Adult stem cells keep you roadworthy

By Francina Jackson

How do adult stem cells work? In healthy tissue the adult stem cell population lies dormant. Dormant stem cells are activated by external trauma signals, which trigger patterns of gene expression and protein biosynthesis, thus activating the stem cells to multiply and regenerate damaged tissue. If you think of your normal tissue as a car, then the adult stem cells are the spare parts you keep in the trunk. Usually your car works well on its own, but occasionally one part or another might wear out and need replacing. Malfunctioning tissues are in a constant state of disrepair and must therefore undergo repeated cycles of regeneration. These cycles place a strain on the stem cell population, often leading to its precocious depletion and a permanent state of tissue degeneration. So, in this case, you have a car that breaks all the time and has a finite number of spare parts in its trunk (which you quickly exhaust). With minimal contention, you accept that your car is a lemon but, as it is the only one you've got, you must begin pursuing more creative avenues to keep it on the road.

Researchers too must be creative as they choose among different approaches for developing therapeutic strategies. One tactic is to identify the genetic basis for the cellular malfunction and correct it within the patient's own stem cell population using gene therapy. This is done to bolster mature tissue function by ensuring that the regenerated portion of the tissue is not fraught with the same deficiencies as the original tissue. Essentially, you are taking a spare part from the trunk and fixing it before using it to fix your car. 

Another approach is to transplant a healthy population of donor stem cells into the dysfunctional tissue. In this case the hope is to fix the defect whilst bypassing the shortcomings inherent to the original tissue. In other words, you decide to get your spare parts from another, and hopefully better, manufacturer.

While both gene therapy and transplantation have merit, neither is perfect. Here my analogy falls short because attempting to identify a malfunction in a cell can in no way be compared to troubleshooting a malfunctioning automobile. Three simple reasons for this are:

1. We have only the tip of the iceberg in terms of understanding how cells work (unlike cars, for which we have expertise and blueprints); 
2. Cells are orders of magnitude more complex than any automobile, with millions of dynamic interactions and cellular processes occurring each moment to sift through; and 
3. Unlike a car, the successful identification of a cellular problem is not always synonymous with the identification of its practical solution (in fact, it often represents years of further research and unanticipated conundrums). 

While stem cell transplantation should bypass these problems, its two main concerns are that transplanted cells might be rejected (the spare parts from the alternate manufacturer are simply incompatible), or that they might differentiate in an incorrect and uncontrolled manner resulting in a tumour.

Researchers do have their work cut out for them in developing stem cell blueprints (the automobile itself has been a work-in-progress for over a century), however networks such as this are certain proof that they are up for the challenge.

Comments

[Francina Jackson]

Hi Ian,
To answer your first question, gene therapy involves correcting the genetic error in patient cells without removal from the body. Viral vectors are frequently used because viruses naturally cause infections by integrating their genomic information into host cells (as such, the perfect vehicle to bypass host defenses and achieve gene delivery is already available in nature). Scientists can design a viral vector that will deliver the missing or modified genomic sequence to the cell, thereby correcting its malfunction.

Your second question (or questions) is/are more complex to answer, however the short answer is a tentative ‘yes’. Avoiding rejection: Two emerging technologies for using your own stem cells are (1) the preservation of umbilical cord stem cells for future use, and (2) induced pluripotent stem (iPS) cells in which patient fibroblasts are reverted to stem cell form. In both of these instances you are making use of the patient's own cells and therefore bypass the issue of rejection all together.

Avoiding tumor growth: the beauty in the potential of stem cell therapy is that you should have the capacity to regenerate a large amount of damaged tissue by transplanting a very small number of stem cells. Upon transplantation the cells should activate and proliferate (transplantation = a trauma signal) and hopefully the tissue into which they are transplanted will provide the necessary signals to correctly dictate their identity as mature cell. In practice it is not this straightforward and, in the end, the approach taken really depends on which disease the stem cells are being used to treat.

Thanks for your questions!

[Ian]

Excellent post! Very informative. Just a couple questions:
1) Does gene therapy involve removing stem cells, fixing them and the putting them back, or is it all done inside a person's body?
2)In theory, could stem cell transplants ever reach a point where we could tailor them to each individual to avoid rejection, thereby allowing for continued tissue regeneration and significantly increased lifespan, or is it more likely to use stem cells outside of the body to grow new tissues for a person, thereby avoiding potential tumor growth?