Necrotic cell-derived high mobility group box 1 attracts antigen-presentingcells but inhibits hepatocyte growth factor-mediated tropism of mesenchymal stemcells for apoptotic cell death

摘要

Tissue damage due to apoptotic or necrotic cell death typically initiates distinct cellular responses, leading either directly to tissue repair and regeneration or to immunological processes first, to clear the site, for example, of potentially damage-inducing agents. Mesenchymal stem cells (MSC) as well as immature dendritic cells (iDC) and monocytes migrate to injured tissues. MSC have regenerative capacity, whereas monocytes and iDC have a critical role in inflammation and induction of immune responses, including autoimmunity after tissue damage. Here, we investigated the influence of apoptotic and necrotic cell death on recruitment of MSC, monocytes and iDC, and identified hepatocyte growth factor (HGF) and the alarmin high mobility group box 1 (HMGB1) as key factors differentially regulating these migratory responses. MSC, but not monocytes or iDC, were attracted by apoptotic cardiomyocytic and neuronal cells, whereas necrosis induced migration of monocytes and iDC, but not of MSC. Only apoptotic cell death resulted in HGF production and HGF-mediated migration of MSC towards the apoptotic targets. In contrast, HMGB1 was predominantly released by the necrotic cells and mediated recruitment of monocytes and iDC via the receptor of advanced glycation end products. Moreover, necrotic cardiomyocyticand neuronal cells caused an HMGB1/toll-like receptor-4-dependent inhibitionof MSC migration towards apoptosis or HGF, while recruitment of monocytes andiDC by necrosis or HMGB1 was not affected by apoptotic cells or HGF. Thus, thetype of cell death differentially regulates recruitment of either MSC ormonocytes and iDC through HGF and HMGB1, respectively, with a dominant,HMGB1-mediated role of necrosis in determining tropism after tissue injury.