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Resistance of Human Liver Mesenchymal Stem Cells to FAS-Induced Cell Death
Irina V Kholodenko1, Alisa M Gisina1, Garik V Manukyan2
1Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia.
Abstract:
Mesenchymal stem cells (MSCs) have a pronounced therapeutic potential in various pathological conditions. Though therapeutic effects of MSC transplantation have been studied for a long time, the underlying mechanisms are still not clear. It has been shown that transplanted MSCs are rapidly eliminated, presumably by apoptosis. As the mechanisms of MSC apoptosis are not fully understood, in the present work we analyzed MSC sensitivity to Fas-induced apoptosis using MSCs isolated from the biopsies of liver fibrosis patients (L-MSCs). The level of cell death was analyzed by flow cytometry in the propidium iodide test. The luminescent ATP assay was used to measure cellular ATP levels; and the mitochondrial membrane potential was assessed using the potential-dependent dye JC-1. We found that human L-MSCs were resistant to Fas-induced cell death over a wide range of FasL and anti-Fas mAb concentrations. At the same time, intrinsic death signal inducers CoCl2 and staurosporine caused apoptosis of L-MSCs in a dose-dependent manner. Despite the absence of Fas-induced cell death treatment of L-MSCs with low concentrations of FasL or anti-Fas mAb resulted in a cellular ATP level decrease, while high concentrations of the inducers caused a decline of the mitochondrial membrane potential. Pre-incubation of L-MSCs with the pro-inflammatory cytokine TNF-α did not promote L-MSC cell death. Our data indicate that human L-MSCs have increased resistance to receptor-mediated cell death even under inflammatory conditions.
Insights
Mesenchymal stem cells (MSCs) from liver fibrosis patients resist Fas-induced apoptosis. These cells show altered ATP levels and mitochondrial potential, indicating unique survival mechanisms even in inflammatory conditions.
Area of Science:
- Immunology
- Cell Biology
- Regenerative Medicine
Background:
- Mesenchymal stem cells (MSCs) show therapeutic promise, but their survival mechanisms, especially apoptosis resistance, remain unclear.
- Transplanted MSCs are often rapidly eliminated, hindering their therapeutic efficacy.
- Understanding MSC apoptosis is crucial for optimizing cell-based therapies.
Purpose of the Study:
- To investigate the sensitivity of liver-derived MSCs (L-MSCs) from liver fibrosis patients to Fas-induced apoptosis.
- To elucidate the underlying mechanisms of L-MSC resistance to receptor-mediated cell death.
- To assess the impact of inflammatory conditions on L-MSC apoptosis.
Main Methods:
- Isolation and culture of L-MSCs from liver fibrosis patient biopsies.
- Flow cytometry for cell death analysis (propidium iodide staining).
- Luminescent ATP assay and JC-1 dye for mitochondrial membrane potential assessment.
Main Results:
- Human L-MSCs demonstrated significant resistance to Fas-induced apoptosis across various concentrations.
- Intrinsic apoptosis inducers (CoCl2, staurosporine) effectively induced L-MSC apoptosis.
- Low FasL/anti-Fas mAb concentrations decreased ATP levels; high concentrations reduced mitochondrial membrane potential.
- TNF-α pre-incubation did not sensitize L-MSCs to cell death.
Conclusions:
- Human L-MSCs exhibit inherent resistance to Fas-mediated apoptosis, even under inflammatory conditions.
- This resistance may involve modulation of cellular ATP levels and mitochondrial membrane potential.
- Findings suggest L-MSCs possess unique survival characteristics relevant to their therapeutic potential.
