Abstract
The liver has a population of resident macrophages termed Kupffer cells that are phagocytic and aid filtration of the portal blood. Following liver injury both the resident macrophages and circulating monocytes influence both liver regeneration and liver fibrosis. Kupffer cells can stimulate hepatocyte proliferation via the secretion of IL-6; macrophages stimulate a ductular proliferation via TWEAK secretion and also secrete Wnts which stimulate liver regeneration. Macrophages can both promote fibrosis and help resolve fibrosis depending upon the phase of liver injury.
We have been developing macrophage therapy for liver fibrosis and found that injected mature macrophages promote scar resolution in mouse models of liver fibrosis via a number of direct mechanism such as MMP expression but also in indirectly via the expression of chemokines which aid the recruitment of inflammatory cells to the scar area and promote scar resolution. Based on these basic research results, we are planning human studies of autologous macrophage therapy for liver cirrhosis in the near future.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Hansel MC et al. The history and use of human hepatocytes for the treatment of liver diseases: the first 100 patients. Curr Protoc Toxicol. 2014;62:14.12.1–14.12.23.
Gupta S. Hepatocyte transplantation. J Gastroenterol Hepatol. 2002;17 Suppl 3:S287–93.
Forbes SJ, Rosenthal N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat Med. 2014;20:857–69.
Furuyama K et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet. 2011;43:34–41.
Sackett SD et al. Foxl1 is a marker of bipotential hepatic progenitor cells in mice. Hepatology. 2009;49:920–9.
Espanol-Suner R et al. Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology. 2012;143:1564–75.
Yanger K et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell. 2014;15:340–9.
Tarlow BD et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell. 2014;15:605–18.
Lorenzini S et al. Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut. 2010;59:645–54.
Kallis YN et al. Remodelling of extracellular matrix is a requirement for the hepatic prosgenitor cell response. Gut. 2011;60:525–33.
Hsieh WC et al. Galectin-3 regulates hepatic progenitor cell expansion during liver injury. Gut. 2015;64:312–21.
Tsuchiya A et al. Polysialic acid/neural cell adhesion molecule modulates the formation of ductular reactions in liver injury. Hepatology. 2014;60:1727–40.
Boulter L et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. 2012;18:572–9.
Terai S et al. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells. 2006;24:2292–8.
Terai S et al. Status and prospects of liver cirrhosis treatment by using bone marrow-derived cells and mesenchymal cells. Tissue Eng Part B Rev. 2014;20:206–10.
Moore JK et al. Systematic review: the effects of autologous stem cell therapy for patients with liver disease. Aliment Pharmacol Ther. 2014;39:673–85.
Gibbons MA et al. Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. Am J Respir Crit Care Med. 2011;184:569–81.
Duffield JS et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115:56–65.
Ramachandran P et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A. 2012;109:E3186–95.
Fallowfield JA et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol. 2007;178:5288–95.
Russo FP et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology. 2006;130:1807–21.
Thomas JA et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology. 2011;53:2003–15.
Williams MJ et al. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion. Gastroenterology. 2014;146:349–56.
Bird TG et al. Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling. Proc Natl Acad Sci U S A. 2013;110:6542–7.
Boulter L et al. Differentiation of progenitors in the liver: a matter of local choice. J Clin Invest. 2013;123:1867–73.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Japan
About this chapter
Cite this chapter
Tsuchiya, A., Forbes, S.J. (2016). Macrophage Therapy for Liver Fibrosis and Regeneration. In: Terai, S., Suda, T. (eds) Gene Therapy and Cell Therapy Through the Liver. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55666-4_2
Download citation
DOI: https://doi.org/10.1007/978-4-431-55666-4_2
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-55665-7
Online ISBN: 978-4-431-55666-4
eBook Packages: MedicineMedicine (R0)