Cellular regeneration: Multi-vesicular bodies

Health

Cellular rejuvenation happens when cells take out the garbage

By Juman Hijab

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Original date: May 26, 2023  

Updated: June 10, 2023

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Cellular regeneration: Multi-vesicular bodies

The second path to cellular rejuvenation: DALL·E-2- interpretation showing four spherical multi-vesicular bodies (MVPs), with multicolored vesicles inside them. The central structure is the nucleus. You can almost imagine the MVP at 3 o'clock merging with a dark blue lysosome so as to degrade the junk in the MVP, 5/24/2023.

How do adult stem cells stay young? Regular spring cleaning


 Adult stem cells have to be with us throughout our life. How else are we going to regenerate new cells for our tissues? Can you imagine our skin that completely renews itself every month without adult stem cells? How about our intestines that regenerate their epithelial lining every week? One trick that cells have is cellular rejuvenation through regular spring cleaning.

The thing is, as cells age, they accumulate damaged proteins, as we would expect with any object undergoing wear and tear with time. In addition, the aging cell's DNA gets reorganized and the nuclear envelope shows signs of damage. Even our energy powerhouses - the mitochondria - do not escape the pathological changes and become dysfunctional (1, 2, 3).

In this article, I describe three ways that cells use to throw out the old and keep the new. This is nature's way of taking out the garbage on a regular basis.

First path to cellular rejuvenation: Asymmetric cell division

The first way that stem cells cut down on damaged proteins is to divide asymmetrically. Many cells do this: they leave the mother cell with the lion's share of the damaged proteins; the daughter cell is now  the younger and more vibrant cell. This asymmetric cell division is typical of bacteria and yeast cells (4, 5). Of note, in some cases, it is the daughter cell that inherits the damaged proteins, as the daughter cell has a shorter life span. This latter situation is common when the daughter cell is a specializing cell, for example an intestinal stem cell becoming a mature intestinal cell (4).

One appropriately-named acronym is for a grouping of damaged proteins named JUNQ (or juxtanuclear quality control proteins). These proteins are segregated to only one daughter cell during cell division, ensuring that the other cell has cleaned out its closets (6).

Cellular rejuvenation; Asymmetric cell division

Hijab, J. Cellular rejuvenation; Asymmetric cell division, May 2023

In systems where the stem cells are attached to a basement membrane, adult stem cells divide vertically. They keep the original stem cell attached to the basement membrane. The newly produced cell is stacked on top of the stem cell and is no longer attached. This  propels the unattached cell to a path of differentiation. (7, 8). This leaves the basement membrane with a population of stem cells that retain their "stemness" and ability to divide. But at the same time, the stem cells are regenerating a fresh supply of specialized tissue cells for that specific organ.

The image below shows several layers of corneal epithelium above the basement membrane: notice that the bottom layer of cells (the ones attached to the basement membrane) are larger with larger nuclei. As the cells move away from the basement membrane, they flatten out, the nucleus becomes smaller and loses its prominence. As the cells mature, they age. The key to maintaining asymmetric cell division in this process is the attachment of the stem cell to the basement membrane. Experimentally, when cells that lose that attachment, they start maturing into specialized cells and lose their capacity to divide.

Basement membrane - cornea


Jose Luis Calvo.

Cornea Basement membrane (straight arrow) between the epithelial cells and the bright pink acellular Bowman's membrane (curved arrow) with collagen fibrils.  Shutterstock.com, ID: 1563776551.

In this way, stem cells that undergo asymmetric division stay young by transferring cellular trash or maturing proteins to daughter cells. The young cells get to stay young for another cycle, and maintain their ability to divide and thrive.

Second path to cellular rejuvenation: creating cellular garbage bins

Sometimes cells age because of stressors in the environment. Unfortunately, aging cells beget aging. Senescent cells spread pathology around them like wildfire by secreting aging-inducing proteins. Those proteins stimulate inflammation, abnormal cellular proliferation, and aging of the niche (12). Is that the end of the road? What do some cells do to combat aging and induce cellular rejuvenation? They create cellular garbage bins and dump the garbage out of the cell. 


A cell's version of our curbside garbage bin are vesicles. These cytoplasmic structures are spherical bodies that encircle the damaged proteins and any stray cytoplasmic DNA. The aging cell goes around and collects all those vesicles (garbage bins) into a round structure called a multi-vesicular body - MVB (9, 10, 11) (see header image). This MVB then connects with the plasma membrane ejecting the vesicles/garbage bins to the outside of the cell.

Cellular rejuvenation: creating garbage bins

Hijab, J. Creating a multi-vesicular body that rounds up all the vesicles (garbage bins) that have encircled the cellular trash, May 2023

Third path to cellular rejuvenation: trash compactors and incinerators

Cells try to repair molecular damage whenever they can. However, sometimes the repair processes are not keeping up or the molecules are too messed up. In such cases, the damaged molecules are tagged and compacted, and then transferred to an incinerator-type structure, the proteasome (5).  In the proteasome, a complex structure made up of protein-degrading enzymes, proteins are digested and disposed of.


In case proteins are too resistant to digestion, the cell packages the damaged molecules into vesicle-type garbage bins which fuse with lysosomes, the cells highly-effective incinerator complex. The lysosome has a lot of enzymes in a very acidic medium that can chew up denatured proteins, old mitochondria, and oxidized lipids and then recycle the parts to be re-used by the cell (5).

Why don't those systems prevent aging?

Cells work beautifully when they are young, removing damaged organelles, messed up molecules, and stray DNA strands from the cytoplasm. They do this through the 3 paths that I described:

  • Asymmetric cell division, to partition out damaged material to one of the daughter cells
  • Packaging cellular trash into garbage-bin type vesicles for disposal outside the cell
  • Transferring cellular trash to protein compactors and incinerators; some of those incinerators have enzymes packaged into a highly acidic compartment (the lysosome)

With those three paths to cellular rejuvenation, it is fair to ask why our organs still age. Here's the thing; youthful systems beget youth and aging systems beget aging. 


Aging systems beget aging

The problem lies in the limits of cells to keep up with the spring cleaning as cells experience wear and tear over time. With aging, those processes described above become less functional and the cell moves towards the dark side of senescence. Cells divide less and less, they produce less vesicles, and their lysosomes become less acidic and display decreased incinerator effectiveness (5, 10, 11, 12,  1314). 


To add insult to injury, vesicles that are secreted  from the cell sends senescent proteins into the blood stream. This  creates its own set of problems, including perpetuating the aging cycle (5, 13, 14).


Youthful systems beget youth

On a positive note, researchers are looking into injecting vesicles derived from young individuals into older ones. Experimental data suggest that cellular bins/vesicles generated from young cells, particularly stem cells, have cellular rejuvenation activity (13, 14, 15).


Even better, researchers are looking at the promise of senolytics, drugs that kill senescent cells, breaking the aging feedback loop (14, 15) as well as drugs that target specific senescence-associated pathologies (14).

Cellular rejuvenation: using youth to decrease aging

Hijab, J. Cellular rejuvenation: Using different therapies to delay or transform aging, May 2023

References

  1. González-Gualda E, Baker AG, Fruk L, Muñoz-Espín D. A guide to assessing cellular senescence in vitro and in vivo. FEBS J. 2021 Jan;288(1):56-80. doi: 10.1111/febs.15570. Epub 2020 Oct 10. PMID: 32961620.
  2. Regulski MJ. Cellular Senescence: What, Why, and How. Wounds. 2017 Jun;29(6):168-174. PMID: 28682291.
  3. Dodig S, Čepelak I, Pavić I. Hallmarks of senescence and aging. Biochem Med (Zagreb). 2019 Oct 15;29(3):030501. doi: 10.11613/BM.2019.030501. Epub 2019 Aug 5. PMID: 31379458; PMCID: PMC6610675.
  4. Bufalino MR, DeVeale B, van der Kooy D. The asymmetric segregation of damaged proteins is stem cell-type dependent. J Cell Biol. 2013 May 13;201(4):523-30. doi: 10.1083/jcb.201207052. Epub 2013 May 6. PMID: 23649805; PMCID: PMC3653353.
  5. Sheldrake AR. Cellular senescence, rejuvenation and potential immortality. Proc Biol Sci. 2022 Mar 9;289(1970):20212434. doi: 10.1098/rspb.2021.2434. Epub 2022 Mar 2. PMID: 35232226; PMCID: PMC8889192.
  6. Ogrodnik M, Salmonowicz H, Brown R, Turkowska J, Średniawa W, Pattabiraman S, Amen T, Abraham AC, Eichler N, Lyakhovetsky R, Kaganovich D. Dynamic JUNQ inclusion bodies are asymmetrically inherited in mammalian cell lines through the asymmetric partitioning of vimentin. Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):8049-54. doi: 10.1073/pnas.1324035111. Epub 2014 May 19. PMID: 24843142; PMCID: PMC4050583.
  7. Chhabra SN, Booth BW. Asymmetric cell division of mammary stem cells. Cell Div. 2021 Sep 29;16(1):5. doi: 10.1186/s13008-021-00073-w. PMID: 34587981; PMCID: PMC8482671.
  8. Berika M, Elgayyar ME, El-Hashash AH. Asymmetric cell division of stem cells in the lung and other systems. Front Cell Dev Biol. 2014 Jul 31;2:33. doi: 10.3389/fcell.2014.00033. PMID: 25364740; PMCID: PMC4206988.
  9. Takahashi A, Okada R, Nagao K, Kawamata Y, Hanyu A, Yoshimoto S, Takasugi M, Watanabe S, Kanemaki MT, Obuse C, Hara E. Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat Commun. 2017 May 16;8:15287. doi: 10.1038/ncomms15287. Erratum in: Nat Commun. 2018 Oct 8;9(1):4109. PMID: 28508895; PMCID: PMC5440838.
  10. Takasugi M. Emerging roles of extracellular vesicles in cellular senescence and aging. Aging Cell. 2018 Apr;17(2):e12734. doi: 10.1111/acel.12734. Epub 2018 Feb 1. PMID: 29392820; PMCID: PMC5847882.
  11. Lananna BV, Imai SI. Friends and foes: Extracellular vesicles in aging and rejuvenation. FASEB Bioadv. 2021 Jul 26;3(10):787-801. doi: 10.1096/fba.2021-00077. PMID: 34632314; PMCID: PMC8493967.
  12. Liu J, Ding Y, Liu Z, Liang X. Senescence in Mesenchymal Stem Cells: Functional Alterations, Molecular Mechanisms, and Rejuvenation Strategies. Front Cell Dev Biol. 2020 May 5;8:258. doi: 10.3389/fcell.2020.00258. PMID: 32478063; PMCID: PMC7232554.
  13. Sahu A, Clemens ZJ, Shinde SN, Sivakumar S, Pius A, Bhatia A, Picciolini S, Carlomagno C, Gualerzi A, Bedoni M, Van Houten B, Lovalekar M, Fitz NF, Lefterov I, Barchowsky A, Koldamova R, Ambrosio F. Regulation of aged skeletal muscle regeneration by circulating extracellular vesicles. Nat Aging. 2021 Dec;1(12):1148-1161. doi: 10.1038/s43587-021-00143-2. Epub 2021 Dec 6. PMID: 35665306; PMCID: PMC9165723.
  14. Ji S, Xiong M, Chen H, Liu Y, Zhou L, Hong Y, Wang M, Wang C, Fu X, Sun X. Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases. Signal Transduct Target Ther. 2023 Mar 14;8(1):116. doi: 10.1038/s41392-023-01343-5. PMID: 36918530; PMCID: PMC10015098.
  15. O'Loghlen A. The potential of aging rejuvenation. Cell Cycle. 2022 Jan;21(2):111-116. doi: 10.1080/15384101.2021.2013612. Epub 2022 Jan 3. PMID: 34978468; PMCID: PMC8837229.

Tags

aging, cells, rejuvenation, stem cell


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