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Directed Differentiation of Primitive and Definitive Hematopoietic Progenitors from Human Pluripotent Stem Cells
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WNT and VEGF/PDGF signaling regulate self-renewal in primitive mesenchymal stem cells
Matteo Mazzella1, Keegan Walker1, Christina Cormier1
1Oakland University.
Research Square
|April 24, 2023
Summary
Mesenchymal stem cell (MSC) self-renewal is crucial for therapy but declines with propagation. Xeno-free medium preserves MSC self-renewal and differentiation potential by modulating key signaling pathways, unlike traditional serum media.
Area of Science:
- Stem Cell Biology
- Regenerative Medicine
Background:
- Therapeutic applications of multipotent mesenchymal stem cells (MSCs) are limited by poor growth and reduced self-renewal capacity during propagation.
- Understanding the molecular mechanisms governing MSC self-renewal is critical for improving cell-based therapies.
Approach:
- Primitive MSCs (pMSCs) were cultured in fetal bovine serum medium (FM) and xeno-free medium (XM) to low (P3) and high (P20) passages.
- Comprehensive characterization included morphology, cell surface marker expression, proliferation assays, telomerase activity, and trilineage differentiation.
- Transcriptome (RNA-seq) and nucleosome occupancy (MNase-seq) analyses were performed to investigate molecular changes.
Key Points:
- pMSCs in FM exhibited reduced self-renewal markers (CD90, CD49f), colony-forming efficiency, proliferation, and telomerase activity, with increased adipogenic differentiation.
- pMSCs in XM maintained fibroblastoid morphology, self-renewal capacity, and differentiation potential.
- XM-cultured pMSCs showed upregulated self-renewal and cell cycle genes, while FM-cultured cells displayed upregulated senescence genes. Nucleosome occupancy patterns correlated with these gene expression changes.
Conclusions:
- Xeno-free medium supports the long-term self-renewal and differentiation potential of primitive MSCs.
- WNT and VEGF/PDGF signaling pathways are implicated in maintaining MSC self-renewal.
- TGFβ and PI3K signaling pathways appear to induce senescence in MSCs.
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