Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, OX3 7FY Oxford, United Kingdom.
University Center of Orthopaedics and Traumatology, University Hospital Carl Gustav Carus at Technische Universität Dresden, 01307 Dresden, Germany.
Proc Natl Acad Sci U S A. 2018 May 8;115(19):E4463-E4472. doi: 10.1073/pnas.1802893115. Epub 2018 Apr 19.
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 mice we identified the underlying mechanism as the transition of multiple quiescent stem cells from G to G HMGB1 also transitions human stem and progenitor cells to G Therefore, exogenous HMGB1 may benefit patients in many clinical scenarios, including trauma, chemotherapy, and elective surgery.
近几十年来的一项重大发现是干细胞的存在及其修复许多（如果不是大多数）组织的潜力。随着人口老龄化，人们已经尝试了许多方法来利用外源性干细胞来促进组织修复，但迄今为止，收效甚微。另一种方法可能更有效，成本也低得多，即通过靶向内源性干细胞来促进组织再生。然而，增强内源性干细胞功能的方法仍然定义不明确。损伤会导致危险信号的释放，这些信号已知可以调节免疫反应，但它们在体内干细胞介导的修复中的作用仍有待阐明。在这里，我们表明，HMGB1 在人类和小鼠的骨折后都会被释放，与 CXCL12 形成异源复合物，并通过 CXCR4 加速体内骨骼、造血和肌肉的再生。在损伤前 2 周用 HMGB1 预处理也加速了组织再生，表明存在获得性的促再生特征。HMGB1 在体内导致细胞周期的持续增加，并且使用 小鼠，我们确定了潜在的机制是多个静止干细胞从 G 期到 G 期的转变 HMGB1 还将人类干细胞和祖细胞转变为 G 期 因此，外源性 HMGB1 可能有益于许多临床情况下的患者，包括创伤、化疗和择期手术。
