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April 26, 2018

Who am I? How cells find their identity

The research group of Alex Schier, Director of the Biozentrum, University of Basel, has investigated more closely how a single embryonic cell develops into a heart, nerve or blood cell. For the first time, the researchers have been able to reconstruct the developmental trajectories of individual embryonic cells. Their results also suggest that cells can change their path during their maturation process. The results of the study with around 40,000 cells have now been published in "Science".

Development of a zebrafish, 28 hours post fertilization.

The origin of every cell of our body is a single cell, the fertilized egg. On the way to become a specialized cell, whether blood, heart or nerve cells, its descendants follow a genetic program. This program determines the identity of a cell, its features and function.

The research team led by Alex Schier, Director of the Biozentrum, University of Basel, and currently still research group leader at Harvard University in Cambridge, has now developed a new method that enables the scientists  for the first time to trace the entire history of the differentiation of individual cells. By combining the differentiation trajectories they have been able to construct a full developmental tree for embryogenesis. Furthermore, the team discovered that during differentiation, cells can leave their path and thus change their identity.

A widely branched tree for cell development
In their study, the team isolated around 40,000 cells and 25 different cell types that form in zebrafish over a period of nine hours. To investigate the maturation of these cells, they analyzed the RNA, a copy of the genetic material. "The RNA tells us, which genes are active and determines the function and characteristics of a cell," says Schier. 

In order to merge and compare the data, Schier’s team developed a new software (URD). While previous studies in this field are based on the examination of a handful of genes, the new high-throughput single-cell RNA sequencing method enables the analysis of all active genes during cell development. With this new technology, the team has been able to reconstruct, for the first time, a widely branched tree that traces the development of each individual cell, starting with the fertilized egg cell. In addition, they mapped the cells to their spatial origin in the early embryo.

Finding cell identity is more flexible than expected 
The results show that the genetic program that a cell follows on the way to maturity is by no means set in stone. «It seems that the developmental path of a cell is more flexible than we previously expected», says Alex Schier. So far, it was assumed that developing cells follow a predetermined path, like marbles rolling down a hill until they stop at their predestined place. The study now suggests that signals from the environment can have such a strong influence on the cells, that they leave the initial trajectory and change their path, thus taking on a new identity. 

Entire development as a cell lineage tree
In a next step, the research group will expand the cell lineage tree, investigate more cell types and follow the development of cells over a longer period of time. «My aim is to merge the developmental trajectories and the lineage trees to one complete whole. "If we can understand the logic behind cell differentiation, we may, one day, be able to answer the question: How many ways are there to build a heart or a brain?"

Original article:
Jeffrey A. Farrell, Yiqun Wang, Samantha J. Riesenfeld, Karthik Shekhar, Aviv Regev and Alexander F. Schier. Single-cell reconstruction of developmental trajectories during zebrafish embryogenesis. Science. Published online26 April 2018.

For analysis of lineage trees, also see the recent paper by Raj et al.:
Raj B, Wagner DE, McKenna A, Pandey S, Klein AM, Shendure J, Gagnon JA, Schier AF: Simultaneous single-cell profiling of lineages and cell types in the vertebrate brain. Nature Biotechnology 2018.

Contact: Communications, Heike Sacher