Human HOXA9 Lentivirus (CMV)

Stem cell function declines during aging, and this decline contributes to aging-associated tissue regeneration and dysfunction. Hox genes are key regulators of stem cell and tissue patterning during embryogenesis, and their roles in aging are poorly understood. Here, researchers show that the epigenetic stress response of muscle stem cells, also known as satellite cells, differs between old and young mice. This alteration includes an aberrant global and site-specific induction of active chromatin marks in activated satellite cells of old mice, leading to the specific induction of Hoxa9, but not other Hox genes. Hoxa9, in turn, activates several developmental pathways and is a defining factor in satellite cell gene expression that distinguishes old from young mice. The activated pathways include most currently known inhibitors of satellite cell function in aged muscle, including Wnt, TGFβ, JAK/STAT, and senescence signaling. Inhibition of aberrant chromatin activation or loss of Hoxa9 improves satellite cell function and muscle regeneration in old mice, while overexpression of Hoxa9 mimics aging-associated defects in satellite cells of young mice, which can be rescued by inhibition of developmental pathways targeted by Hoxa9.

By analysing the downstream effects of Hoxa9 induction through lentiviral-mediated Hoxa9 overexpression, researchers found a strong reduction in the colony forming and proliferative capacity of SCs from young adult mice (Figure 1a–c). The overexpression of other Hox genes exerted similar effects (Figure 1d), but the results with Hoxa9 may be most relevant to physiological aging, as only Hoxa9 was upregulated in activated SCs from aged mice. The impaired myogenic capacity of SCs in response to Hoxa9 overexpression was associated with increased rates of apoptosis and decreased cell proliferation (Figure 1e–h). Furthermore, Hoxa9 induction was associated with the repression of several cell cycle regulators and the induction of cell cycle inhibitors and senescence-induced genes (Figure 1i) as well as with increased staining for senescence-associated β-galactosidase (Figure 1j, k).

Figure 1. Overexpression of Hox genes inhibits SC function. (Schwoerer S, et al., 2016)