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Ferroptosis Profiles of Human Mesenchymal Stromal Cell Subsets at the Single-Cell Level
Xin Wen1,2, Shuai Ding2, Yujie Zhou1
1Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, China Pharmaceutical University, Nanjing, China.
Abstract:
Mesenchymal stromal cells (MSCs) have been widely used in clinical trials for various diseases, due to their broad differentiation potential and effective immunomodulatory effects. However, the cell death profiles of MSC subsets remain inadequately characterized. In this study, we unexpectedly identified unique differentially expressed ferroptotic genes in MSC subsets from four different tissues (adipose, bone marrow, dermis, and umbilical cord) and revealed a critical role of ferroptosis in umbilical cord derived MSCs (UC-MSCs). Furthermore, increased ferroptosis level and ferroptosis sensitivity were detected in the C1 subset of UC-MSCs, and the upregulation in the ferroptosis level and sensitivity was examined during an expansion of UC-MSCs with the treatment with an ferroptosis inducer. In addition, we detected an increase in the proportion of C1 UC-MSCs after treatment with a ferroptosis inducer (Erastin) or inhibitor (Fer-1). Overall, this study further revealed the intricate nature of MSCs and will help facilitate the use of optimal subtypes to improve their clinical efficacy in the future.
Insights
Mesenchymal stromal cells (MSCs) exhibit unique ferroptosis gene profiles. Umbilical cord MSCs (UC-MSCs), particularly the C1 subset, show increased ferroptosis, impacting their clinical applications.
Area of Science:
- Cell Biology
- Immunology
- Regenerative Medicine
Background:
- Mesenchymal stromal cells (MSCs) are utilized in clinical trials for their differentiation and immunomodulatory properties.
- Characterization of cell death pathways, specifically ferroptosis, in MSC subsets is crucial for understanding their behavior.
- Umbilical cord-derived MSCs (UC-MSCs) are a promising cell source, but their ferroptosis profiles require detailed investigation.
Purpose of the Study:
- To investigate the ferroptosis profiles of MSC subsets from various tissues.
- To elucidate the role of ferroptosis in UC-MSCs, particularly the C1 subset.
- To assess the impact of ferroptosis modulation on UC-MSC populations.
Main Methods:
- Analysis of differentially expressed ferroptotic genes in MSC subsets from adipose, bone marrow, dermis, and umbilical cord tissues.
- Assessment of ferroptosis levels and sensitivity in UC-MSC subsets.
- Treatment of UC-MSCs with ferroptosis inducers (Erastin) and inhibitors (Fer-1) during expansion.
Main Results:
- Unique ferroptotic gene expression patterns were identified across different MSC tissue origins.
- The C1 subset of UC-MSCs demonstrated significantly increased ferroptosis levels and sensitivity.
- Expansion of UC-MSCs with ferroptosis modulators altered the proportion of C1 UC-MSCs.
Conclusions:
- Ferroptosis plays a critical role in UC-MSCs, especially the C1 subset.
- Understanding MSC ferroptosis is essential for optimizing cell-based therapies.
- Targeting ferroptosis may allow for the selection and expansion of specific MSC subtypes for improved clinical efficacy.

