Figure 7.

Molecular model of senescence of hMSC and its relation to tumorigenesis processes based on differential gene expression. In the 18th passage there was a predominance of cells exhibiting the phenotypic characteristics of senescence. These cells showed significant changes in gene expression. Of the 18 genes found (box of molecular signature, above left), 11 are new candidates for senescence markers in hMSCs derived from human umbilical cord vein (underlined genes). Throughout the cultivation of these cells, chromosome changes associated with senescence (as endoreduplication) and giant cell tumor of bone (GCTB) (as ‘tas’ and amplification of 20q) were also found predominantly in the cells with constitutional karyotype alterations (hMSC/inv) (provided by Cornélio et al. in preparation). Molecules known to be involved in the secretory-associated senescence phenotype (SASP) associated with tumorigenesis were identified mainly in senescent hMSCs/inv (table in the right corner). Four of these molecules are specifically associated with giant cell tumor of bone (GCTB): MMP1, CXCL12, LAMA5, and TGFB1 (underlined in the table in the right corner). The senescent hMSCs/n and hMSCs/inv survived until the 24th passage without any spontaneous transformation. Thus, we hypothesize that cells with this expression profile in hostile microenvironments of tissue injury, inflammation, or stress may generate an imbalance favoring re-entry into the cell cycle and starting tumor formation of mesenchymal origin, such as in GCTB.