Fully reduced HMGB1 accelerates the regeneration of multiple tissues by transitioning stem cells to G(ALERT)

Geoffrey Lee, Ana Isabel Espirito Santo, Stefan Zwingenberger, Lawrence Cai, Thomas Vogl, Marc Feldmann, Nicole J. Horwood, James K Chan, Jagdeep Nanchahal

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A major discovery of recent decades has been the existence of stem cells and their potential to repair many, if not most, tissues. With the aging population, many attempts have been made to use exogenous stem cells to promote tissue repair, so far with limited success. An alternative approach, which may be more effective and far less costly, is to promote tissue regeneration by targeting endogenous stem cells. However, ways of enhancing endogenous stem cell function remain poorly defined. Injury leads to the release of danger signals which are known to modulate the immune response, but their role in stem cell-mediated repair in vivo remains to be clarified. Here we show that high mobility group box 1 (HMGB1) is released following fracture in both humans and mice, forms a heterocomplex with CXCL12, and acts via CXCR4 to accelerate skeletal, hematopoietic, and muscle regeneration in vivo. Pretreatment with HMGB1 2 wk before injury also accelerated tissue regeneration, indicating an acquired proregenerative signature. HMGB1 led to sustained increase in cell cycling in vivo, and using Hmgb1 -/- mice we identified the underlying mechanism as the transition of multiple quiescent stem cells from G0 to GAlert HMGB1 also transitions human stem and progenitor cells to GAlert Therefore, exogenous HMGB1 may benefit patients in many clinical scenarios, including trauma, chemotherapy, and elective surgery.

Original languageEnglish
Pages (from-to)E4463-E4472
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America (PNAS)
Issue number19
Early online date19 Apr 2018
Publication statusPublished - 8 May 2018


  • Animals
  • Cell Cycle
  • Cells, Cultured
  • Chemokine CXCL12/metabolism
  • Fractures, Bone/therapy
  • HMGB1 Protein/physiology
  • Hematopoietic Stem Cells/cytology
  • Humans
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal/cytology
  • Osteogenesis
  • Receptors, CXCR4/metabolism
  • Regeneration
  • Signal Transduction
  • Wound Healing

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