Research Paper Volume 15, Issue 5 pp 1237—1256

Figure 1. Senescent MSC transcriptome regulates cell cycle, TGF-β, and vesicle-mediated pathways. Pre- and senescent MSC transcriptome pathway analysis was performed using Ingenuity Pathway Analysis (IPA). Pathways that were significantly regulated were reported using the (A) ‘Related Disease and Function Pathways’ and (B) ‘Standout Canonical Pathways’. Pathways that were reported in (A) and (B) have important overlapping implications. Activation z-scores showed positive enrichment in pathways such as formation of γH2AX in nucleus and cell cycle. These pathways can directly alter the development of senescence phenotype, cell cycle control of chromosomal replication, and kinetochore metaphase signaling. Physical characteristics of cellular movement, growth, and proliferation were downregulated and can affect Wnt/β-Catenin canonical pathway. Cell signaling, morphology, and cancer pathways can correlate to canonical pathways of caveolar-mediated endocytosis, TGF-β, and p53 signaling. List of significantly regulated genes that play important roles in pathways of interest: (C) cell cycle regulation, (D) cell adhesion and focal adhesion, (E) TGF-β, and (F) caveolar-mediated. Senescent expression values were normalized to pre-senescent values. Fold changes are reported as log2 differences and genes were limited to those that were FDR < 25%, and p < 0.05. More comprehensive gene list for TGF-β and caveolar-mediated pathways (p < 0.05) are highlighted in the volcano plots (G). Green represents genes that were downregulated and red represents genes that were upregulated. Significant transcripts (p < 0.05) with FDR < 0.25 are represented by larger circles with black outlines, whereas significant transcripts (p < 0.05) that reported FDR > 0.25 are represented by smaller circles. Several of these genes include TGF-βR2, BMP2, and VAMP isoforms. Pre- and senescent MSC samples were processed (n = 4) and differentially regulated pathways were considered significant if p < 0.05.