Abstract 1445: Angiogenesis and Survival Potential of Mesenchymal Stem Cells Declines with Age Due to Decreased Expression of Pro-Angiogenic Genes
Clinical trials of autologous bone marrow derived stem cells (BMDSC) for the treatment of ischemic cardiovascular disease have confirmed a therapeutic benefit but in most cases the improvements have been modest. One reason for this may be that BMDSCs from aged subjects with coronary artery disease are less effective in repair and consequently therapy than those from younger healthy subjects. This is supported by clinical data but the molecular basis has not been determined. An essential feature of BMDSC therapy is the promotion of new blood vessel growth, a function that requires secretion of pro-angiogenic cytokines from the cells at sites of injury. We hypothesize that aging reduces the expression of pro-angiogenic and survival genes, reducing the therapeutic potential of autologous BMDSC in elderly subjects. Bone marrow mesenchymal cells were isolated from mice (4 per group) at age 2mo, 8mo and 26mo and replicate mRNA samples were subjected to microarray and real time (RT) PCR analysis. Microarray results indicated over 2000 down-regulated (t-test <2-fold; p<0.01) and over 2000 (t-test <2-fold; p<0.01) up-regulated transcripts associated with aging. In the angiogenesis category, the most dramatic change was on the level of HGF (272-fold decrease; p<0.001). There were also significant decreases in the levels of IGF-1 (26-fold decrease; p<0.001) Angiopoietin 1 (3-fold decrease; p<0.001), and VEGF A and C (4-fold and 2-fold decrease respectively; p<0.001). Interestingly the differentiation-associated genes BNP4 and Notch1 were significantly up-regulated during aging (15 and 5-fold respectively; p<0.001) and cells from all groups demonstrated similar potential for osteogenic differentiation. These studies demonstrate for the first time that mesenchymal stem cells from the BM suffer a dramatic loss of survival and pro-angiogenic genes during aging. This supports our hypothesis that autologous BMDSCs from aged subjects are therapeutically defective.