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Mesenchymal Stem Cells Respond to Hypoxia by Increasing Diacylglycerols
Kinga Lakatos1, Stefanos Kalomoiris2, Béla Merkely1
1Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
Abstract:
Mesenchymal stem cells (MSC) are currently being tested clinically for a plethora of conditions, with most approaches relying on the secretion of paracrine signals by MSC to modulate the immune system, promote wound healing, and induce angiogenesis. Hypoxia has been shown to affect MSC proliferation, differentiation, survival and secretory profile. Here, we investigate changes in the lipid composition of human bone marrow-derived MSC after exposure to hypoxia. Using mass spectrometry, we compared the lipid profiles of MSC derived from five different donors, cultured for two days in either normoxia (control) or hypoxia (1% oxygen). Hypoxia induced a significant increase of total triglycerides, fatty acids and diacylglycerols (DG). Remarkably, reduction of DG levels using the phosphatidylcholine-specific phospholipase C inhibitor D609 inhibited the secretion of VEGF and Angiopoietin-2, but increased the secretion of interleukin-8, without affecting significantly their respective mRNA levels. Functionally, incubation of MSC in hypoxia with D609 inhibited the potential of the cells to promote migration of human endothelial cells in a wound/scratch assay. Hence, we show that hypoxia induces in MSC an increase of DG that may affect the angiogenic potential of these cells.
Insights
Hypoxia increases diacylglycerols (DG) in mesenchymal stem cells (MSC), impacting their angiogenic potential. Inhibiting DG synthesis affects the secretion of key growth factors, altering endothelial cell migration.
Area of Science:
- Biochemistry
- Cell Biology
- Regenerative Medicine
Background:
- Mesenchymal stem cells (MSC) are utilized in clinical settings for their paracrine signaling capabilities.
- Hypoxia influences MSC proliferation, differentiation, survival, and secretory functions.
Purpose of the Study:
- To investigate alterations in the lipid composition of human bone marrow-derived MSC under hypoxic conditions.
- To determine the functional consequences of hypoxia-induced lipid changes on MSC paracrine signaling and angiogenic potential.
Main Methods:
- Lipid profiling of MSC from five donors using mass spectrometry after 2-day culture in normoxia versus hypoxia (1% oxygen).
- Treatment with a diacylglycerol (DG) inhibitor (D609) to assess its effect on secreted factors and endothelial cell migration.
- Analysis of VEGF, Angiopoietin-2, and interleukin-8 secretion and corresponding mRNA levels.
Main Results:
- Hypoxia significantly increased total triglycerides, fatty acids, and diacylglycerols (DG) in MSC.
- DG reduction via D609 inhibited VEGF and Angiopoietin-2 secretion but increased interleukin-8 secretion, without altering mRNA levels.
- Inhibition of DG synthesis in hypoxic MSC impaired their ability to promote human endothelial cell migration in vitro.
Conclusions:
- Hypoxia induces a significant increase in DG levels within human bone marrow-derived MSC.
- The observed increase in DG is linked to altered secretion of angiogenic and inflammatory factors.
- Hypoxia-induced changes in DG may modulate the angiogenic potential of MSC, highlighting a novel regulatory mechanism.
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