Abstract
Human mesenchymal stem cells (MSCs) are adult multipotent stem cells which can be isolated from bone marrow, adipose tissue as well as other tissues and have the capacity to differentiate into a variety of mesenchymal cell types such as adipocytes, osteoblasts and chondrocytes. Differentiation of stem cells into mature cell types is guided by growth factors and hormones, but recent studies suggest that metabolic shifts occur during differentiation and can modulate the differentiation process. We therefore investigated mitochondrial biogenesis, mitochondrial respiration and the mitochondrial membrane potential during adipogenic differentiation of human MSCs. In addition, we inhibited mitochondrial function to assess its effects on adipogenic differentiation. Our data show that mitochondrial biogenesis and oxygen consumption increase markedly during adipogenic differentiation, and that reducing mitochondrial respiration by hypoxia or by inhibition of the mitochondrial electron transport chain significantly suppresses adipogenic differentiation. Furthermore, we used a novel approach to suppress mitochondrial activity using a specific siRNA-based knockdown of the mitochondrial transcription factor A (TFAM), which also resulted in an inhibition of adipogenic differentiation. Taken together, our data demonstrates that increased mitochondrial activity is a prerequisite for MSC differentiation into adipocytes. These findings suggest that metabolic modulation of adult stem cells can maintain stem cell pluripotency or direct adult stem cell differentiation.
Highlights
Human mesenchymal stem cells are adult multipotent stem cells that can be isolated from several tissues including bone marrow and adipose tissue
In mesenchymal stem cells (MSCs), a marked increase in mitochondrial mass and oxygen consumption was observed upon osteogenic differentiation, which is associated with the upregulation of the mitochondrial biogenesis regulator Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1a) and anti-oxidant enzymes such as catalase and superoxide dismutase 2 (SOD2) [13]
Human mesenchymal stem cells were cultured in adipogenic differentiation medium and showed robust Oil Red O staining after 21 days, indicated by the presence of lipid droplets and the formation of adipocytes (Figure 1A)
Summary
Human mesenchymal stem cells (hMSCs) are adult multipotent stem cells that can be isolated from several tissues including bone marrow and adipose tissue. Mitochondrial transfer from MSCs can increase alveolar epithelial cell survival after lipopolysaccharide challenge [3] and fusion between MSCs and cardiomyocytes leads to the development of cells with a cardiac progenitor phenotype, which is dependent on the transfer of functional MSC mitochondria [15].
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