Researchers here outline a method of pushing stem cells in several different tissues into greater activity, thereby accelerating regeneration from injury and potentially improving ongoing tissue maintenance. Given a few more decades of development, regenerative medicine will probably bear little resemblance to today's approaches of cell transplantation, and will instead rely upon a combination of (a) delivering signal molecules or otherwise controlling cell behavior, and (b) repairing damage that accumulates in important cell populations, such as stem cells. If stem cells are kept in a well maintained state, and can be directed to perform as needed, then a major component of the progression of aging will be eliminated. This is, of course, a very large project. There are hundreds of types of cell in the body, and every tissue has its own distinct stem cell populations, all significantly different from one another. The present state of the art in stem cell research is barely th e first step on a long road ahead.

Adult stem cells are an essential component of tissue homeostasis with indispensable roles in both physiological tissue renewal and tissue repair following injury. The regenerative potential of stem cells has been very successful for hematological disorders. In contrast, there has been comparatively little clinical impact on enhancing the regeneration of solid organs despite continuing major scientific and public interest. Strategies that rely on ex vivo expansion of autologous stem cells on an individual patient basis are prohibitively expensive, and success in animal models has often failed to translate in late-phase clinical trials. The use of allogeneic cells would overcome the problems of limited supply but commonly entails risky lifelong immunosuppressive therapy. Some safety concerns remain about induced pluripotent stem cells. Furthermore, successful engraftment of exogenous stem cells to sites of tissue injury requires a supportive inductive niche, and the typical proinflammatory scarred bed in damaged recipient tissues is suboptimal.

An attractive alternative strategy, which overcomes many of the limitations described above, is to promote repair by harnessing the regenerative potential of endogenous stem cells. This requires identification of key soluble mediators that enhance the activity of stem cells and can be administered systemically. An interesting observation was made in 1970 that a priming injury at a distant site at the time of or before the second trauma resulted in accelerated healing. This phenomenon was explained only recently, when it was shown that a soluble mediator is released following the priming tissue injury which transitions stem cells elsewhere in the body to a state the authors termed GAlert, which is intermediate between G0 (quiescence) and G1. In the presence of activating factors the primed GAlert cells enter the cell cycle more rapidly than quiescent stem cells, leading to accelerated tissue repair. However, the identity of the soluble mediators that transition stem cells to G Alert remain to be clarified.

Our long-standing interest in tissue injury has recently centered on alarmins, a group of evolutionarily unrelated endogenous molecules with diverse homeostatic intracellular roles, which, when released from dying, injured, or activated cells, trigger an immune/inflammatory response. Much effort has been focused on their deleterious role in autoimmune and inflammatory conditions, and of the few studies that have investigated their role in tissue repair, none has used a combination of human tissues and multiple animal-injury models to characterize their effects on endogenous adult stem cells in vivo. Here we show that high mobility group box 1 (HMGB1) is a key upstream mediator of tissue regeneration which acts by transitioning CXCR4+ skeletal, hematopoietic, and muscle stem cells from G0 to GAlert and that, in the presence of appropriate activating factors, exogenous administration before or at the time of injury leads to accelerated tissue repair.