A Novel Therapy for Liver Fibrosis Using Ex Vivo Modified Mesenchymal Stem Cells

Background & Aims: An ideal approach to treat liver fibrosis would be suppression of fibrogenesis while promoting regeneration of impaired liver. We have previously shown that a large number of bone marrow (BM)-derived cells migrate into fibrotic liver and produce matrix metalloproteinases (MMPs). Here we examined the origin of those MMP-expressing cells and tried to develop a regeneration therapy for fibrotic liver using ex vivo modified MSC.
Methods: BM hematopoietic (HSC) or mesenchymal stem cells (MSC) were examined for their MMP expression. They were genetically labeled with EGFP and transplanted to wild type mice. MSC were infected with lentiviruses expressing OGFRL1, a novel G-CSF-induced BM cell-derived factor. They were injected into spleen of CCl₄-treated mice to examine the effects on regeneration of fibrotic liver.
Results: Freshly isolated MSC, but not HSC, expressed MMP-13, MMP-9 and MMP-2, all of which were decreased following culture passages. BM-derived hematopoietic cells, but not MSC, migrated to fibrotic liver after CCl₄ injections. Intrasplenic injections of OGFRL1-expressing MSC increased MMP-13 and MMP-9 expression, and stimulated BrdU uptake into hepatocytes after partial hepatectomy.
Conclusion: Although MSC express large amounts of MMPs, they are not mobilized spontaneously from BM following fibrogenic stimuli. Ex vivo modified MSC that express an anti-fibrotic and regeneration-stimulating factor would be a potential therapeutic option for liver fibrosis.