Intrinsic regulation of hemangioma involution by platelet-derived growth factor

Infantile hemangioma is a vascular tumor that exhibits a unique natural cycle of rapid growth followed by involution. Previously, we have shown that hemangiomas arise from CD133+ stem cells that differentiate into endothelial cells when implanted in immunodeficient mice. The same clonally expanded stem cells also produced adipocytes, thus recapitulating the involuting phase of hemangioma. In the present study, we have elucidated the intrinsic mechanisms of adipocyte differentiation using hemangioma-derived stem cells (hemSCs). We found that platelet-derived growth factor (PDGF) is elevated during the proliferating phase and may inhibit adipocyte differentiation. hemSCs expressed high levels of PDGF-B and showed sustained tyrosine phosphorylation of PDGF receptors under basal (unstimulated) conditions. Inhibition of PDGF receptor signaling caused enhanced adipogenesis in hemSCs. Furthermore, exposure of hemSCs to exogenous PDGF-BB reduced the fat content and the expression of adipocyte-specific transcription factors. We also show that these autogenous inhibitory effects are mediated by PDGF receptor-β signaling. In summary, this study identifies PDGF signaling as an intrinsic negative regulator of hemangioma involution and highlights the therapeutic potential of disrupting PDGF signaling for the treatment of hemangiomas

Genome-Wide Profiling of MicroRNAs in Adipose Mesenchymal Stem Cell Differentiation and Mouse Models of Obesity

In recent years, there has been accumulating evidence that microRNAs are key regulator molecules of gene expression. The cellular processes that are regulated by microRNAs include e.g. cell proliferation, programmed cell death and cell differentiation. Adipocyte differentiation is a highly regulated cellular process for which several important regulating factors have been discovered, but still not all are known to fully understand the underlying mechanisms. In the present study, we analyzed the expression of 597 microRNAs during the differentiation of mouse mesenchymal stem cells into terminally differentiated adipocytes by real-time RT-PCR. In total, 66 miRNAs were differentially expressed in mesenchymal stem cell-derived adipocytes compared to the undifferentiated progenitor cells. To further study the regulation of these 66 miRNAs in white adipose tissue in vivo and their dependence on PPARγ activity, mouse models of genetically or diet induced obesity as well as a mouse line expressing a dominant negative PPARγ mutant were employed

Mammalian Stem Cells Reprogramming in Response to Terahertz Radiation

We report that extended exposure to broad-spectrum terahertz radiation results in specific changes in cellular functions that are closely related to DNA-directed gene transcription. Our gene chip survey of gene expression shows that whereas 89% of the protein coding genes in mouse stem cells do not respond to the applied terahertz radiation, certain genes are activated, while other are repressed. RT-PCR experiments with selected gene probes corresponding to transcripts in the three groups of genes detail the gene specific effect. The response was not only gene specific but also irradiation conditions dependent. Our findings suggest that the applied terahertz irradiation accelerates cell differentiation toward adipose phenotype by activating the transcription factor peroxisome proliferator-activated receptor gamma (PPARG). Finally, our molecular dynamics computer simulations indicate that the local breathing dynamics of the PPARG promoter DNA coincides with the gene specific response to the THz radiation. We propose that THz radiation is a potential tool for cellular reprogramming