Scientists map cells into a lineage tree of flatworms and discover secrets of the regenerative process

Monday, 16 July 2018

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Animals as common as earthworms or lizards regenerate their tails and limbs with ease. Learning the tricks that different animals employ to regenerate missing body parts has great potential to help produce human adult cell types or organs in vitro to cure diseases or injuries.

The stem cells in human adult bodies have very limited potential for regeneration and can give rise only to a few cell types. However planarians – a type of flatworm – have a population of adult stem cells that can generate all cell types. Planarians can be chopped into pieces and regenerate a complete new worm in a matter of days.

To investigate this process, scientists carried out the research at the Max Delbrück Centre for Molecular Medicine (MDC) in Berlin and the Institute for Computational Biology at the Technical University of Munich, using single-cell transcriptomics to develop a cell map of a planarian and reconstructed the lineage relationships of its cells.

Dr Jordi Solana, Research Fellow who is now based in the Department of Biological and Medical Sciences at Oxford Brookes University said: “By obtaining messenger RNA (ribonucleic acid) signatures of many planarian cells, we identified and characterized all major planarian cell types including the stem cells.

Overall, studying how planarian stem cells regenerate tissues after amputation will help scientists to understand how to reproduce this with human stem cells in the laboratory, since these hold great promise for regenerative medicine.

Dr Jordi Solana, Research Fellow, Oxford Brookes University

“Since planarian cells are constantly regenerating all cell types to replace old aged cells, what we obtained represented a snapshot of the process, with all intermediate progenitor cells caught in the act of becoming mature cell types, a process called differentiation."

Using computer algorithms, the research team reconstructed the differentiation trajectories by connecting each individual cell to those with the most similar profiles. This allowed them to isolate each stem, progenitor or mature cells and reconstruct their order in the maturation process.

Dr Mireya Plass from MDC explains: “To understand how cells differentiate, we need to compare gene expression profiles from cells at various differentiation stages, like the ones we find in planarians.

“We dissociated whole animals and characterized thousands of individual cells by sequencing their messenger RNA transcripts."

The reconstruction allows scientists to study which genes are activated in the maturation process of each individual cell type and the order in which they need to be activated.

Lineage-tree-of-flatworm-800x450Further to this, the scientists found several new cell types that have previously been overlooked in molecular studies but play an important role in the regeneration of flatworms. These cell types seem to store fat and sugars. By studying their proportion in animals that were regenerating, the research team discovered that these cell types were decreasing in numbers.

“This discovery opens up the possibility that the planarians use these cells to fuel the regeneration process until they are able to eat again – an important aspect in the process that allows planarians to regenerate,” continued Dr Solana.

“Overall, studying how planarian stem cells regenerate tissues after amputation will help scientists to understand how to reproduce this with human stem cells in the laboratory, since these hold great promise for regenerative medicine."

Professor Nikolaus Rajewsky, head of MDC and senior author of the study added: “It opens the door to powerful new approaches to study cell composition of organs, tissues and developmental stages and understand molecular mechanisms of regeneration.”

Dr Jordi Solana is now starting his own research group at Oxford Brookes University, where he will use single-cell techniques to continue this line of research. His group will focus on characterizing stem cells and regeneration in different invertebrates and highlight how these processes have evolved.

The study, Cell type atlas and lineage tree of a whole complex animal by single-cell transcriptomics, is published in Science and can be found online.