Molecular Characterization of Differentiated-Resistance MSC Subclones by Single-Cell Transcriptomes

Area of Science:

• Stem cell biology
• Cancer research
• Molecular oncology

Background:

• Mesenchymal stem cells (MSCs) have potential therapeutic applications, but their tumorigenicity mechanism is unclear, limiting clinical efficacy.
• Subclones within MSC populations may contribute to tumorigenicity, necessitating single-cell level investigation.

Purpose of the Study:

• To investigate the role of MSC subclones in tumorigenicity using single-cell transcriptomics.
• To identify molecular pathways associated with differentiation-resistant MSCs (DR-MSCs) and their potential carcinogenic role.

Main Methods:

• Single-cell RNA sequencing of MSCs during osteogenic differentiation.
• Analysis of the yes-associated protein 1 (YAP1) network and inhibition using Verteporfin.
• Correlation analysis of YAP1, OCT4, and CDH6 expression in clinical cancer data.

Main Results:

• Single-cell analysis revealed distinct MSC clusters: differentiation-resistant MSCs (DR-MSCs), precursor osteoblasts (PO), and differentiated osteoblasts (DO).
• DR-MSCs exhibited upregulated expression of YAP1, OCT4, and CDH6, resembling cancer-initiating cells.
• YAP1 inhibition suppressed DR-MSC characteristics, reduced YAP1, OCT4, and CDH6 expression, and inhibited cancer cell viability.

Conclusions:

• Single-cell sequencing identified a carcinogenic pathway in differentiation-resistant MSC subclones.
• Upregulation of YAP1, OCT4, and CDH6 in DR-MSCs is a key driver of MSC-involved tumorigenicity.
• Targeting YAP1 presents a potential therapeutic strategy for cancers involving MSCs.