Rejuvenating Strategies for Stem Cell-Based Therapies in Aging

Abstract

Recent advances in our understanding of tissue regeneration and the development of efficient approaches to induce and differentiate pluripotent stem cells for cell replacement therapies promise exciting avenues for treating degenerative age-related diseases. However, clinical studies and insights from model organisms have identified major roadblocks that normal aging processes impose on tissue regeneration. These new insights suggest that specific targeting of environmental niche components, including growth factors, ECM, and immune cells, and intrinsic stem cell properties that are affected by aging will be critical for the development of new strategies to improve stem cell function and optimize tissue repair processes.

Fig. 1. Intrinsic regulators of SC function and their dysregulation with aging

The figure summarizes molecular interactions identified independently in multiple systems, and these interactions are depicted in a generic cell type when not specified. Quiescent SC (middle panel): p16 is upregulated in old satellite cells and HSCs. In satellite cells the epigenetic de-repression of the INK4A locus (loss of Bmi1) is a consequence of accumulated ROS due to mTOR-dependent inhibition of the autophagic flux. An increase in p38 signaling further contributes to p16 induction in old satellite cells. In HSCs, p16 induction is a consequence of DNA damage and telomere shortening. Both satellite cells and HSCs display changes in epigenetic marks with aging. Moreover, Mesenchymal stem cells display a generalized reduction in the heterochromatin-associated H3K9me3 with age. Differentiation (top panel): In old HSCs, elevated Cdc42 leads to cell polarity defects that favor self-renewal expansion at the expense of differentiation. Upon regenerative pressure, old satellite cells show unbalanced self-renewal and differentiation due to increased symmetric divisions. Symmetric segregation of p38 signaling in old satellite cells, due to p38 hyperactivation or altered β1-integrin activity and insensitivity to Fgf2, prevents asymmetric division and leads to stem cell exhaustion by differentiation. Activation (bottom panel): Upon proliferative pressure, these changes result in satellite cell senescence as well as HSC senescence and apoptosis.