Instructing Scar Tissue to Change Itself into Healthy Tissue

I'd wager that the future of cell therapy probably won't involve much in the way of cell transplants, not even those created from the patient's own tissues. Instead it will be based on instructing existing cell populations in the body to take specific actions - progress here will proceed at a pace determined by how well researchers can catalog and understand the enormously complex networks of cell signaling that exists in every tissue type.

Even though there is a long way to go yet in creating that catalog, a range of possible therapies are already under investigation based on what is presently understood of controlling cell behavior. There is certainly no shortage of methods for changing the cell and its environment - only a shortage in knowing which of the million levers to pull and dials to set in order to achieve the desired result with minimal side-effects. Consider that a cell is a collection of machines built out of proteins, and the controlling mechanisms are driven by the presence and levels of yet more proteins: any technique that manipulates the level of a certain protein can be used to potentially good effect. So there is plain old gene therapy to make cells produce more of a protein encoded by a specific gene. There is RNA interference to block a specific protein. There are all sorts of other ways to tinker with how much of a specific protein is produced from the blueprint of a specific gene at a given time: gene expression is a process of many intricate stages, and the research community can presently accurately target most of them, provided the time is put in.

So all this said, we see technology demonstrations like the one noted below: no transplants, just instructing cells to do something different.

Gene therapy reprograms scar tissue in damaged hearts into healthy heart muscle

A cocktail of three specific genes can reprogram cells in the scars caused by heart attacks into functioning muscle cells, and the addition of a gene that stimulates the growth of blood vessels enhances that effect. "The idea of reprogramming scar tissue in the heart into functioning heart muscle was exciting. The theory is that if you have a big heart attack, your doctor can just inject these three genes into the scar tissue during surgery and change it back into heart muscle."

During a heart attack, blood supply is cut off to the heart, resulting in the death of heart muscle. The damage leaves behind a scar and a much weakened heart. Eventually, most people who have had serious heart attacks will develop heart failure.

Changing the scar into heart muscle would strengthen the heart. To accomplish this, during surgery, [researchers] transferred three forms of the vascular endothelial growth factor (VEGF) gene that enhances blood vessel growth or an inactive material (both attached to a gene vector) into the hearts of rats. Three weeks later, the rats received either Gata4, Mef 2c and Tbx5 (the cocktail of transcription factor genes called GMT) or an inactive material.

The GMT genes alone reduced the amount of scar tissue by half compared to animals that did not receive the genes, and there were more heart muscle cells in the animals that were treated with GMT. The hearts of animals that received GMT alone also worked better as defined by ejection fraction than those who had not received genes. [The] hearts of the animals that had received both the GMT and the VEGF gene transfers had an ejection fraction four times greater than that of the animals that had received only the GMT transfer.

There will be a lot more of this sort of thing going on in the years ahead.

Comments

Although we agree about many things, I would take your bet on the prevalence of cell transplants vs. in situ reprogramming.

If you modify the genes of cells in culture, then you have a sterling opportunity to check your work for any potentially harmful mistakes before introducing the modified cells into the patient. This partially circumvents the gene delivery specificity problem as long as sequencing technology becomes cheap enough, and there is reason to believe that sequencing technology follows an analogue of Moore's law, becoming ever cheaper at a rapid rate.

Another potential problem is targeting the therapy to the right population of cells, yet cell transplant provides the solution of using the cell itself as the vehicle for targeting. Cells are very flexible in their ability to recognize and home-in on particular physiological environments using many chemical and mechanosensory cues. If additional specificity is needed, that can be engineered into the cells along with the therapeutic genes.

Once the determinants of (stem) cell fate are better understood, admittedly a large and ongoing project, highly migratory and invasive cells can be introduced into the blood that will differentiate into mature cells of the requisite type in the requisite location expressing potentially very many genetic modifications that would be difficult to deliver individually. Deletion of telomerase could bypass the inherent danger of invasive stem-like cells and the success of this deletion could be checked alongside any other changes before the cells are used. Apoptotic pathways could be exploited to remove any excess cells that fail to find their target location.

The transition to widespread use of cell transplantation therapies might necessitate passage through an uncomfortable phase in which the transplants are very expensive, because the infrastructure for mass-production of personalized cell lineages does not exist. I wonder if this might be the prospect that makes you baulk at the enormous promise of the transplantation approach. I know you're keen to refute the "social and distributive justice" objections to rejuvenation biotechnology, but nonetheless I expect plenty of overseas travel to procure very exclusive first generation Chinese cell phones, if you get my drift.

Posted by: José at January 4th, 2013 11:04 PM

This is very exciting. I wonder if this outcome is specific only to heart cells? For instance, in Peyronie's disease, scar tissue in the erectile tissue of the penis causes much pain and deformation, and even impotence. Could something like this be a much better treatment than a collagenase injection into the penile scars, and return the tissue back into healthy tissue?

Will be interesting to see if this can be expanded into other diseases.

Posted by: David at February 25th, 2013 4:58 PM

It would be great to see this used in cases of Pulmonary Fibrosis, that way one could get rid of scar tissue forming in the lungs and restore healthy lung tissues capable of oxygen transport. Although the primary cause, most of the times unknown, would not be cured this way, but it would be a major help for easing and prolonging patients life.

Posted by: Szilard at May 3rd, 2016 10:08 AM

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