Of stem cells, cytokines, tunneling nanotubules, mitochondria, and skin.

As many of you know, Dr. George and myself work with human mesenchymal stem cells, exploring their tremendous potential as microscopic factories of healing and restoration. MSC’s have been compared to our bodies internal duct tape, due to their utility in fixing just about anything. We often refer to them as factories, specialized in making healing polypeptide molecules. Because our work involves expanding MSC’s in bioreactors, we sometimes refer to them as farms from which we harvest cytokines. How about a bartender mixing rejuvenative cytokine cocktails? A MASH unit ready to be mobilized to the front lines to effect repair and restoration to damaged tissues? But perhaps none of these metaphors truly does them justice. The more we learn about how they do their magic, the more we realize just how clever, and useful, these cells really are. Today we will share a few bits from current medical literature to illustrate that very point.

Mesenchymal stem cells reside in many parts of the human body. We work primarily with bone marrow derived MSC’s. They live in close proximity (in fact they are described as paired with) hematopoetic stem cells. These are the stem cells are responsible for making red and white blood cells, and are intimately tied together with our body’s immune system. This makes sense too when we talk about migration of  via the blood stream (bone marrow is very vascular), of MSC’s. When tissues in your body are damaged (let’s say your heart), the damaged/dying cells release a certain pattern of cytokines into your bloodstream. This signal (communication) is sensed by the MSC’s in your bone marrow, who then migrate to the damaged heart tissue. The damaged tissue also produces special chemoattractant chemicals, providing a navigation signal to MSC’s, and other chemicals that help them to snag onto the damaged cells (sort of a lifeline). The MSC’s then engraft (attach to) the tissue and begin proliferating (dividing), and some differentiate to become cardiomyocytes (heart cells). In experimental models, infusing MSC’s into the circulation of an animal (or human) having heart attack can have significant, even lifesaving results.

Now, several years ago we thought that engraftment and differentiation was the main way that bone-marrow derived MSC’s effect their therapeutic effect. But since, then, many experiments have proven that very few new heart cells derived from MSC’s. Rather it turn out that MSC’ main function seems to be to secrete cytokines, in a precise pattern and sequence, to essentially orchestrate damage control and healing. It has also been noted that some cell-to-cell (CTC) communications take place by secretion of cytokines in the spaces between cells.  When cells are in close proximity we call them “paracrine” signals.  When communication takes place within cells themselves we call that “autocrine”.  And then there is communication that involves cells that “reach out and touch” one another (see picture below).
This past year we saw two rather interesting publications that extend our understanding, by suggesting it is not just cytokines that are shared. In a paper entitled Human Mesenchymal Stem Cells Reprogram Adult Cardiomyocytes Toward a Progenitor-Like State Through Partial Cell Fusion and Mitochondria Transfer we see evidence that MSC’s can share more than just chemicals with damaged cells, they can actually fuse with them and inject entire organelles (cell organs) into them. I like to call this “organelle transplant”. Now the key organelle here is mitochondria. Remember from high school biology that mitochondria are the engines of cells, taking fuel and turning into usable energy. Dying cells run out of energy, and mitochondrial damage can presage cell death. In this case, it looks like MSC’s are resuscitating cells on the critical list by injecting fresh mitochondria into them. It’s like an engine rebuild. What is also interesting is that the MSC’s were also reprogramming the heart cells backward to become more like progenitor cells, in other words sharing some of their “stemness” with them. So these cells could then divide into more new heart cells of various types.

A second recently published paper is entitled Tunneling-nanotube: A new way of cell-cell communication. Tunneling-nanotubes (TNTs are a kind of cell-cell communication exhibited by certain cells (e.g. brain cells, and possibly skin cells) under stress. The hypothesis is that damaged cells use TNTs as a highway to transfer materials and energy to healthy cells. TNTs transfer cellular compartments, such as endoplasmic reticulum (ER), mitochondria, Golgi and endosomes. Interestingly, it is always the damaged cell that extends a TNT to a healthy cell. All the more reason to attract some MSC’s as the perfect “organelle donors”.

So what, you might ask, does all this have to do with skin? All the mechanisms described for heart damage have also been observed with skin wounds. When you were a fetus and had 10 times as many MSC’s available, you could heal wounds very quickly without any scarring. Older persons scar with fibrosis, leading to altered architecture (e.g. wrinkles). And wounds, by the way, don’t have to be acute injuries like cuts or bruises. Every time you go out into the sun (especially if unprotected) your skin undergoes injury. The DNA in your skin cells is damaged. Chemicals are released. Some of those cells will be repaired. Some will die. But repeated insult and repair leads to photoaging. Spots, wrinkles, sags, etc. Add to that some intrinsic (genetically programmed) aging. With chronic, repeated injury there are changes that take place in the skin (subsurface scarring). This is why cosmetic surgery, lasers, devices, and various skin concoctions are prevalent in the marketplace.

I want to paint for you a picture of a new era. We’ll call it the age of regenerative medicine. In the future you will be able to re-invigorate your skin’s own healing mechanisms, rid yourself of chronically damaged tissues, and rebuild with fresh new cells. Not with exogenous materials from other sources (be they plants, animals, or other humans) but with your body’s own innate healing mechanisms. Imagine little nanobots migrating into your dermal layers and repairing them, inside out. Injecting mitochondria where needed. Reprograming your skin cells to be more “progenitor-like”. Like when you were a baby!

So now it seems like all those metaphors for mesenchymal stem cells actually oversimplify the many ways in which they accomplish their purpose. Maybe we could think of them more like self-propelled crash carts that contain many different instruments, medicines, sensors, and devices to effect resuscitation and repair? But then they seem to do longer term rehab as well. It’s hard to come up with a perfect metaphor when it seems like every day we discover something new about them.

Does all this sound like something that belongs in a galaxy far, far away in a distant future time? Not so. In fact, these discoveries are being “translated” (applied clinically) right now. I think we are on the verge of a revolution in dermatology, aesthetic and otherwise. Within the next few years you will see a proliferation of knowledge, and applications, in stem cell biology as it relates to skin. Stay tuned.

References

Zhejiang, J. Mei-xiang Xiang, Ai-na He, Jian-an Wang,†‡ and Chun Gui
Protective paracrine effect of mesenchymal stem cells on cardiomyocytes. Univ Sci B. 2009 August; 10(8): 619–624.

Acquistapace, A., Bru, T., Lesault, P.-F., Figeac, F., Coudert, A. E., le Coz, O., Christov, C., Baudin, X., Auber, F., Yiou, R., Dubois-Randé, J.-L. and Rodriguez, A.-M. (2011), Human Mesenchymal Stem Cells Reprogram Adult Cardiomyocytes Toward a Progenitor-Like State Through Partial Cell Fusion and Mitochondria Transfer. STEM CELLS, 29: 812–824. doi: 10.1002/stem.632

Zhang, Y. Tunneling-nanotube: A new way of cell-cell communication
Communicative & Integrative Biology 4:3, 324-325; May/June 2011;