WTF is a Stem Cell Niche?

Once upon a time, you fell and scraped your knee. You've lost cells and risk infection. Why was the tissue triggered to regenerate in the first place? Welcome to the stem cell niche!

What are epithelial tissues?

Every day our body makes and loses billions of cells. There are different types of tissues in the body: muscle (cardiac, smooth, skeletal), nervous (brain, spinal cord, nerves), epithelial, and connective (fat, bone, tendons). Epithelial tissues, such as the olfactory epithelium, are interesting since they cover all the surfaces of our body (inside and out) and act as a barrier, or knight’s shield, to the outside world. Hence, these were the first tissues to develop evolutionarily. They protect, absorb, and secrete. Not surprisingly, the majority of cancers originate from epithelial tissue since their high rate of turnover could easily escalate to uncontrolled cell proliferation with the potential to metastasize (the definition of cancer!). These epithelial cancers are called carcinomas.

Below the epithelium is the basement membrane and mesenchymal tissue, which together act like a rather strange 'pillow cushion' with networks of vessels linking the epithelium to the rest of the body. These vessels allow the epithelium to receive nutrients and oxygen from the bloodstream and immune protection from lymphatics.

Epithelia can either be simple or stratified. The olfactory epithelium is a pseudostratified tissue, meaning the cells appear to be organized into layers, but are actually all attached to the basement membrane on the basal side. Cells can be squamous, columnar or cuboidal, based on (you guessed it) their shape! In the olfactory epithelium the cells are columnar in appearance. In fact, the entire respiratory epithelial tract has pseudostratified, ciliated, columnar cells. Interestingly, another tissue with columnar cells is the intestinal lining with villi (albeit these are simple, not stratified epithelia), serving a similar role to the cilia on OSNs binding odorants. The extra surface area enabled by these smaller projections allows for more sensitized odorant detection or nutrient absorption.

Moreover, the exposed nature of epithelia led to the evolution of polarity in these tissues. The outer, lumen facing surface of the epithelia is referred to as its apical side, while the side facing the basement membrane is referred to as basal. Tight junctions between cells tend to be apical, reinforcing protection at the barrier. Polarity of cells has an impact on the division of cells either vertically or horizontally across epithelia. Vertical divisions indicate a change in the level of differentiation of cells, while horizontal divisions do not. Typically, more differentiated cells are on the apical side, while more undifferentiated cells (like stem cells) are on the basal side. Polarity proteins are expressed inside cells and molecularly establish this organization.

What are stem cells?

Stem cells are critical for tissue development, repair, plasticity and regeneration. A somatic stem cell is an undifferentiated cell that can give rise to both downstream differentiated lineages and themselves within a tissue for a long time. When a stem cell divides it yield 2 daughter cells: one to be differentiated into a specific lineage (“one of you”) and one identical to itself (“one of me”), in order to not deplete the stem cell reserves. This is called asymmetric cell division. Other cells besides stem cells can divide in this way. This may be triggered by a combination of niche signals:

• Triggering inflammatory cytokine signalling cascade

• Changes in cell polarity protein expression

• Unequal distribution of cell fate determinant proteins and organelles

• Orientation of the spindle positioning complex vertically or horizontally

Homeostasis and regeneration are regulated by the activation and function of somatic stem cells. The more exposed the epithelia is, such as the gut lining or the skin, the more readily the cells will be sloughed off and overturned. This is because exposure tends to come hand in hand with damage and infection, the two main triggers of the immune system!

Nevertheless, tissues and organs with little cellular turnover, like the brain and muscle, have also been found to have somatic stem cells. The function of tissues that are largely postmitotic encourages little regeneration for a reason, though. Let’s take the central nervous system as an example. We spend our entire lives strengthening (long term potentiation) or weakening (synaptic pruning) the synaptic connections that hold precious information learned over the years. Why would we want to get rid of neurons at the first sign of infection or damage when all those connections are at stake? That’s right: we don’t. Neurogenesis (regeneration of neurons) is not the most adaptable solution. Instead, the central nervous system prioritizes keeping malfunctioning, damaged neurons rather than killing them off altogether. This different pathology implies that neurodegenerative and psychiatric disorders may have alternative immune mechanisms compared to the rest of the human body. A better understanding of how gene expression change and signal circuits are altered could yield translational, therapeutic potential.

What is a stem cell niche?

A niche is a microenvironment. Therefore, a stem cell niche is the microenvironment where stem cells live and interact with neighboring components, regulating their behavior. Specific and different factors, signals or interactions may stimulate quiescence or activation of stem cells, respectively. There tends to be two populations of stem cells: quiescent dormant (sleeping beauties) and primed active (hyper roadrunners). The sleeping beauty stem cells tend to wake up when activated to become transient amplifying cells, the hyper roadrunners, which are constitutively dividing and differentiating into a specific cell type in the tissue.

Essential to communication between organ systems are the pervasive nervous, endocrine and immune systems. In the case of the olfactory epithelium, the olfactory sensory neurons are present, directly impacting the status of the stem cells. Likewise, hormones and immune profiles may have an impact on the purpose of the stem cells: regeneration.

The organization of epithelial tissue gives a lot of nuanced clues about the crucial link between the immune system and stem cell regeneration. Neutrophils, the first immune responders at the site of infection or damage, squeeze across endothelial linings in basement membrane vessels to reach the epithelium above. Which epithelial cells are going to be the first to interact with the neutrophils? The ones at the bottom: stem cells! The stem cells may evolutionarily been organized this way, at the basal side of the epithelium, so that they can first receive the signal of the passerby neutrophils: “Hey, you’re going to have to wake up soon, there is infection/damage in your turf and you’re in charge of regenerating the lost tissue”.

All in all, a better understanding of the stem cell niche could yield great insight to unlock new mechanisms and regenerate tissue across organ systems. How other cells within the epithelium directly interact with neurons can allow us to mimic the signals exogenously with drugs. Once we understand the mechanisms and interactions in a singular epithelium, broadening the scope to finding overarching trends across all epithelia could distinguish which mechanisms are specific to a certain tissue’s function, how the mechanisms are different biochemically and why they would be different in the first place evolutionarily!

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