CD11b(+) Gr1(+) bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice.

For the past decade, clinical trials and experimental studies have suggested that infusion therapy of whole bone marrow cells (BMC) has beneficial effects towards liver regeneration, injury and fibrosis/cirrhosis by stimulating the proliferation of hepatocytes, increasing progenitor cells and enhancing matrix degradation.1–3 However, the underlying mechanisms are unknown, in part because whole BMC contain a wide range of cell types including several types of stem and precursor cells of monocytic and granulocytic lineages.4 Events associated with hepatic fibrosis are well characterized, notably the excessive production of extracellular matrix (ECM) by activated hepatic stellate cells (HSCs).5 Activated HSCs produce not only huge amounts of ECMs including collagen, but also other fibrosis-related mediators including transforming growth factor (TGF)-β1, interleukin (IL)-6, IL-10 and retinoic acid.5–7 Interestingly, treatments with TGF-β1, IL-6 and retinoic acid can differentiate naive T cells into regulatory T cells (Tregs) or Th-17 cells in vitro, in which TGF-β1 is considered as an initial driver of this commitment.8 Moreover, activated HSCs produce these mediators, implicating activated HSCs in immune regulation. Recent studies underscore this immunoregulatory potential of HSCs, wherein they can act as intrahepatic antigen presenting cells to activate T, natural killer (NK), and NKT cells9, 10 and are also involved in the induction of CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) and CD4+CD25+Foxp3+ Tregs in an interferon (IFN)-γ and retinoic acid-dependent manner, respectively.11, 12 MDSCs expressing both markers of CD11b and Gr1 are now appreciated as a negative regulator of immune responses in cancer and other diseases. In addition, MDSCs are closely related to the induction of Tregs in the tumor microenvironment, which could produce IL-10 through the activity of the transcription factor, Foxp3.13–15 Moreover, IL-10 is recognized as an anti-inflammatory and anti-fibrotic mediator.5, 6 These findings provide a rationale for the possible immunoregulatory role of HSCs in vivo during BMC infusion therapy. In fact, infused BMC have been detected in fibrotic areas within 24 hours and can replace 25% of recipient hepatocytes by 4 weeks.16 However, the mechanisms underlying the effects of BMC are still uncertain, and most studies of infused BMC therapy have focused on hepatocyte regeneration and ECM degradation as long-term effects of BMC (at least 2 week after BMC infusion) in liver fibrosis.1, 2 Contrary to these previous findings, in the current study, we show that HSCs directly interact with infused BMC, especially CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ cells among whole BMC isolates at an early phase in vivo (within 24 hours). This interaction drives production of IL-10 in both types of cells, leading to increased Tregs in the recipient liver, which attenuates fibrosis.