Deciphering cell language

New insights into the intercellular communications mechanism that regulates cell repositioning leads the way towards the development of targeted therapies in regenerative medicine

Understanding the language of cells in order to redirect them when necessary: this is one possibility unveiled by researchers at the Center for Regenerative Medicine of Barcelona (CMR[B]), led by Dr. Samuel Ojosnegros, who describe in their latest paper the intercellular communications mechanism involved in cell relocation.

The work, published in Proceedings of the National Academy of Sciences (PNAS), was carried out in collaboration with the groups of Elena Martínez (IBEC) and Melike Lakadamyali (ICFO), among others. The fruitful collaboration also gave rise to the publication of work by Verónica Hortigüela, former PhD student in Elena’s group, who bioengineered a nanopatterning strategy that provides control over this communication mechanism.

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Above: Three-dimensional reconstruction of cells expressing the EphB2 receptor in the membrane of cells that have been stimulated with the ephrin ligand. Cells collide leaving a trace of projections at the base of the substrate.

“We wanted to understand this communications system, which is very sophisticated, as much in detail as possible,” says Samuel Ojosnegros, first author of the study.  “Although we already knew the agents involved, until now we didn’t have the tools to decipher the language – that is, their operating mechanism.”

To study the messages sent by cells, in a joint effort between institutes in Barcelona and California, the authors developed a new microscopy technique that allows them to observe communication signals in living cells. This technique is able to show protein aggregation at the sub-pixel level, which is represented by a colour scale, and allows real-time sequences of how a cell responds to a specific stimulus at high resolution to be recorded.

This communications system is used by cells as a kind of internal GPS to reach their destination in the organs during embryonic development, the regeneration of stem cells, and during the metastasis of invasive tumours.

One of the current limitations of regenerative medicine is the difficulty of ensuring that the stem cells that are transplanted to a patient reach and position themselves in the desired destination. “Once this mechanism is understood, we can take the first steps to be able to manipulate it to steer stem cells much more efficiently, since it is the system they naturally use,” says Dr. Ojosnegros.

Condensation versus polymerization

Cell communication is a precisely orchestrated process based on the existence of membrane receptor proteins that are capable of capturing external signals from the environment and translating them internally. In the study, the CMR[B] team focused on Eph membrane receptors and their ligand ephrin.

“Thanks to our microscopy techniques, we could observe that the Eph receptor, in the presence of ephrin, begins to aggregate creating large structures. This aggregation  follows two differentiated patterns: polymerization (monomer clustering) and condensation (oligomer clustering),” explains Dr. Ojosnegros. “The balance between these two processes regulates the dynamic range of response, because although polymerization involves the activation of the monomers, in condensation the cluster is absorbed by the cell, thus cutting the signal.”

Article citation 1: Ojosnegros, S., Cutrale, F., Rodrígues, D., Otterstrom, JJ., Chiu, CL., Hortigüela, V., Tarantino, C., Seriola, A., Mieruszynski, S., Martinez, E., Lakadamyali, M., Raya, A., Fraser, Se. (2017) Eph-ephrin signaling modulated by polymerization and condensation of receptors. PNAS, epub ahead of print

Article citation 2: Verónica Hortigüela, Enara Larrañaga, Francesco Cutrale, Anna Seriola, María García-Díaz, Anna Lagunas, Jordi Andilla, Pablo Loza-Alvarez, Josep Samitier, Samuel Ojosnegros, Elena Martínez (2017) Nanopatterns of surface-bound ephrinB1 produce multivalent ligand-receptor interactions that tune EphB2 receptor clustering. NANO Letters, epub ahead of print