Journal article

Publication year: 2012

Pages: 907-916

Journal: Gut

Volume number: 61

Issue number: 6

ISSN: 0017-5749

eISSN: 1468-3288

DOI Link: https://doi.org/10.1136/gutjnl-2011-300608

Publisher: BMJ Publishing Group

Abstract: 

Objective Reports on the effects of bone marrow-derived cells on hepatic fibrosis are contradictory. Impaired fibrosis but increased inflammation has recently been demonstrated 10 weeks after bone marrow transplantation (BM-Tx) in Abcb4(-/-) mice. It is hypothesised that BM-Tx might have long-term therapeutic potential by altering the immunological and matrix remodelling processes leading to hepatic regeneration.

Methods After lethal irradiation of recipient mice, BM cells from GFP+ donor mice (allogeneic Tx) or Abcb4(-/-) mice (syngeneic Tx) were transplanted via tail vein injection. Readouts were performed 2, 10 and 20 weeks after Tx. Liver integrity was assessed serologically and histologically. Surrogate markers for fibrogenesis, T helper (Th) response, inflammation, graft-versus-host disease and fibrolysis were analysed by quantitative real-time PCR, zymography and immunohistology.

Results 20 weeks after syngeneic and allogeneic BM-Tx, hepatic grading and staging were significantly improved. In contrast, 2 weeks after BM-Tx inflammatory grading, expression of inflammatory cell markers and associated chemokines and their receptors were increased and subsequently declined. In parallel, CD8+/GFP+ donor-derived T cells infiltrated the liver 2 weeks after BM-Tx. The Th1 cyokine interferon gamma was increased 2 and 10 weeks after BM-Tx whereas the Th2 associated interleukin 13 was not altered. The gene expression of matrix metalloproteinases MMP-2, MMP-7, MMP-9 and MMP-13 was transiently upregulated and MMP-9 protein remained elevated 20 weeks after BM-Tx with enhanced gelatinase activity located within the fibrotic areas. Neutrophils were identified as major sources of MMP-9.

Conclusion These results show that BM-Tx causes an antifibrotic Th1 response combined with transient inflammatory effects and subsequently upregulated MMP activity. Antifibrotic Th polarisation and prolonged proteolytic activity, especially of MMP-9, might be responsible for long-term amelioration of hepatic fibrosis.

Harvard Citation style: Roderfeld, M., Rath, T., Pasupuleti, S., Zimmermann, M., Neumann, C., Churin, Y., et al. (2012) Bone marrow transplantation improves hepatic fibrosis in Abcb4^-/- mice via Th1 response and matrix metalloproteinase activity, Gut, 61(6), pp. 907-916. https://doi.org/10.1136/gutjnl-2011-300608

APA Citation style: Roderfeld, M., Rath, T., Pasupuleti, S., Zimmermann, M., Neumann, C., Churin, Y., Dierkes, C., Voswinckel, R., Barth, P., Zahner, D., Graf, J., & Roeb, E. (2012). Bone marrow transplantation improves hepatic fibrosis in Abcb4^-/- mice via Th1 response and matrix metalloproteinase activity. Gut. 61(6), 907-916. https://doi.org/10.1136/gutjnl-2011-300608