Age-related inflammation triggers skeletal stem/progenitor cell dysfunction

Abstract

Aging is associated with impaired tissue regeneration. Stem cell number and function have been identified as potential culprits. We first demonstrate a direct correlation between stem cell number and time to bone fracture union in a human patient cohort. We then devised an animal model recapitulating this age-associated decline in bone healing and identified increased cellular senescence caused by a systemic and local proinflammatory environment as the major contributor to the decline in skeletal stem/progenitor cell (SSPC) number and function. Decoupling age-associated systemic inflammation from chronological aging by using transgenic Nfkb1KO mice, we determined that the elevated inflammatory environment, and not chronological age, was responsible for the decrease in SSPC number and function. By using a pharmacological approach inhibiting NF-κB activation, we demonstrate a functional rejuvenation of aged SSPCs with decreased senescence, increased SSPC number, and increased osteogenic function. Unbiased, whole-genome RNA sequencing confirmed the reversal of the aging phenotype. Finally, in an ectopic model of bone healing, we demonstrate a functional restoration of regenerative potential in aged SSPCs. These data identify aging-associated inflammation as the cause of SSPC dysfunction and provide mechanistic insights into its reversal. regeneration | skeletal stem cell | senescence | inflammation | bone healing

Maresin 1 resolves aged‐associated macrophage inflammation to improve bone regeneration

“…In advanced age, this inflammatory phase is protracted impeding proper osteoblast differentiation and leading to diminished fracture healing which manifests as delayed bone union, increased rates of re-fracture, failure of orthopedic implants, and nonunion of acute fractures. 1,[5][6][7]10 Here, we present a potentially therapeutic intervention which involves a reversal of inflammaging shortly after injury by actively shifting pro-inflammatory macrophage signaling to anti-inflammatory macrophage using a small molecule naturally occurring in macrophages.…”

“…Chronic increase in the number of inflammatory cells and the amount of inflammatory cytokines has been linked to dysfunctional cellular differentiation and dysregulated matrix production at the site of tissue injury. 1,2 This phenomenon has been identified as a potential cause of the dysregulated tissue repair and decreased regeneration capacity after acute injury in advanced age. 3,4 Bone fracture healing is one regenerative process hindered by inflammaging.…”

Skeletal stem cells: insights into maintaining and regenerating the skeleton

“…Further, several groups have recently shown that dysfunction in the niche can lead to skeletal dysfunction. For example, inflammation via enhanced NF-κB and TNFα signaling reduces SSC abundance and function but can be counteracted pharmacologically to rejuvenate SSCs to improve fracture healing in models of aging and diabetes (Josephson et al, 2019;Tevlin et al, 2017). Thus, gaining a better understanding of the niche factors required for healthy SSC biology is an important direction of research.…”

The Roles of H19 in Regulating Inflammation and Aging

“…Age-associated inflammation is the main reason for stem cell dysfunction. This linkage is mediated by NF-kB and another inflammation signaling (116,117). H19 promotes the osteogenic differentiation of osteoblast cells through the MiR-675/smad3 pathway.…”