Epigenetic stress responses induce muscle stem cell aging by Hoxa9 developmental signals [microarray]

Background and Aims: Analysis of aging-induced impairments in satellite cells (SCs) – the stem cells of skeletal muscle that are required for its regeneration. Hox genes are known to control stem cell function and development of various tissues. Methods: We used AlfpCre mice for liver specific deletion of Trp53 in a conditional knockout mouse model to analyze liver carcinogenesis. Results: Here, we show that liver-specific deletion of p53 in mice consistently induces formation of liver carcinoma depicting bilineal differentiation. Freshly isolated p53-/- liver progenitor cells and hepatocytes exhibit chromosomal imbalances and an enhanced clonogenic capacity compared to p53-positive cells or p21-deficient cells. Primary cultures of hepatocytes and liver progenitor cells from p53-/- mice formed tumors with bilineal differentiation when transplanted into immuno-compromised mice. Together, these results indicate that loss of p53 alone is sufficient to induce primary liver cancer with bilineal differentiation originating from chromosomal instable cultured liver progenitor cells or hepatocytes. Conclusions: The study shows that p53-dependent checkpoints inhibit transformation of liver progenitor cells and hepatocytes involving p21-independent mechanisms. In this study the function of the Hoxa9 was analyzed in murine satellite cells. Satellite cells derived from young adult (3-4 month old) C57BL/6J mice were FACS sorted, cultured and transduced with lentiviral particles in order to induce Hoxa9 overexpression. RNA was extracted. Agilent Mouse 8x60K arrays were used.