A key factor in the way in which a disease progresses are the interactions between cells in the disease state. Cell-cell interaction describes the interplay between cell surfaces that allow cells to communicate with each other and respond to changes in their environment and is crucial for the development and maintenance of healthy cells. This process is facilitated by the release of signals from one cell type that interact with another cell to induce changes in that cell.
Mishra et al., in their recently published paper demonstrate a newly developed approach for the elucidation of these cell-cell interaction mechanisms, known as Systematic Elucidation and Assessment of Regulatory Cell-to-cell Interaction Networks (SEARCHIN), combining the use of several lab techniques and computer programs to analyse cell interaction. The need for SEARCHIN is derived from the laborious elucidation process that is currently needed to whittle down the cell-cell interactions that drive changes in disease. SEARCHIN is a method that streamlines this process and offers the opportunity to develop a high-throughput method for clarifying cellular interaction. To demonstrate their approach, the authors modelled the disease amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterised by the death of motor neurons (MNs – cells that control movement) in the brain and spinal cord. Specifically they chose to investigate the interaction between MNs and astrocytes, cells that provide support to motor neurons, assisting them in several functions, which have been hypothesised to contribute to the MN death observed in ALS, though the reason behind this is currently poorly understood.
Previous data shows exposure to ALS astrocytes is enough to induce death in healthy MNs. Mishra et al., initially showed that this was caused by the release of a toxic signal from the astrocytes that induces changes in MNs leading to their death. The researchers then instigated use of their SEARCHIN approach. Briefly, the process first identifies candidate signals released by the astrocytes and the algorithms assign each signal a probability for MN interaction. These probabilities are then combined and ranked to suggest an overall probability. Of the three interactions that were deemed most likely to induce death in the MNs the amyloid precursor protein (APP – a protein that facilitates cell-cell interaction) and death receptor 6 (DR6 – a protein that, when activated by a cell signal, induces cell death) interaction was chosen to further model the efficacy of SEARCHIN.
In confirmation of these results, Mishra et al., then found that expression levels of APP were significantly higher in ALS astrocytes than heathy cells and preventing production of APP in ALS astrocytes also prevented MN cell death. The role of DR6 was also characterised. Similarly, preventing activation of DR6 in MNs prevented cell death therefore demonstrating that SEARCHIN was effective in finding potential causes behind MN death in ALS and showing its potential use in a wide range of diseases.
These findings represent a huge leap forward in the ability to effectively characterise cell-cell interaction. Current methodologies require the step by step elucidation of each mechanism in a pathway, whereas the methods outlined here amalgamate several of these steps to produce a much more efficient characterisation process. The findings also have implications for the treatment of ALS, shedding light on a previously unreported pathway for astrocyte-facilitated MN degeneration and providing a new avenue of research that can be targeted in the effective treatment of ALS, something that may find its way to clinical trials within the next few years.