Abstract

Cancer-Associated Subclones Among Mesenchymal Stem Cells Revealed by Single-Cell Transcriptome Analyses

Jiang Zhong, Assistant Professor, University of Southern California

Despite the clinical benefits, detrimental effects of mesenchymal stem cells (MSCs) in clinical reports have been reported, in some cases fomenting tumorigenicity. Some of MSC subpopulations may be responsible for variation in the efficacy of bone marrow transplantation (BMT) and MSC-based therapy as well as tumorigenicity. Such heterogeneity of MSCs was not fully addressed until the arrival of the single-cell transcriptome technology. Recently, we report three discrete stages of osteogenesis based on a single-cell transcriptome analysis of individual MSCs during osteocyte differentiation. We identified a subpopulation of osteogenesis-resistant MSCs that have cancer stem cell characteristics. Further analysis indicated that the YAP1, ß-Catenin and Cadherin4/6 pathways involved in osteogenesis-resistance. Clinical surveys using 51 clinical databases across 6,965 patients revealed a correlation between YAP1/ ß-Catenin/Cadherin4/6 over-expression and cancer progression. This study suggested that a differentiation-resistant population of MSC with cancer stem cell characteristics is responsible for the tumorigenicity of MSC. Therefore, intervention of the YAP1, ß-Catenin and Cadherin4/6 pathway could potentially prevent tumorgenicity in MSC therapies by addressing the preexisting subpopulation of MSCs namely those differentiation-resistant populations associated with active YAP1-Cadherin pathway. Biologically active molecules targeting YAP1/ ß-Catenin/Cadherin could improve MSC therapy for a defined subset of patients by minimizing the tumorgenicity of MSCs.