Local Elimination of Senescent Cells Promotes Bone Defect Repair during Aging

Abstract

Due to the declined function of bone marrow mesenchymal stem cells (BMSCs), the repair of bone defects in the elderly is retarded. Elimination of senescent cells emerges as a promising strategy for treating age-related diseases. However, whether the local elimination of senescent BMSCs can promote bone regeneration in the elderly remains elusive. To tackle the above issue, we first screened out the specific senolytics for BMSCs and confirmed their effect of eliminating senescent BMSCs in vitro. Treatment with quercetin, which is determined the best senolytics for senescent BMSCs, efficiently removed senescent cells in the population. Moreover, the self-renewal capacity was restored as well as osteogenic ability of BMSCs after treatment. We then designed a microenvironment-responsive hydrogel based on the MMPs secreted by senescent cells. This quercetin-encapsulated hydrogel exhibited a stable microstructure and responsively released quercetin in the presence of senescence in vitro. In vivo, the quercetin-loaded hydrogel effectively cleared the local senescent cells and reduced the secretion of MMPs in the bone. Due to the removal of local senescent cells, the hydrogel significantly accelerated the repair of bone defects in the femur and skull of old rats. Taken together, our study revealed the role of removing senescent cells in bone regeneration and provided a novel therapeutic approach for bone defects in aged individuals.

Rejuvenation of Mesenchymal Stem Cells to Ameliorate Skeletal Aging

“…It may also be likely that bioengineered delivery vehicles will need to be combined with the senolytic agents to optimize the dosage and efficacy of this strategy. Recently, Xing et al reported quercetin delivered by hydrogel as an effective senolytic that locally eliminated senescent BM-MSCs in vitro and restored the self-renewal capacity as well as the osteogenic ability as a result [ 205 ].…”

Multi-Crosslinked Strong and Elastic Bioglass/Chitosan-Cysteine Hydrogels with Controlled Quercetin Delivery for Bone Tissue Engineering

“…When a hydrogel is employed as the carrier for the local administration of Que, the key issue concerned is how to efficiently load enough amount of Que into the hydrogel and manage its controlled and sustained release. Direct loading of Que into hydrogels with the aid of organic solvents such as ethanol and dimethyl sulfoxide has been explored [ 33 , 36 , 53 ]. In doing so, the organic solvent should be removed from the resulting hydrogels otherwise such Que-loaded hydrogels may cause potential side effects due to the solvent release; in addition, this kind of Que-loaded hydrogel usually shows a severe initial burst because in many cases, hydrogels constructed with natural polymers have limited ability to administer the controlled and sustained release of drugs or biomolecules [ 8 ].…”

“…In the present instance, Que was first loaded into ABG NPs and the resulting NPs were then embedded into CH-CY gels. In comparison to some Que-loaded hydrogels reported in the literature [ 33 , 36 , 53 , 54 , 55 ], presently developed Que-loaded composite hydrogels can fulfill several missions at the same time: (I) the Que-load in the composite gels can be tailored by altering either the Que-load in ABG NPs or the content of Que-loaded ABG NPs in the composite gels; (II) ABG NPs would contribute significantly to the mechanical enhancement of the composite gels; and (III) ABG NPs would cooperate with the gel matrix to synergistically modulate the release of Que. Figure 5 C presents the Que release profiles for GEL-1, GEL-2, and GEL-3 gels.…”

“…Quercetin (Que) is a kind of naturally sourced flavonoid compound and it shows a wide spectrum of biological activities [ 31 , 32 ], including antioxidation, anti-inflammation, anti-hypertension, anti-carcinogenicity, immunomodulatory actions, and so on. Que has also been used for bone repair due to its functions for promoting osteogenesis, anti-oxidation, anti-inflammation, and so on [ 33 , 34 , 35 , 36 , 37 , 38 ].…”

Cellular uptake and retention studies of silica nanoparticles utilizing senescent fibroblasts

“…The removal of senescent cells represents a paradigm shift in medicine 45 . Targeted selective killing of senescent cells using platforms based on nanomaterials has the potential to fight various age-related diseases [46][47][48][49][50] . A fundamental issue to advance on the application of nanomedicine tools onto aging is to understand how NPs uptake and accumulate under senescence conditions.…”