprised to discover that rare cell state called transient regeneration-activating cell states (TRACS) induced during whole-body Regeneration. Also, the intestine was essential for both stem cell maintenance and regulating tissue remodeling after amputation.

Benham-Pyle said, “I didn’t expect the intestine to change its output and remodel its function after injury globally. But if you think about it, it does make sense. The planarian normally grows its body plan based on its nutrient environment. The worm eats, and that fuels a burst of stem cell proliferation and the addition of new biomass. When you cut the animal, especially in extreme injury, it often loses its ability to eat. The growth and remodeling now need to be fueled by nutrients already existing within the body plan. So, after amputation, the intestine alters its function to scavenge material from dying cells within the animal, and to convert those materials into new healthy cells in a regenerated worm.”

“We had to do all of our manuscript revisions during the COVID-19 pandemic when we were at 50% research capacity. Sean McKinney and the Microscopy Center found ways to automate imaging. We worked out a system where I could give them forty to eighty slides at a time, of all different samples and RNAi conditions, to be imaged on overnight runs. They could generate terabytes of imaging data for use on the scanning confocal microscope, which helped give us the big lift we needed to get the paper accepted. They set a very high bar for microscopy facilities.”

“Taking a step back, what this paper does is take a global look at what sorts of cells need to be in a signaling environment to stimulate stem cells to create new tissue and replace missing tissue.”

“It turns out that several genes that we characterized, for instance in the intestine, have also been implicated in immune evasion in the context of cancer or in wound healing. Many of the same mechanisms that stem cells use to avoid the immune system and fuel proliferation and growth during Regeneration may be the same mechanisms that are co-opted by tumors. By understanding what non-stem cell states and tissue types are helping to create that signaling environment, we might eventually find new targets for either stimulating healthy and normal wound healing in contexts where regenerative capacity is limited or limiting growth capacities of things that we don’t want to grow, like tumors.”

“Now that we have a map, we can go and figure out how the cells are talking to each other, what they’re doing, and how they’re doing it.”

Journal Reference:
  1. Benham-Pyle, B.W., Brewster, C.E., Kent, A.M. et al. Identification of rare, transient post-mitotic cell states induced by injury and required for whole-body Regeneration in Schmidtea Mediterranea. Nat Cell Biol (2021). DOI: 10.1038/s41556-021-00734-6


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