Prevention of Liver Fibrosis by Intrasplenic Injection of High-Density Cultured Bone Marrow Cells in a Rat Chronic Liver Injury Model

Abstract

Endothelial progenitor cells (EPCs) from bone marrow have proven to be functional for the prevention of liver fibrosis in chronic liver injury. However, expansion of EPCs in culture is complicated and expansive. Previously, we have established a simple method that could enrich and expand EPCs by simple seeding bone marrow cells in high density dots. The purpose of this study is to evaluate whether cells derived from high-density (HD) culture of rat bone marrow cells could prevent the liver fibrosis in a chronic liver injury rat model, induced by carbon tetrachloride (CCl4). Flow cytometric analysis showed that cells from HD culture were enriched for EPCs, expressing high levels of EPC markers. Intrasplenic injection of HD cultured bone marrow cells in the CCl4-induced liver injury rat showed an enhanced antifibrogenic effect compared with animals treated with cells from regular-density culture. The antifibrogenic effect was demonstrated by biochemical and histological analysis 4 weeks post-transplantation. Furthermore, cells from HD culture likely worked through increasing neovascularization, stimulating liver cell proliferation, and suppressing pro-fibrogenic factor expression. HD culture, which is a simple and cost-effective procedure, could potentially be used to expand bone marrow cells for the treatment of liver fibrosis.

Bone marrow endothelial progenitor cells activate hepatic stellate cells and aggravate carbon tetrachloride induced liver fibrosis in mice via paracrine factors

“…In another study, infusion of enriched population of EPCs in 6 week‐CCl 4 treated rats has shown anti‐fibrogenic effect of the cells in terms of biochemical and histological evidences. However, the study has failed to observe any differentiation of transplanted cells into hepatocytes or endothelial cells, indicating that the donor cells function mainly through a paracrine effects to prevent liver fibrosis and regeneration, rather than by direct differentiation . In the present study, we observed GFP‐EPCs around LSECs during the 4th week of CCl 4 treatment.…”

“…These results suggest that EPCs contributes little towards endothelial regeneration during liver injury. It has been earlier shown that the intraperitoneal administration of EPCs into rat model of liver injury by CCl 4 enhances liver regeneration and suppresses liver fibrogenesis . In the above study, Liu et al.…”

Cytokines, hepatic cell profiling and cell interactions during bone marrow cell therapy for liver fibrosis in cholestatic mice

“…Even a small increase in the number of endothelial cells during fibrosis, as observed in our results after cell therapy, could have an important role in tissue remodeling. However, these cells are also associated with tissue tumorigenesis and metastasis, and it is noteworthy that only when healthy animals were injected with BMC, endothelial progenitor cells percentage was highly increased, suggesting that the safety of BMC transplantation is associated with the presence of a chronic liver injury in our model [ 25 , 26 ].…”

Comparison of the Treatment Efficiency of Bone Marrow‐Derived Mesenchymal Stem Cell Transplantation via Tail and Portal Veins in CCl4‐Induced Mouse Liver Fibrosis

“…Many stem cell types, such as HSCs [ 4 ], BM stem cells [ 6 , 7 , 11 , 23 – 25 , 27 , 33 – 35 ], and adipose-derived stem cells [ 36 – 40 ], have been investigated for liver transplantation and treatment of end-stage liver disease (ESLD). Although recent studies have shown positive effects of stem cell therapy in ESLD treatment, there are controversies regarding the source of stem cells and administration strategies.…”