Alerting stem cells to regenerate

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Science Translational Medicine  02 May 2018:
Vol. 10, Issue 439, eaat8523
DOI: 10.1126/scitranslmed.aat8523


Alarmin delivery accelerates tissue regeneration by transitioning quiescent stem cells to the metabolically active GAlert state.

Stem cells play a critical role in maintaining tissue homeostasis, as well as repairing injured or diseased tissues. Researchers have attempted to deliver exogenous stem cells to improve tissue regeneration by using a variety of approaches, including expanding and implanting the patient’s own cells, transplanting allogeneic cells, and using induced pluripotent stem cells. Unfortunately, all of these strategies are characterized by poor cell engraftment at the desired site, among other disadvantages. A promising alternative approach is to harness the regenerative capability of the patient’s own endogenous stem cells. Toward this aim, Lee and colleagues have turned to alarmins (endogenous molecules that trigger an immune response to cell damage) and their role in modulating endogenous stem cell–guided tissue repair.

After bone fracture, the authors observed increased concentrations of the alarmin high mobility group box 1 (HMGB1) in both humans and mice. Delivery of fully reduced HMGB1 resulted in increased osteogenesis when used to prime human mesenchymal stem cells in vitro, as well as when delivered locally at the time of injury in an in vivo murine fracture model. Accelerated fracture healing occurred due to the formation of a heterocomplex between HMGB1 and the chemokine CXCL12 (also known as stromal cell-derived factor 1), which then bound to the CXCR4 receptor. Importantly, this series of steps transitioned CXCR4–expressing stem cells from the deeply quiescent, nonproliferative state (G0) to an intermediate, metabolically active state (GAlert). GAlert stem cells are in between resting (G0) cells and actively proliferating (G1) cells and as a result, they can enter the cell cycle and contribute to tissue regeneration more quickly. HMGB1 also had a similar effect accelerating muscle and hematopoietic regeneration.

Stem cell therapies are promising for a wide range of diseases and injuries; however, exogenous stem cell delivery has had little clinical success. Here, the authors detail a promising alternative approach, in which delivery of the alarmin HMGB1 was found to accelerate endogenous tissue regeneration. HMGB1 delivery has the potential to be broadly applicable to any CXCR4-expressing cell and for a wide range of clinical applications, including acute injuries and chemotherapy.

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