HGFA Signaling Enhances the Stem Cell Response to Injury

In recent years, researchers interested in the mechanisms of regeneration have explored the changing landscape of signals in the blood, both in the short term following injury and over the long term during the aging process. A number of interesting findings have emerged, especially in the course of parabiosis studies in which the circulatory systems of old and young individuals are joined. The field is still evolving fairly rapidly, and some results from just a few years ago now look more uncertain in the face of later evidence. Nonetheless, new mechanisms and areas of focus continue to emerge, such as that described in the open access paper I'll note today. The researchers involved have identified hepatocyte growth factor activator (HGFA) as a key signal in the regenerative process, and a possible path to enhance regeneration in mammals.

As we all know only too well, regeneration falters with advancing age. Our stem cells, the cell populations responsible for turning out new cells to replace those lost to injury or required to rebuild damaged structures, decline over the course of aging. In older individuals, stem cells are ever less active, spending more time quiescent, or the population size is reduced. This may be in part a fairly direct result of the molecular damage that causes aging, but in the most studied stem cell populations, such as those in muscle tissue, it appears that aged stem cells are still quite capable if give the right signals. In older tissues those signals are not present to the necessary degree, or are overridden by other signals that are a reaction to damage in the surrounding environment.

It is thought that the decline in stem cell activity, and consequent failure and frailty of tissues, is part of an evolved balance between death by cancer and death through lack of tissue maintenance - too much cellular activity by damaged cells will ultimately produce cancerous cells. On the other hand, the progress of the stem cell therapy industry to date suggests that the evolved balance has some room for adjustment in favor of more regeneration in the old. Further, we should expect the cancer research community to continue to make progress of its own: greater regeneration in the old can advance hand in hand with a greater ability to effectively treat cancer. Looking beyond that partnership, true rejuvenation therapies, those that repair the molecular damage that is the root cause of aging, should reactivate stem cells and restore regenerative prowess without any further downside.

Alerting stem cells to hurry up and heal

This recent study builds upon a previous finding that when one part of the body suffers an injury, adult stem cells in uninjured areas throughout the body enter a primed or "alert" state. Alert stem cells have an enhanced potential to repair tissue damage. In this new study, researchers identified a signal that alerts stem cells and showed how it could serve as a therapy to improve healing. Searching for a signal that could alert stem cells, the researchers focused their attention on the blood. They injected blood from an injured mouse into an uninjured mouse. In the uninjured mouse, this caused stem cells to adopt an alert state. The researchers identified the critical signal in blood that alerted stem cells: an enzyme called Hepatocyte Growth Factor Activator (HGFA). In normal conditions, HGFA is abundant in the blood, but inactive. Injury activates HGFA, so HGFA signaling can alert stem cells to be ready to heal.

Leveraging this discovery, the researchers asked the question: What happens if HGFA alerts stem cells before an injury occurs? Does this improve the repair response? They injected active HGFA into mice that received either a muscle or skin injury a couple of days later. The mice healed faster, began running on their wheels sooner and even regrew their fur better than mice that did not receive the HGFA booster. These findings indicate that HGFA can alert many different types of stem cells, rousing them from their normal resting or "quiescent" state, and preparing them to respond quickly and efficiently to injury. "This work shows that there are factors in the blood that control our ability to heal. We are looking at how HGFA might explain declines in healing, and how we can use HGFA to restore normal healing."

HGFA Is an Injury-Regulated Systemic Factor that Induces the Transition of Stem Cells into GAlert

Tissue damage induces the activation of quiescent stem cells, initiating a cascade in which stem cells enter the cell cycle, divide, and proliferate to generate the cells required to repair or regenerate damaged tissue. Stem cell activation is a limiting step in the process of tissue repair. In many stem cell pools, the first cell division following activation is slow and can take many days to complete, whereas subsequent cell divisions are much more rapid. Defects in stem cell activation, such as a lengthening in the time of first cell division or a failure in stem cells to activate, can result in significant impairments in the healing process. Little is known about the biologic regulation of stem cell quiescence and activation. Approaches to accelerate the rate-limiting step of stem cell activation could have broad therapeutic applications in regenerative medicine.

We previously reported an acceleration of the activation properties of quiescent stem cells in response to a prior injury, distant from the tissue in which the stem cells were residing. We described this regulation as a transitioning of stem cells from the G0 to the GAlert state of quiescence, where GAlert stem cells are poised to activate quickly in response to injury and to repair tissue damage more effectively. Because of the enhanced functional properties of GAlert stem cells, there may be clinical applications for factors that induce the GAlert state. However, the endogenous signals that stimulate the G0-to-GAlert transition of stem cells in response to distant injuries have not been previously described. Here, we show that a single systemic factor, hepatocyte growth factor activator (HGFA), is sufficient to induce the transition of multiple pools of stem cells into GAlert and that administration of HGFA to animals, prior to an injury, improves the subsequent kinetics of tissue repair.

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