What are some examples of cell to cell interactions?

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The coordination of 37.2 trillion cells is required for our bodies to function, but it can be difficult enough to coordinate a classroom of thirty students. How then are so many cells coordinated at once, without our conscious thought?

Cells coordinate their activities through a variety of cell-cell interactions. In this Common questions in molecular biology blog post, I explore different kinds of cell-cell interactions. I’ll start with a few examples of cell-cell interactions including how cells are both linked together and communicate through gap junctions, and two classes of cell signaling, paracrine and endocrine signaling. I’ll highlight why understanding cell-cell interaction provides insights into not only our overall biology, but also how diseases develop. Throughout, I’ll provide real world examples of how cell-cell interactions can be studied using single-cell sequencing and NanoString’s CosMx™ Spatial Molecular Imager.

What are different forms of cell-cell interactions?

When cells communicate or engage with one another, it is a form of cell-cell interaction. While most cell-cell interactions involve ligand and receptor interactions (discussed more below), some forms of cell-cell interactions are based on physical contact. For example, cells in the epithelium must work together to form a barrier. One way that they do so is through the function of tight junctions. Tight junctions are a type of molecular quilting that holds adjacent cells together tightly. Desmosomes are another way that cells are held together. Desmosomes are essentially molecular rivets that connect the plasma membranes of adjacent cells.

Gap junctions function both as a way of physically connecting cells to one another while also providing a method of intercellular communication. At the most basic level, gap junctions are like small tubes connecting adjacent cells to one another. The tube acts to structurally connect the cells together while also serving as an avenue for small molecules such as ions to pass between cells. Gap junctions are particularly important for coordinating cellular activity. For example, communication between gap junctions is necessary for creating a coordinated impulse for the heart to beat.

Many kinds of cell-cell interactions are mediated through the actions of ligands and their associated receptors. This includes cell signaling, and also the action of specialized cells, such as between activated T cells and cancerous cells. Ligands are produced by one cell and bind very specifically to a receptor on a target cell. Ligand binding to the receptor ultimately results in some kind of biological change within the target cell. Often, this biological change involves alterations in gene transcription.

While there are three classes of cell signaling — autocrine, paracrine, and endocrine — only the latter two are forms of cell-cell interaction.

There are three general classes of cell signaling: autocrine, paracrine, and endocrine signaling. Autocrine signaling is not a form of cell-cell interaction. Rather, the ligand and receptor are both present on the same cell. Paracrine signaling occurs between nearby, but not necessarily adjacent, cells. For example, the Hedgehog signaling pathway functions in one particular region. The closer cells are to the Hedgehog signal results in differences in cell fate. This is an important component of pattern formation during embryonic development.

Cells do not necessarily need to be near one another to interact. In the case of the endocrine system, cells can be in completely different parts of the body. For example, the hypothalamic pituitary adrenal (HPA) axis is important for regulating our circadian rhythms and response to stress. The HPA axis alone constitutes two locations in the brain (the hypothalamus and pituitary gland), the kidneys (the adrenal glands sit on top of the kidneys) and the ligand produces by the adrenal glands in response to signals from the brain, cortisol, can bind to receptors in every cell in the body.

What is the importance of cell-cell interactions?

Cell-cell interactions such as cell signaling highlight one of the key principles of molecular biology: right amount, right time, and right place. Aberrations in cell signaling are associated with a wide variety of diseases. For example, using our example of the HPA axis above, over-activation of the HPA axis is implicated in a variety of neuropsychiatric disorders including anxiety, depression, and post-traumatic stress disorder. Defects in hedgehog signaling are also implicated in cancer progression. For example, hedgehog signaling is thought to be involved in increased malignancy in cancer cells. Other lines of evidence suggest that changes in hedgehog signaling are also the culprit behind the development of drug resistant cancers and expansion of cancer stem cells.

CosMx™ SMI for Single-Cell Imaging instrument photo

Herein lies the utility for better understanding disease processes using single-cell sequencing and NanoString’s CosMx SMI. The CosMx Spatial Molecular Imager facilitates the capture of both multinomic and spatial information of single cells. For instance, with Hedgehog signaling, different cells and subpopulations of cells will respond according to how much Hedgehog protein they are exposed to. Consequently, spatial positioning of cells corresponds to unique differences across the population.

Given the variability of impacts on individual cells in space, to fully understand their function requires examination in their spatial context. With this information in hand, researchers may someday understand the mechanisms behind why and how Hedgehog signaling can contribute to tumor malignancy, evolution of resistance to treatment, and development of cancer stem cells. In addition, because the CosMx SMI provides such fine resolution, one could specifically examine the genomics and spatial positioning of rare cancer stem cells.

There are many examples of cell-cell interactions, including direct contact various ligand/receptor interactions

For our bodies to function requires massive coordination across all 37.2 trillion of our cells. Cell-cell interaction is the method behind this coordination. There are many different examples of cell-cell interactions. In this blog post, I highlighted a few of these, including various ways cells can coordinate via direct contact with one another plus ligand and receptor interactions. Ligand and receptor interactions can occur between very specific types of cells, such as in the immune system, or in the context of cell signaling. Cell signaling can occur between cells in close contact between one another, or across the entire body.

Understanding cell-cell interaction is important for not only understanding our biology, but for how and why certain diseases like cancer develop. New developments in molecular biology, such as single-cell sequencing using NanoString’s CosMx Spatial Molecular Imager are going to be crucial for understanding cell-cell interactions in their spatial context. These new insights may yield promising avenues for future cancer research and treatment.

By Geoffrey Hummelke
For research use only. Not for use in diagnostic procedures.