Improvement of liver fibrosis by infusion of cultured cells derived from human bone marrow

Abstract

We develop "autologous bone marrow cell infusion (ABMi) therapy" for the treatment of human decompensated liver cirrhosis and confirm the efficacy and safety of this treatment in multicenter clinical studies. With the goal of further expanding the applications of ABMi, we first cultured human bone marrow cells and then determined whether a cell fraction found to be effective in improving liver fibrosis can be amplified. Cells harvested after two passages (P2 cells) consistently contained approximately 94% mesenchymal stem cells (MSCs); conversely, the cells harvested after only medium change (P0 cells) contained many macrophages. MSCs (2.8 × 10(8)) in P2 cells were harvested from 3.8 × 10(8) bone marrow-derived mononuclear cells after 22 days. DNA-chip analysis also showed during the culturing step that bone marrow-derived cells decreased with macrophage phenotype. The infused 5 × 10(5) P2 cells significantly improved liver fibrosis in the nonobese diabetic/severe combined immunodeficient (NOD-SCID) mouse carbon tetrachloride (CCl4) liver cirrhosis model and induced the expression of matrix metalloproteinase (MMP)-9 and suppressed expressions of alpha smooth muscle actin (αSMA), tumor necrosis factor alpha (TNFα) and transforming growth factor beta (TGFβ) in the liver. Cultured human bone marrow-derived cells (P2 cells) significantly inhibited liver fibrosis. The increase of MMP-9 and suppressed activation of hepatic stellate cells (HSCs) through the regulation of humoral factors (TNFα and TGFβ) contribute to the improvement of liver fibrosis by MSCs comprising about 94% of P2 cells. MSCs in cultured human bone marrow-derived mono-nuclear cells (BM-MNCs) proliferate sufficiently in cell therapy, so we believe our cultured bone marrow-derived cell therapy can lead to expanded clinical applications and enable outpatient therapy.

Enhanced survival of mice infused with bone marrow‐derived as compared with adipose‐derived mesenchymal stem cells

“…We previously demonstrated the safety and effectiveness of ABMi therapy; we also showed the potential for BMSC to improve liver fibrosis and functioning by carbon tetrachloride induction in non‐obese diabetic/severe combined immunodeficient mice. These results provide a basis for the development of new types of cell therapy using BMSC . Importantly, as the number of transplanted cells may represent an improvement in the efficacy of cell‐based therapy, the present data clearly show that BMSC represent a better candidate for this purpose.…”

“…These results provide a basis for the development of new types of cell therapy using BMSC. 8,9 Importantly, as the number of transplanted cells may represent an improvement in the efficacy of cell-based therapy, the present data clearly show that BMSC represent a better candidate for this purpose.…”

Human liver mesenchymal stem/progenitor cells inhibit hepatic stellate cell activation: in vitro and in vivo evaluation

“…MSC-based therapy for treating liver fibrosis based on the differentiation potential and immunoregulatory properties of MSCs is currently under evaluation [9, 29–31]. Cell-free mechanisms have also been proposed [31–33]. Our study investigated ADHLSC-HSC interactions with an in vitro co-culture system.…”

Status of and candidates for cell therapy in liver cirrhosis: overcoming the “point of no return” in advanced liver cirrhosis

“…As shown in Table 1, allogeneic umbilical tissue-derived MSCs have also improved MELD scores and serum levels of albumin and bilirubin. Moreover, as shown in Table 2, human MSCs have been safely administered in rodents, also exhibiting some therapeutic effects, thereby supporting the low immunogenicity of MSCs [84][85][86][87][88].…”