Leading science, pioneering therapies
CRM Publications

Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling.

TitleBone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling.
Publication TypeJournal Article
Year of Publication2013
AuthorsBird TG, Lu W-Y, Boulter L, Gordon-Keylock S, Ridgway RA, Williams MJ, Taube J, Thomas JA, Wojtacha D, Gambardella A, Sansom OJ, Iredale JP, Forbes SJ
JournalProc Natl Acad Sci U S A
Volume110
Issue16
Pagination6542-7
Date Published2013 Apr 16
ISSN1091-6490
KeywordsAnimals, Bile Ducts, Intrahepatic, Bone Marrow Transplantation, Colony-Forming Units Assay, Flow Cytometry, Immunohistochemistry, In Situ Hybridization, Fluorescence, Macrophages, Mice, Mice, Inbred C57BL, Microscopy, Confocal, Real-Time Polymerase Chain Reaction, Regenerative Medicine, Signal Transduction, Tumor Necrosis Factors
Abstract

Tissue progenitor cells are an attractive target for regenerative therapy. In various organs, bone marrow cell (BMC) therapy has shown promising preliminary results, but to date no definite mechanism has been demonstrated to account for the observed benefit in organ regeneration. Tissue injury and regeneration is invariably accompanied by macrophage infiltration, but their influence upon the progenitor cells is incompletely understood, and direct signaling pathways may be obscured by the multiple roles of macrophages during organ injury. We therefore examined a model without injury; a single i.v. injection of unfractionated BMCs in healthy mice. This induced ductular reactions (DRs) in healthy mice. We demonstrate that macrophages within the unfractionated BMCs are responsible for the production of DRs, engrafting in the recipient liver and localizing to the DRs. Engrafted macrophages produce the cytokine TWEAK (TNF-like weak inducer of apoptosis) in situ. We go on to show that recombinant TWEAK activates DRs and that BMC mediated DRs are TWEAK dependent. DRs are accompanied by liver growth, occur in the absence of liver tissue injury and hepatic progenitor cells can be isolated from the livers of mice with DRs. Overall these results reveal a hitherto undescribed mechanism linking macrophage infiltration to DRs in the liver and highlight a rationale for macrophage derived cell therapy in regenerative medicine.

DOI10.1073/pnas.1302168110
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID23576749
PubMed Central IDPMC3631632
Grant ListG0600033 / / Medical Research Council / United Kingdom
G0900446 / / Medical Research Council / United Kingdom
G0901697 / / Medical Research Council / United Kingdom
G1000868 / / Medical Research Council / United Kingdom
WT081604AIA / / Wellcome Trust / United Kingdom
/ / Medical Research Council / United Kingdom