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Dr.
Amer Mahmood, Assistant Professor/Scientist, King Saud University
The ability of bone marrow stromal cells (BMSCs; also known as mesenchymal stem cells and skeletal stem cells) to differentiate into various mesoderm-type cells, including osteoblastic cells osteoblasts (Bianco et al., 2008; Abdallah et al., 2008) is being exploited in cell-based therapy for repair of bone defects (Robey et al., 2006, Larsen et al., 2009). However, the molecular phenotype of ex vivo BMSCs predicting their bone-forming capacity is not yet well elucidated. The ability of cells to form mineralized matrix ex vivo and express number of biomarkers relevant for bone formation (e.g. production of alkaline phosphatase (ALP), type I collagen (ColI), osteopontin (OP), bone sialoprotein (BSP), and osteocalcin (OC)), is a conventional method to characterize the ex vivo osteoblastic phenotype (Aubin et al., 2002), although it is not an efficient predictive tool of the in vivo bone-forming capacity (Kuznetsov et al., 1997). Large-scale methods for gene profiling using DNA microarrays is used to define the phenotype of ex vivo cultured cell populations in terms of expression of a large number of genes, that is, “molecular signature,” (Scheideler et al., 2008). Thus, the efficient use of hBMSCs in therapy requires identification of an ex vivo cellular molecular phenotypic and biomarkers associated with commitment of hBMSCs to the osteoblastic cell lineage.
Trans-differentiation is a process whereby a cell type committed to a specific developmental lineage switches into another cell type of a different lineage through genetic reprogramming. In vivo transplantation studies showed that adult MSCs were able to differentiate into mesoderm-derived cells, in addition to cells with neuroectodermal and endodermal characteristics, suggesting that trans-differentiation occurs in mammalian systems (Song and Tuan, 2004). However, it is not well elucidated the molecular phenotypes that regulate the trans-differentiation of pre-committed hBMSCs to a given mesenchymal cell lineage in response to inductive extracellular cues. Understanding the process of trans-differentiation between osteoblasts and adipocytes is important to identify genes and other factors that may contribute to the pathophysiology of bone or joint disorders. Any disturbance of the balance between osteogenesis and adipogenesis may lead to metabolic diseases such as obesity, and diabetes. Therefore therapeutic interventions must focus on manipulating the "thin line" between osteoblastogenesis and adipogenesis.
SIRT1 is required for oncogenic transformation of neural stem cells and for the survival of “cancer cells with neural stemness” in a p53-dependent manner
Jeongrak Park, Student, Sogang University
Cancer stemness, observed in several types of glioma stem cells (GSCs), has been demonstrated to be an important barrier for efficient cancer therapy. We have previously reported that cancerous neural stem cells (F3.Ras.CNSCs), derived from immortalized human neural stem cells by a single oncogenic stimulation, form glial tumors in vivo. We searched for a commonly expressed stress modulator in both F3.Ras.CNSCs and GSCs and identified silent mating type information regulation 2, homolog (SIRT1) as a key factor in maintaining cancer stemness. We demonstrate that the expression of SIRT1, expressed in “cancer cells with neural stemness,” is critical not only for the maintenance of stem cells, but also for oncogenic transformation. Interestingly, SIRT1 is essential for the survival and tumorigenicity of F3.Ras.CNSCs and GSCs but not for the U87 glioma cell line. These results indicate that expression of SIRT1 in cancer cells with neural stemness plays an important role in suppressing p53- dependent tumor surveillance, the abrogation of which may be responsible not only for inducing oncogenic transformation but also for retaining the neural cancer stemness of the cells, suggesting that SIRT1 may be a putative therapeutic target in GSCs.
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