These interactions contribute to the navigation of monocytes into target tissues during their maturation into macrophages.5 The delivery of MCP-1 and MIP-1α-expressing BMMs to injured mice caused up-regulation of hepatic MCP-1 and MIP-1α and the recruitment of endogenous macrophages. These macrophages produced MMP-13, whose actions include the degradation of fibrillar collagens and gelatin as well activation of other MMPs (such as MMP-9).6 Donor BMMs also express MIP-2

and KC, which are examples of CXC chemokines that recruit neutrophils through the surface receptor CXCR2.5 One day after BMM delivery, hepatic expression of these neutrophil chemoattractants was markedly up-regulated, with elevated hepatic neutrophil selleck chemical numbers. This is in keeping with the role of macrophage-mediated neutrophil recruitment in fibrosis

resolution following cessation of cholestatic injury.24 In our model, recruited neutrophils produce MMP-9. MMP-9 overexpression reduces myofibroblast number and inhibits fibrogenesis during experimental liver injury.25 The simultaneous trend of increased MMP-12 (macrophage metalloelastase) and MMP-8 (neutrophil collagenase) expression following BMM therapy reinforces the fibrolytic role of recruited leukocytes. The markedly elevated hepatic IL-10 levels in BMM recipients may modify the behavior of resident and incoming leukocytes and the degree of injury.26 Simultaneous up-regulation of IL-10 and MMPs following BMM therapy may reduce myofibroblast activation26 and promote apoptosis.27 The chemokine-mediated recruitment of host effector cells to the injured Selleckchem Selumetinib liver, importantly at a time when the prevailing hepatic environment is antiinflammatory, represents a novel and realistic mechanism for the therapeutic actions of comparatively few donor

cells in the context of the whole organ. The improved liver function following BMM therapy is multifactorial. There is a less fibrotic cellular milieu, a proregenerative stimulus to LPCs, and elevated levels of cytokines such as CSF-1, VEGF, and IGF-1 that are involved in reparative processes during tissue injury.9, 28, 29 Hepatocyte proliferation was not significantly increased following BMM therapy. There was significant activation of the 4��8C LPC compartment, compatible with the recent observation that BM infusion transiently stimulated LPCs and improved serum albumin in a series of cirrhotic patients.30 We have previously noted the close spatial relationship between LPCs and endogenous macrophages in vivo.12 The cytokine TWEAK is a member of the TNF superfamily and is currently the only known mitogen that is selective for LPCs but not mature hepatocytes.13 TWEAK acts through its cognate receptor Fn14 to stimulate LPC proliferation. Interestingly, endogenous hepatic macrophages have recently been identified as a cellular source of TWEAK during chronic liver injury.