Iron Overload Impairs Bone Marrow Mesenchymal Stromal Cells from Higher-Risk MDS Patients by Regulating the
Lei Huang1, Zhaoyun Liu1, Hui Liu1
1Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China.
Abstract:
The bone marrow microenvironment plays important roles in the progression of the myelodysplastic syndrome (MDS). The higher incidence of ASXL1 and TET2 gene mutations in our iron overload (IO) MDS patients suggests that IO may be involved in the pathogenesis of MDS. The effects of IO damaging bone marrow mesenchymal stromal cells (MSCs) from higher-risk MDS patients were investigated. In our study, IO decreased the quantity and weakened the abilities of proliferation and differentiation of MSCs, and it inhibited the gene expressions of VEGFA, CXCL12, and TGF-β1 in MSCs regulating hematopoiesis. The increased level of reactive oxygen species (ROS) in MSCs caused by IO might be inducing apoptosis by activating caspase3 signals and involving in MDS progression by activating β-catenin signals. The damages of MSCs caused by IO could be partially reversed by an antioxidant or an iron chelator. Furthermore, the MSCs in IO MDS/AML patients had increased levels of ROS and apoptosis, and the expressions of caspase3 and β-catenin were increased even further. In conclusion, IO affects gene stability in higher-risk MDS patients and impairs MSCs by inducing ROS-related apoptosis and activating the Wnt/β-catenin signaling pathway, which could be partially reversed by an antioxidant or an iron chelator.
Insights
Iron overload (IO) damages bone marrow mesenchymal stromal cells (MSCs) in myelodysplastic syndrome (MDS) patients. This damage, linked to reactive oxygen species (ROS) and Wnt/β-catenin signaling, impairs hematopoiesis but can be partially reversed.
Area of Science:
- Hematology
- Oncology
- Cell Biology
Background:
- The bone marrow microenvironment is crucial in myelodysplastic syndrome (MDS) progression.
- Iron overload (IO) is increasingly recognized as a potential factor in MDS pathogenesis, particularly with mutations like ASXL1 and TET2.
Purpose of the Study:
- To investigate the damaging effects of iron overload (IO) on bone marrow mesenchymal stromal cells (MSCs) from higher-risk myelodysplastic syndrome (MDS) patients.
- To elucidate the mechanisms by which IO impairs MSCs and affects hematopoiesis.
- To explore potential therapeutic interventions for IO-induced MSC damage.
Main Methods:
- Assessed the quantity, proliferation, and differentiation abilities of MSCs under IO conditions.
- Quantified gene expression of key hematopoietic regulators (VEGFA, CXCL12, TGF-β1) in MSCs.
- Investigated the role of reactive oxygen species (ROS), apoptosis (caspase3), and Wnt/β-catenin signaling in IO-induced MSC damage.
- Evaluated the effects of an antioxidant and an iron chelator on IO-damaged MSCs.
- Analyzed MSCs from patients with iron overload myelodysplastic syndrome/acute myeloid leukemia (IO MDS/AML).
Main Results:
- IO significantly decreased MSC quantity and impaired their proliferation and differentiation capabilities.
- IO inhibited the expression of VEGFA, CXCL12, and TGF-β1 in MSCs, affecting hematopoiesis.
- Increased ROS levels in MSCs due to IO induced apoptosis via caspase3 activation and promoted MDS progression through β-catenin signaling.
- Antioxidants or iron chelators partially reversed the IO-induced damage to MSCs.
- MSCs from IO MDS/AML patients exhibited elevated ROS, apoptosis, caspase3, and β-catenin levels.
Conclusions:
- IO negatively impacts gene stability and impairs MSC function in higher-risk MDS patients.
- The primary mechanisms involve IO-induced ROS-related apoptosis and activation of the Wnt/β-catenin signaling pathway.
- Therapeutic strategies involving antioxidants or iron chelation show potential for mitigating IO-induced MSC damage in MDS.
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