Abstract
The direct reprogramming of somatic cells is a promising approach for regenerative medicine, especially in the production of mesoderm layer-derived cells. Meta-analysis studies provide precise insight into the undergoing processes and help increase the efficiency of reprogramming. Here, using 27 high-throughput expression data sets, we analyzed the direct reprogramming of mesodermal cells in humans and mice. Fibroblast-derived cells showed a common expression pattern of up- and down-regulated genes that were mainly involved in the suppression of the fibroblast-specific gene expression program, and may be used as markers of the initiation of reprogramming. Furthermore, we found a specific gene expression profile for each fibroblast-derived cell studied, and each gene set appeared to play specific functional roles in its cell type, suggesting their use as markers for their mature state. Furthermore, using data from protein-DNA interactions, we identified the main transcription factors (TFs) involved in the conversion process and ranked them based on their importance in their gene regulatory networks. In summary, our meta-analysis approach provides new insights on the direct conversion of mesodermal somatic cells, introduces a list of genes as markers for initiation and maturation, and identifies TFs for which manipulating their expression may increase the efficiency of direct conversion.
Highlights
The mesoderm is the middle layer of three primary embryonic germ layers, and forms vital organs such as the heart, blood, and bones
We investigated the direct conversion of human fibroblasts to five different cell types, and for each conversion, we identified an overall list of differentially expressed genes (DEGs), a list of genes that expressed solely in one cell type that we believe could be used as markers to follow process of the direct conversion, we found the DE-transcription factors (TFs) that control the expression of DEGs and ranked them based on centrality analysis of the gene regulatory network (GRN), and we revealed the most affected biological processes for each conversion
We presented the direct reprogramming of human fibroblasts to osteoblasts, multilineage blood progenitors (MBPs), monocytic phagocytes, endothelial cells, and cardiomyocytes, and in the second section, we analyzed various somatic cell conversions in the mesoderm layer from non-fibroblastic cells, with specific attention to the conversion of mouse pre-B cells to macrophages
Summary
The current study deals with the direct reprogramming of mesodermal layer cells to each other through the meta-analysis of the gene expression profiles of cells obtained from high-throughput transcriptome profiling experiments. We used 27 publicly available human and mouse data sets corresponding to mesodermal cell direct cell lineage conversions (Table 1). We considered the direct reprogramming of fibroblasts to osteoblasts, multilineage blood progenitors (MBP), endothelial cells, monocytic phagocytes, and cardiomyocytes in humans (Fig. 1). Expression data sets that have studied the direct conversion of fibroblasts to other somatic cells by different protocols are publicly available. By analyzing and comparing nine expression data sets for the direct conversion of human fibroblast to osteoblasts, MBP, endothelial cells, monocytic phagocytes, and cardiomyocytes, we found that 379 genes had the same expression pattern in at least eight out of nine data sets (Fig. 2a). GATA4, MEF2C, TBX5, MESP1 and MYOCD TFS and miR-133 along with SNAI1 suppression were used to convert fibroblasts to Cardiomyocytes. Gata[4], Hand[2], Mef2c, Tbx[5], and Myocardin were used to convert fibroblasts to Cardiomyocytes
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