Fully reduced HMGB1 accelerates the regeneration of multiple tissues by transitioning stem cells to GAlert
| Autor: | Lee, G, Espirito Santo, AI, Zwingenberger, S, Cai, L, Vogl, T, Feldmann, M, Horwood, NJ, Chan, JK, Nanchahal, J |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
HMGB1
Mice Knockout Receptors CXCR4 Wound Healing Medical Sciences Cell Cycle chemical and pharmacologic phenomena tissue regeneration Biological Sciences Hematopoietic Stem Cells Chemokine CXCL12 immunology Fractures Bone Mice PNAS Plus stem cells Osteogenesis Animals Humans Regeneration GAlert HMGB1 Protein Muscle Skeletal Cells Cultured Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance While stem cell therapy has become the standard of care for hematological disorders, challenges remain for the treatment of solid organ injuries. Targeting endogenous cells would overcome many hurdles associated with exogenous stem cell therapy. Alarmins are released upon tissue damage, and here we describe how upregulation of a physiological pathway by exogenous administration of a single dose of HMGB1, either locally or systemically, promotes tissue repair by targeting endogenous stem cells. We show that HMGB1 complexed with CXCL12 transitions stem cells that express CXCR4 from G0 to GAlert. These primed cells rapidly respond to appropriate activating factors released upon injury. HMGB1 promotes healing even if administered 2 wk before injury, thereby expanding its translational benefit for diverse clinical scenarios. 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. |
| Databáze: | OpenAIRE |
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