Human Mesenchymal Stem Cells-mediated Transcriptomic Regulation of Leukemic Cells in Delivering Anti-tumorigenic Effects

Abstract

Treatment of leukemia has become much difficult because of resistance to the existing anticancer therapies. This has thus expedited the search for alternativ therapies, and one of these is the exploitation of mesenchymal stem cells (MSCs) towards control of tumor cells. The present study investigated the effect of human umbilical cord-derived MSCs (UC-MSCs) on the proliferation of leukemic cells and gauged the transcriptomic modulation and the signaling pathways potentially affected by UC-MSCs. The inhibition of growth of leukemic tumor cell lines was assessed by proliferation assays, apoptosis and cell cycle analysis. BV173 and HL-60 cells were further analyzed using microarray gene expression profiling. The microarray results were validated by RT-qPCR and western blot assay for the corresponding expression of genes and proteins. The UC-MSCs attenuated leukemic cell viability and proliferation in a dose-dependent manner without inducing apoptosis. Cell cycle analysis revealed that the growth of tumor cells was arrested at the G0/G1 phase. The microarray results identified that HL-60 and BV173 share 35 differentially expressed genes (DEGs) (same expression direction) in the presence of UC-MSCs. In silico analysis of these selected DEGs indicated a significant influence in the cell cycle and cell cycle-related biological processes and signaling pathways. Among these, the expression of DBF4, MDM2, CCNE2, CDK6, CDKN1A, and CDKN2A was implicated in six different signaling pathways that play a pivotal role in the anti-tumorigenic activity exerted by UC-MSCs. The UC-MSCs perturbate the cell cycle process of leukemic cells via dysregulation of tumor suppressor and oncogene expression.

Possible Therapeutic Role of Bone Marrow-Derived Mesenchymal Stem Cells in a Rat Model of Hepatocellular Carcinoma

“…Notably, treating HCC with MSCs alone or in combination with 5FU predominantly arrest the cell cycle progression of tumor cells in the G0/G1 phase of the cell cycle, and thus fewer cells proceeded to the subsequent S and G2/M phases. The observed disruption of cell cycle progression in the tumor cells suggests that treatment with MSCs leads to potent growth inhibition of tumor cells without being subject to apoptosis (Sarmadi, Ahmadloo et al 2020).…”

Identification of molecularly unique tumor-associated mesenchymal stromal cells in breast cancer patients

“…The role of MSCs in tumorigenesis is subject to discussion, as several studies have demonstrated that MSCs have a protective or tumor-suppressive role [38][39][40][41]. Others have demonstrated that MSCs may aid, promote and direct tumor formation in a wide range of primary tumors [42][43][44][45][46].…”

The Dual Role of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Carcinogenesis

“…Sarmadi et al showed that human umbilical cord MSCs affected the proliferation of leukemic cells—the growth of tumor cells was stopped at the G0/G1 phase. This result may be associated with the impaired expression of genes encoding cell cycle regulators, such as cell division protein kinase 6 (CDK6), cyclin E2 (CCNE2), cyclin-dependent kinase inhibitor (CDKN) 1A, CDKN2A, dumbbell former 4 protein (DBF4), mouse double minute 2 homolog (MDM2), proteasome activator complex subunit 3 (PSME3), and G0/G1 switch 2 (G0S2) [ 81 ].…”