A high-throughput screening study of stem cells in hemangioma formation

Infantile hemangioma (IH) is the most common tumor of infancy. The goal of this investigation is to understand the process of hemangioma-genesis by characterizing the progenitor hemangioma-derived stem cell (HemSC) and its lineage and non-lineage specific derivatives. For this purpose, a high-throughput screening (HTS) was performed to study the role of stem cells in IH formation with the following specific aims: 1) HT phenotypic analysis (HTS for biomarkers based on cellular phenotype - monoclonal antibody cell-surface marker screening panel and bioimaging), and 2) HT gene expression analysis (whole genome oligo microarrays, qPCR, and microfluidic single-cell gene expression) to provide distinct gene set signatures for diagnostic assays and drug targeting.;The hypothesis is that the HemSC is a vascular stem/progenitor cell whose proliferation is dysregulated, but not a fully transformed cell, which orchestrates hemangioma pathophysiology via a sophisticated activation of multiple signaling and regulatory networks.;The results show that relative to normal human umbilical vein endothelial cells (HUVEC), HemSCs are characterized by higher expression of genes involved in vasculogenesis and associated signaling pathways. At the single-cell level, HemSCs show variability in gene expression (transcriptional bursts and unidentified lineage-specific subpopulations may account for the variability). Gene expression was confirmed by phenotypic expression of specific cell surface markers.;When a stem cell is dysregulated, the cell remains in an immature, arrested stage of development. The results of this study indicate that if IH does indeed derive from a dysregulated stem cell arrested at an early stage of development, further identification and characterization of the HemSCs - cellular precursors of IH tumor formation - will lead to practical implications for clinical application. By identifying the transcriptional and epigenetic dynamics of the dysregulated stem cell, a therapeutic approach can be developed to "rewire" or redirect cellular transitions at an early stage.