Basement membrane - healthy stem cells

Health

Adult stem cells stay young attached to the basement membrane

By Juman Hijab

Reading time: minutes

Original date: December 6, 2022  

Updated: December 25, 2022

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Basement membrane - healthy stem cells

Basement membrane is key for healthy stem cells

How young stem cells stay young

Adult stem cells develop a strong attachment to a membrane called the basement membrane.

This membrane acts like a floor for stem cells to sit on. The basement membrane also acts as an "oil of Olay" layer that helps keep stem cells young.


What keeps stem cells young? What helps them preserve their "stemness" (or ability to divide)?


In this article, I will discuss: 

  • how stem cells attach to the basement membrane and 
  • why that attachment helps them stay young. 

Unfortunately, stem cells that lose their connection to the basement membrane start maturing (differentiating). When stem cells differentiate, they are on the way to senescence. (1, 2).

Most adult stem cells are attached to a 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 (34), 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.

Basement membrane - shepherd's pie analogy

Basement membrane gets sandwiched between the potatoes and meat layers.

How do the stem cells attach to 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.
Basement membrane - cornea

Cornea Basement membrane (straight arrow) between epithelial cells and the bright pink acellular Bowman's membrane (curved arrow) with collagen fibrils

The sketch below illustrates the velcro-like character of the basement membrane with collagen and fibronectin proteins attaching to the integrin proteins that are embedded in the plasma membrane of the stem cell. Not shown are laminin proteins which are also critical in the health of the stem cell.

Basement membrane velcro character

Basement membrane velcro-like character with collagen fibers attaching the plasma membrane proteins (receptors)

Why does the basement membrane attachment keep the stem cells young?

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 (1011121314, 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). 

What happens if stem cells lose their atttachment to the basement membrane?

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, 1214,  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. 

Picture credits

  1. blamb. Drawing of blister formation in skin disease such as Epidermolysis bullosa, where the epidermis separates from the basement membrane and dermis, Shutterstock.com, ID: 105160253
  2. hlphoto. Shepherd's pie. Shutterstock.com, ID: 182339030. 
  3. Jose Luis Calvo. Cornea showing, from top to bottom, the non-keratinized stratified squamous corneal epithelium, a thin acellular Bowman’s layer (arrow), and the corneal stroma with collagen fibers and interspersed keratocyte. Shutterstock.com, ID: 1563776551.
  4. VectorMine. Extracellular matrix labeled infographic vector illustration scheme. Biological diagram with collagen fiber, fibronectin, phospholipid bilayer and cytoskeleton filaments.Shutterstock.com, ID: 1175980375

References

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  2. Liu C, Pei M, Li Q, Zhang Y. Decellularized extracellular matrix mediates tissue construction and regeneration. Front Med. 2022 Feb;16(1):56-82. doi: 10.1007/s11684-021-0900-3. Epub 2021 Dec 28. PMID: 34962624; PMCID: PMC8976706.
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  5. Rees WD, Tandun R, Yau E, Zachos NC, Steiner TS. Regenerative Intestinal Stem Cells Induced by Acute and Chronic Injury: The Saving Grace of the Epithelium? Front Cell Dev Biol. 2020 Nov 12;8:583919. doi: 10.3389/fcell.2020.583919. PMID: 33282867; PMCID: PMC7688923.
  6. Pozzi A, Yurchenco PD, Iozzo RV. The nature and biology of basement membranes. Matrix Biol. 2017 Jan;57-58:1-11. doi: 10.1016/j.matbio.2016.12.009. Epub 2016 Dec 28. PMID: 28040522; PMCID: PMC5387862.
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  8. Choi HR, Byun SY, Kwon SH, Park KC. Niche interactions in epidermal stem cells. World J Stem Cells. 2015 Mar 26;7(2):495-501. doi: 10.4252/wjsc.v7.i2.495. PMID: 25815134; PMCID: PMC4369506.
  9. Hunt GC, Singh P, Schwarzbauer JE. Endogenous production of fibronectin is required for self-renewal of cultured mouse embryonic stem cells. Exp Cell Res. 2012 Sep 10;318(15):1820-31. doi: 10.1016/j.yexcr.2012.06.009. Epub 2012 Jun 16. PMID: 22710062; PMCID: PMC3582329.
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