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Considering the Regenerative Signals Emitted by Transplanted Stem Cells

Posted: June 2, 2013 at 2:54 am

Enhanced regeneration can result from introducing new stem cells into a patient, and this effect is the basis for a very broad range of first generation transplant therapies. In most cases the benefit doesn't result from the transplanted stem cells setting forth to create replacement cells for damaged tissue. Instead it is caused by chemical signals produced by the transplanted cells: these signals spur native cell populations to take action. So naturally the next step here is for researchers to gain a good enough understanding of stem cell signals to remove the need for cell transplants, replacing them with a therapy based on introducing the signal molecules directly.

It's very hard to say how rapidly this line of research will progress in comparison to the ongoing development of therapies that involve cells, a field in full swing. But in the long term it seems likely that directly adjusting the state and behavior of a patient's native cells will win out over indirect methods. Using the signals may just be another indirect method to be replaced by something better down the line, such as targeted epigenetic engineering that reprograms specific cell populations without going through any of the evolved signal paths.

But that is a way from here, as the use of stem cells in therapy is still two decades away from its peak usage and effectiveness - if we want to take the standard view of fifty year cycles in broad technologies, waxing to full effectiveness and then waning as they are replaced by something better. The cycle may run faster this century: we'll see whether that is the case or not, something that is determined by the degree to which the timing depends on human organization versus technological capacity. The former isn't speeding up, while the latter is.

Meanwhile, here is an open access paper that illustrates the way in which scientists are presently looking at stem cell signals. The research community is clearly on the way towards a range of these signal compounds repackaged and repurposed as drug candidates to induce exceptional regeneration. I expect that line of development will be well underway by the early 2020s.

hESC-secreted proteins can be enriched for multiple regenerative therapies by heparin-binding

Tissue regeneration and maintenance dramatically and invariably decline with age, eventually causing failure of multiple organ systems in all mammals. In muscle, the loss of tissue regeneration with age is thought to be imposed by signaling changes in the satellite stem cell niche, and interestingly, the aging of stem cell niches is to some extent similar between muscle, brain, blood, and other tissues. Our previous work found that human embryonic stem cells (hESCs) produce soluble secreted molecules that can counteract the age-imposed inhibition of muscle regeneration, an "anti-aging" activity that is lost when the hESCs differentiate.

Numerous mitogenic proteins are expressed by hESCs and are known to act through [key regulatory signaling pathways] implicated in the control of adult tissue regeneration. The precise identity of the pro-myogenic factors that are secreted by hESCs and the molecular mechanism of their action in muscle stem and progenitor cells is still work in progress; however, the effects of one of these molecules, FGF-2, was studied here in detail. FGF-2 is known to be secreted by hESCs and is also contained in the growth/expansion medium of embryonic stem cells.

This work builds upon our findings that proteins secreted by hESCs exhibit pro-regenerative activity, and determines that hESC-conditioned medium robustly enhances the proliferation of both muscle and neural progenitor cells. Importantly, this work establishes that it is the proteins that bind heparin which are responsible for the pro-myogenic effects of hESC-conditioned medium, and indicates that this strategy is suitable for enriching the potentially therapeutic factors. Additionally, this work shows that hESC-secreted proteins act independently of the mitogen FGF-2, and suggests that FGF-2 is unlikely to be a pro-aging molecule in the physiological decline of old muscle repair. Moreover, hESC-secreted factors improve the viability of human cortical neurons in an Alzheimer's disease (AD) model, suggesting that these factors can enhance the maintenance and regeneration of multiple tissues in the aging body.

You'll find more on the role of FGF-2 regarding stem cells and aging back in last year's archives. The authors quoted above suggest that past work on FGF-2 can't be the whole picture, based on their observations, and something more complex is taking place - which is the usual story in life science research. Nothing is ever simple.


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