Stem Cell Therapy for Liver Disease: Parameters Governing the Success of Using Bone Marrow Mesenchymal Stem Cells

Institute of Biopharmaceutical Science, National Yang-Ming University, Taipei, Taiwan.
Gastroenterology (Impact Factor: 16.72). 06/2008; 134(7):2111-21, 2121.e1-3. DOI: 10.1053/j.gastro.2008.03.015
Source: PubMed


Liver transplantation is the primary treatment for various end-stage hepatic diseases but is hindered by the lack of donor organs and by complications associated with rejection and immunosuppression. There is increasing evidence to suggest the bone marrow is a transplantable source of hepatic progenitors. We previously reported that multipotent bone marrow-derived mesenchymal stem cells differentiate into functional hepatocyte-like cells with almost 100% induction frequency under defined conditions, suggesting the potential for clinical applications. The aim of this study was to critically analyze the various parameters governing the success of bone marrow-derived mesenchymal stem cell-based therapy for treatment of liver diseases.
Lethal fulminant hepatic failure in nonobese diabetic severe combined immunodeficient mice was induced by carbon tetrachloride gavage. Mesenchymal stem cell-derived hepatocytes and mesenchymal stem cells were then intrasplenically or intravenously transplanted at different doses.
Both mesenchymal stem cell-derived hepatocytes and mesenchymal stem cells, transplanted by either intrasplenic or intravenous route, engrafted recipient liver, differentiated into functional hepatocytes, and rescued liver failure. Intravenous transplantation was more effective in rescuing liver failure than intrasplenic transplantation. Moreover, mesenchymal stem cells were more resistant to reactive oxygen species in vitro, reduced oxidative stress in recipient mice, and accelerated repopulation of hepatocytes after liver damage, suggesting a possible role for paracrine effects.
Bone marrow-derived mesenchymal stem cells can effectively rescue experimental liver failure and contribute to liver regeneration and offer a potentially alternative therapy to organ transplantation for treatment of liver diseases.

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Available from: Vincent W Yang, Jan 03, 2014
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    • "MSCs is another source of HSPCs, which has been isolated from various tissues, such as bone marrow, adipose tissue and so on. Some studies have demonstrated that MSCs can differentiate into hepatocyte under defined conditions in vitro26, and regenerate the liver in vivo27. Although all these cells have the potential to treat liver failure, the differences among them in the treatment of liver failure are worth to explore. "
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    ABSTRACT: Cell-based therapies (CBTs) are considered the effective approaches to treat liver failure. However, which cell type is the most suitable source of CBTs for acute liver failure (ALF) or chronic liver failure (CLF) remains unclear. To investigate this, mature hepatocytes in adult liver (adult HCs), fetal liver cells (FLCs), induced hepatic stem cells (iHepSCs) and bone marrow derived mesenchymal stromal cells (BMSCs) were used to CBTs for ConA-induced ALF and Fah-deficient induced CLF in mice. The results showed that only BMSCs remitted liver damage and rescued ALF in ConA-treated mice. In this process, BMSCs inhibited ConA-induced inflammatory response by decreasing the mRNA expressions of TNF-α, IFN-γ and FasL and increasing IL-10 mRNA expression. However, in the CLF model, not BMSCs but adult HCs transplantation lessened liver injury, recovered liver function and rescued the life of Fah-/- mice after NTBC withdrawal. Further study showed that adult HCs offered more effective liver regeneration compared to other cells in Fah-/- mice without NTBC. These results demonstrated that BMSCs and adult HCs are the optimal sources of CBTs for ConA-induced ALF and Fah-deficient induced CLF in mice, respectively. This finding deepens our understanding about how to select a proper CBT for different liver failure.
    Scientific Reports 09/2014; 4:6494. DOI:10.1038/srep06494 · 5.58 Impact Factor
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    • "The transplanted cells likely play multiple roles in the repair process. They may differentiate directly into hepatocytes, or release growth factors to protect intrinsic hepatocytes, stimulate regeneration, regulate inflammatory response, and/or decompose the extracellular matrix (ECM) [9], [11]–[13]. Although non-cultured autologous bone marrow-derived cells have been successfully applied in patients [7], [10], the use of in vitro culture-expanded cells for treatment could reduce the initial amount of bone marrow needed. "
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    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.
    PLoS ONE 09/2014; 9(9):e103603. DOI:10.1371/journal.pone.0103603 · 3.23 Impact Factor
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    • "From clinically applied stem cells, mesenchymal stem cells (MSCs) have been described as well-characterized stem cells that can be isolated from adult tissues (Jiang et al., 2002). Positive indications of their applications in various diseases have made them clinically promising (Bang et al., 2005, Garcia-Olmo et al., 2005, Kuo et al., 2008, Le Blanc et al., 2008, Nakamizo et al., 2005, Pisati et al., 2007). Many advantages in their application over the embryonic stem cells has made them potential candidates in regenerative medicine (Thomson et al., 1998). "
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    ABSTRACT: Stem cell therapy in recent years has gained much attention as being the modern therapeutic approach to treat diseases. Mesenchymal stem cells (MSCs) are seen as the most reliable cells applied in therapy over other stem cells because of their versatility. Bone and cartilage diseases (osteo-diseases) are the major target of therapy using MSCs. In this perspective, we have analyzed statistically data available on clinical trials registry databases. We report that MSC therapy for osteo-diseases needs optimization in its standards to achieve acceptable results so that we can apply it in daily routine clinical practice.
    Cell Biology International 05/2014; 38(10). DOI:10.1002/cbin.10293 · 1.93 Impact Factor
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