HSC Aging and Senescent Immune Remodeling

Abstract

Aging-associated changes in the function of the immune system are referred to as senescent immune remodeling (SIR). Here we review the current understanding on the cellular and molecular mechanisms underlying SIR. We focus on aging-associated changes in T and B cells, and discuss recent evidence supporting the notion that aging of the hematopoietic stem cell (HSC) compartment directly contributes to SIR due to aging-associated alterations in stem cell differentiation. We conclude by outlining strategies to attenuate SIR, including approaches to rejuvenate HSCs, which may open new avenues for targeting SIR in the clinic.

Figure 1. Senescent immune remodeling starts with aging of HSCs

Wnt signaling in old HSCs switches from a canonical β-catenin-dependent pathway to a non-canonical pathway associated mainly to Wnt5a [69]. This again increases the activity of the small RhoGTPase CDC42 and results in an increase of Ca²⁺ (or induction of JNK pathways) to regulate transcription factors such as NFAT. There seems to be a substantial Wnt/NOTCH crosstalk resulting in upregulated intrinsic NOTCH signaling and less polarity. Apolarity might be linked to the mode of the cell division and thus fate of the daughter cells. These changes in polarity could also be influenced by the down-regulation of the global chromatin regulator Satb1 upon aging [96] and changes of cytokines in the niche (i.e. CXCL12) [97]. Potential modification targets that have been identified so far are CDC42 inhibitor (CASIN)[54], Sat1b [96], Wnt pathways [67, 69, 98] or Calcium signaling (i.e. via for example physical activity [98]). With respect to later stages in T-cell development, certain cytokines such as IL-7, IL-12, IL-15 or IL-22 and growth factors such as KGF (important for the stability of the thymic microenvironment) have been introduced as potential targets for restoring T-cell function, immunity and response to vaccination [14]. Notably, in these stages, Sat1b also seems to be crucial for Th2-type T-cell development in a (canonical) Wnt-dependent manner [99]. Potential novel and currently used targets for attenuation of SIR are marked in green.