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Tumor necrosis factor inhibits the terminal event in mesenchymal stem cell differentiation
M Filipak1, R L Sparks, C Y Tzen
1Section of Experimental Pathology, Mayo Clinic, Rochester, Minnesota 55905.
Abstract:
Control of the terminal event in cellular differentiation is an important normal regulatory process, and the expression of defects in the control of this process has been implicated in the pathogenesis of cancer. To determine if tumor necrosis factor (TNF), which is an important biological response modifier, can inhibit terminal differentiation, we have studied 3T3 T mesenchymal stem cells. This experimental cell system was employed because a well-defined series of steps in differentiation has been defined and cells at each stage of differentiation can be isolated. For example, nonterminal differentiated cells can be isolated, and their transition to a terminal differentiation state can be evaluated. The most interesting results in the current studies show that TNF blocks the terminal event in mesenchymal stem cell differentiation. Inhibition of the terminal event of differentiation by TNF is reversible and is not associated with inhibition of selective or general protein synthesis. Evidence is also presented that cell clones that are defective in their ability to undergo the terminal event in differentiation secrete factor(s) that inhibit the terminal event in differentiation. These observations suggest that the inhibition of the terminal event in differentiation may be mediated via autocrine or paracrine regulatory molecules such as tumor necrosis factor.
Insights
Tumor necrosis factor (TNF) blocks the final step in mesenchymal stem cell differentiation. This inhibition is reversible and suggests that TNF or similar molecules may regulate cell differentiation.
Area of Science:
- Cellular Biology
- Molecular Biology
- Cancer Pathogenesis
Background:
- Cellular differentiation is a crucial regulatory process.
- Defects in differentiation control are linked to cancer development.
- Tumor necrosis factor (TNF) is a key biological response modifier.
Purpose of the Study:
- To investigate if TNF inhibits terminal differentiation in mesenchymal stem cells.
- To understand the role of TNF in regulating the final stages of cell differentiation.
Main Methods:
- Utilized 3T3 T mesenchymal stem cells, a well-defined differentiation model.
- Isolated cells at various differentiation stages to evaluate transitions.
- Assessed the impact of TNF on terminal differentiation events.
Main Results:
- TNF was found to block the terminal event of mesenchymal stem cell differentiation.
- This TNF-induced inhibition was reversible.
- Inhibition of differentiation by TNF did not affect overall protein synthesis.
Conclusions:
- TNF inhibits the terminal event in mesenchymal stem cell differentiation.
- Defective differentiation clones secrete inhibitory factors, suggesting autocrine/paracrine regulation.
- Tumor necrosis factor may mediate the inhibition of terminal differentiation via autocrine or paracrine pathways.