Adult stem cells stay young attached to the basement membrane

Adult stem cells are the cells that replenish dead or injured cells in our organs. Thus, there are intestinal stem cells, skin stem cells, muscle stem cells, and so on. Even though adult stem cells form a minute fraction of the total cells of each organ (3, 4), they are a dynamic force. For example, the intestinal stem cells divide enough  times to replace the intestinal lining every few days (5).

 
The basement membrane material is produced primarily by the cells of the connective tissue. Imagine a shepherd's pie with a layer of meat and vegetables on the bottom representing the connective tissue. Sitting on top of this nourishing layer are the mashed potatoes, representing our epithelial layers. In this analogy, the meat layer's role is to produce a thin and flexible intervening layer: The basement membrane.

The connective tissue (the "meat" layer) produces collagen fibers, laminins, and other macromolecules (6, 7, 8). All those molecules work together velcro-like to attach the stem cells to the basement membrane. The result - to continue with the pie analogy - is that the mashed potato base is firmly attached to the membrane constructed by the meat layer.  

This is critical as the three elements (the stem cells, the basement membrane, and the connective tissue) all communicate through those protein networks. Below is a histologic image of corneal epithelium. In this, we can see:

• the 4-5 epithelial cell layers (deep pink color with the darker nucleus in each cell)
• the ultra-thin basement membrane just underneath the lowest layer of epithelial cells (straight  -arrow)
• Underneath the basement membrane is another layer (Bowman's membrane - curved arrow) which is a thicker layer of pink collagen fibers (there are no cells in this layer)
• Underneath those two membranous structures is the connective tissue with collagen fibers as well as interspersed cells.

The specific proteins within the basement membrane - like fibronectin, laminin, Oct 4 - form bridging connections to the proteins of stem cell membrane proteins as shown in the diagram above. These connections provide the support needed by the stem cells to maintain their ability to self-renew (9). Interestingly, the levels of the proteins have to be fine-tuned. Too much or too little of those activation proteins pushes the cell intro differentiation (9).  

In addition, the stem cell plasma membrane proteins (integrins) are given the message by the basement membrane protein network to keep the cells quiescent (10, 11, 12, 13, 14, 15), that is divide infrequently. Even though stem cells stay quiet, they remain pretty active under the surface. They are actively engaged with the basement membrane proteins (6, 11). Those integrin-mediated interactions induce the production of new basement membrane proteins (particularly laminins and collagen IV). 

This creates a positive feedback loop between the basement membrane and the stem cells. The basement membrane encourages the stem cell to produce more basement membrane proteins. The basement membrane proteins then encourage the stem cells to produce more integrins. And the cycle reinforces itself. In support of this, experiments have shown that lower levels of integrins in the epithelium is a marker that the stem cell has started the process of differentiation (16). 

Healthy stem cells are the result of healthy connections between the three primary elements of a tissue (the connective tissue, the basement membrane, and the stem cells). For example, studies have shown that increasing the adhesion of stem cells to the basement membrane (for example, by Selenium supplementation - 17) help the stem cells maintain their "stemness". This makes sense; the more adhesive the cell is to the basement membrane, the stronger will be its direct positive feedback from the basement membrane proteins (16).

On the flip side, stem cells that are separated from the proteins of the basement membrane lose their ability to self-renew and start differentiating into mature cells (10, 12, 14,  18). For example, if you look at the image of the corneal epithelium above, you can see that the bottom layer of cells are larger with larger nuclei. As they move away from the basement membrane, the cells have flattened out, the nucleus is much smaller and has lost its prominence, and the cell is decidedly more pink than deep pink.

As the cells have matured, they have aged.