Moving Beyond Stem Cells as a Basis For Regeneration

One can draw a timeline of stem cell research that has stem cell therapies in the modern sense emerging as an evolution of bone marrow transplantation: as biotechnology became more sophisticated researchers identified the agents producing beneficial effects in these treatments, meaning the stem cells found in bone marrow, and from there got rid of much of the baggage to create a new generation of better and more focused therapies. This sketch is a gross oversimplification of a complex period of development in medical science, but will suffice for this post.

Today, as stem cell therapies are becoming a mainstream commercial concern, entering the phase of growth and improvement that attends the heyday of every technology, researchers are already laying the groundwork for the next evolution in this series of treatments. For just as stem cells are the agents of change identified in bone marrow, so too are various signaling proteins the agents of change that might be identified in stem cells. The bone marrow was dispensed with once biotechnology was up to the task and in the next round of progress so too will be the cells.

While not true (or at least not yet proven) for all stem cell treatments, it has become increasing clear in recent years that many cell transplants produce benefits not because the transplanted cells are themselves doing much in the way of building or shoring up tissue, but rather because they are altering the local signaling environment in ways that instruct native cells to get back to work - or even to perform works of regeneration that they never would have accomplished under normal circumstances. So what prevents researchers from throwing out the cells today and just using the signals? The fact that these signaling changes are still very poorly understood. Inroads are being made, and you might recall recent work on the roles of GDF-11 or FGF-2 in this vein, but they are still just inroads.

Here is an open access example of exploration in the this direction, a task well suited to the modern tools of biotechnology, focused on the measurement and cataloging of protein levels and epigenetic patterns. The cost of these tools has dropped so precipitously this past decade that I imagine matters will progress quite rapidly towards an index of all of the regenerative signals of consequence altered by stem cell transplants.

Mechanisms of action of hESC-secreted proteins that enhance human and mouse myogenesis

Adult stem cells persist in the body as we age, but their regenerative capacity declines over time, leading to an inability of tissues and organs to maintain homeostasis and repair damage with advancing age. Old skeletal muscle loses its regenerative ability due to the failure of satellite cells (muscle stem cells) to divide and generate fusion competent myoblasts and terminally differentiated myofibers in response to muscle injury or attrition.

Previous studies have demonstrated that aging of the stem cell niche is responsible for the decline of tissue regeneration and productive homeostasis not only in skeletal muscle but also in a variety of postnatal tissues, and that old muscle can be rejuvenated to repair almost as well as young through several means. These findings may prove to be important for the development of therapies for age-related tissue degeneration and trauma. However, not all of the factors that influence the niche are known, and the various physiological molecules and balance of signaling crosstalk that modulate healthy regeneration are not well established. In addition, while numerous approaches have been utilized to reverse age-related tissue deterioration in murine models, none are suitable for clinical translation. As one example, skewing the signaling strength of one pathway (either up or down) over a long timespan is likely to be deleterious for cells and tissues, potentially leading to more cellular dysregulation or oncogenic progression. In contrast, modulation of multiple interactive signaling pathways to their "youthful" levels may have beneficial effects on tissue repair and maintenance.

Our initial study demonstrated that embryonic stem cells produce soluble proteins that robustly enhance adult muscle stem cell function even in an aged environment, and that production of such proteins is lost when these cells differentiate. Furthermore, the MAPK pathway was determined to be critical in modulating the activity of these embryonic protein(s). These findings are supported by microarray analysis conducted on cardiomyocytes subjected to hESC-conditioned medium, demonstrating that MAPK pathway signaling was among the main induced signaling cascades. Here we uncover the molecular identity of active hESC-produced proteins and demonstrate that specific FGFs are sufficient to enhance mouse and human myogenesis.

While FGFs had significant effects on cell proliferation of human and mouse myogenic progenitors, antibody neutralization of FGF-2, FGF-6 or FGF-19 did not significantly reduce the pro-myogenic properties of hESC conditioned medium, [suggesting that] many other active growth factors and MAPK ligands are secreted by the hESCs. Ultimately, the precise molecular definition of most of the pro-regenerative proteins from the hESC secretome will allow one to design optimal therapeutic applications with low off-target and side effects.


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