Methodology Matters Greatly in Regenerative Therapies

You can't just throw stem cells or signal proteins to change the behavior of existing cells at injured tissue and expect reliably good results. A great deal of craft and sophistication goes into even the first generation stem cell transplant treatments, and the need for this complexity is demonstrated by the variability of outcomes seen in stem cell trials. The results are all over the map even for treatments that use the same types of cell to spur regeneration the same types of tissues. There are all sorts of factors at work: how the cells are cultured, how they are supported after being delivered into tissues, what signals are provided along with the cells, whether or not the cells are further engineered before being introduced into the patient, and so forth. The same is true for therapies that do not involve cell transplants, but instead deliver signal molecules to attempt to spur native cells to do the work of healing.

The research results linked below well illustrate this point, as the scientists demonstrate a selection of methods and combinations of methods for heart regeneration in rats. There are large differences in the outcomes, both in the degree of regeneration of healthy tissue (good) and in the generation of scar tissue rather than healthy tissue (bad). The results demonstrate that small changes in technique that alter the timing of the introduction of supporting molecules can have large effects on cell behavior and the bottom line of healing.

In practice this means that it is hard to write off any one particular approach to signal therapies and cell therapies in regenerative medicine as a dead end just because the results to date have been less than promising. It may be that all that is needed is one more adjustment to the delivery method, or the biomaterials, or the signals and factors delivered with the cells. Unfortunately finding the flecks of gold amidst all of the sand is a slow and painful process, even with the large-scale funding presently pouring into this field. There is an enormous space of possible approaches to try, growing rapidly as fundamental research delivers new information on relevant cellular mechanisms, but very few of them are of any real use. The difference in quality between a mediocre and a good approach is large, so settling for mediocre results in return for evading a large amount of work is not a viable trade-off. On that note, I think that you'll find the stained cross-sectional images of regenerated heart tissue from the publicity materials to be particularly interesting:

Repairing The Heart With A Protein-Hydrogel Combo

Even if a person survives a heart attack, the lack of blood flow damages tissue, which often leads to heart failure. Now researchers have developed a new approach to therapy that combines two experimental techniques for reviving heart tissue after a heart attack. One approach is to inject a scaffolding material to reinforce the weakened muscle wall. Another is to inject stem cells or growth factors to help repair the damaged tissue. The researchers devised a special trick to deliver a growth protein trapped within a hydrogel. The gel protects the protein, keeps it at the heart attack site, and supports the damaged walls of the heart right after a heart attack. They used a tissue-signaling protein called Sonic hedgehog that is known to protect cardiac cells and help them grow by inducing the formation of blood vessels.

The researchers mixed it with negatively charged heparin, which is a widely used anticoagulant, and a polycation, which attaches to the oppositely charged heparin molecules to form micrometer-sized liquid droplets. Next, they combined the droplets with a polyethylene glycol gel. The gel targets the signaling protein to damaged tissue because it degrades in the presence of an inflammatory enzyme secreted after a heart attack.

To test the new strategy, the researchers induced heart attacks in rats, and divided the animals into four groups. One group got an injection of the new combination material at the site of the heart attack, while the others got injections of only the protein-containing droplets, only the hydrogel, or saline. After two and four weeks, echocardiograms showed that hearts treated with the combination therapy pumped more blood per beat. The team also examined cross sections of hearts removed four weeks after treatment. Rats treated with the hydrogel-protein combination had at least 25% less scar tissue than those in the other groups.

Coacervate Delivery of Growth Factors Combined with a Degradable Hydrogel Preserves Heart Function after Myocardial Infarction

Numerous technologies have been evaluated for alleviating or reversing the damage caused by cardiac ischemia. These technologies fall into two general categories: bioactive therapies and structural "bulking" therapies. The former aims to provide the resources and signals necessary for tissue preservation and regeneration, and several therapeutic approaches including stem cells, growth factors, and gene therapy have been evaluated in U.S. controlled clinical trials. On the other hand, the primary aim of structural therapies is to reinforce the damaged heart wall and thereby alleviate wall stress to prevent wall thinning and ventricular dilation. Clinical trials have been initiated to evaluate intramyocardial injections of alginate and cell-seeded collagen. However, no biological or structural therapy has shown enough promise to receive USFDA approval for treatment of MI. Therefore, new approaches need to be developed and those that combine both bioactive and structural components are particularly appealing

To this end, we developed a bioactive therapy of sustained release of the morphogen Sonic hedgehog (Shh) and the anti-inflammatory cytokine interleukin-10 (IL-10) from a coacervate delivery vehicle. This is combined with a structural therapy consisting of a biodegradable polyethylene glycol (PEG) hydrogel, harnessing the benefits of both components. Upon injection into the hearts of rats after heart attack, we found that each component synergistically improved the benefit of the other. Furthermore, their combination was critical to preserve heart function. These findings indicate that, when combined, growth factor delivery and an injectable hydrogel represent a promising therapeutic approach for treatment after heart attack.


So they used Sonic hedgehog/interleukin + a hydrogel combination to increase efficiency of the signalling, that makes sense as the gel helps mitigate the effects of negative signalling.

It is not complex to test combinations to seek the best synergy so the experiment here has panned out exactly as expected.

Personally I think the use of MSCs is a far easier pathway to this kind of repair and in the treatment of arterial plaques. I am currently reviewing a number of papers that show MSCs can mitigate foam cell formation and abrogate plaque. There are some barriers to MSC use but they are not impossible to work out.

Posted by: Steve H at August 20th, 2015 3:52 AM

I wonder if that treatment could be combined with nano-antioxidants like C60 or PEG-HCC's?
PEG-HCC certainly has some interesting results. I'd like to have a shot of that if I came into the hospital with some kind of trauma.

Posted by: Arren Brandt at August 21st, 2015 6:38 AM

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