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Decellularized Extracellular Matrix Mitigates the Senescent Phenotype and Restores Osteogenic Potential in Human
Connor J Dorais1, Nikolia M Kruger1,2, David H Ramos-Rodriguez1
1Department of Orthopaedic Surgery, UC Davis Health, Sacramento, California, USA.
Abstract:
Autologous cell-based approaches for bone repair using mesenchymal stromal cells (MSCs) in older patients are limited in part by cellular senescence, resulting in impaired MSC self-renewal and differentiation. Currently, the field lacks a standardized method to induce senescence in human MSCs and characterize them for experimental use, as well as effective strategies to mitigate the harmful effects of the senescence-associated secretory phenotype (SASP). We previously demonstrated that MSC-secreted decellularized extracellular matrix (dECM) enhances the osteogenic potential and survival of MSCs. We hypothesized that senescent MSCs would exhibit improved osteogenic potential and reduced SASP activity when maintained on dECM. We first demonstrated that a senescent phenotype can be reliably induced in human MSCs through ionizing irradiation coupled with a 21-day preconditioning phase in culture, evidenced by increased beta-galactosidase staining and enlarged cell area. We then observed that senescent MSCs on dECM exhibit improved osteogenic potential and reduced SASP compared to cells on tissue culture plastic, evidenced by quantifying markers of osteogenic differentiation and ELISAs for known inflammatory cytokines. These data support the promise of dECM as an instructive biomaterial to enhance the regenerative potential of MSCs from older patients for autologous bone repair.
Insights
Senescent mesenchymal stromal cells (MSCs) show enhanced bone repair potential on decellularized extracellular matrix (dECM). This biomaterial mitigates harmful effects, improving MSC function for older patients.
Area of Science:
- Biomaterials Science
- Regenerative Medicine
- Cell Biology
Background:
- Cellular senescence impairs mesenchymal stromal cell (MSC) function in older patients, limiting autologous bone repair.
- Standardized methods for inducing and characterizing MSC senescence and mitigating the senescence-associated secretory phenotype (SASP) are lacking.
- Previous work showed MSC-secreted decellularized extracellular matrix (dECM) enhances MSC osteogenic potential and survival.
Purpose of the Study:
- To investigate if senescent MSCs exhibit improved osteogenic potential and reduced SASP when cultured on dECM.
- To establish a reliable method for inducing senescence in human MSCs for experimental use.
- To evaluate dECM as a potential biomaterial for enhancing bone repair in older individuals.
Main Methods:
- Human MSCs were induced into senescence using ionizing irradiation and a 21-day preconditioning period.
- Senescence was confirmed by increased beta-galactosidase staining and enlarged cell area.
- Senescent MSCs were cultured on dECM and tissue culture plastic; osteogenic differentiation and SASP markers were quantified.
Main Results:
- A reliable method for inducing MSC senescence was established.
- Senescent MSCs cultured on dECM demonstrated enhanced osteogenic potential compared to those on tissue culture plastic.
- Culturing senescent MSCs on dECM led to a reduction in SASP, as evidenced by lower levels of inflammatory cytokines.
Conclusions:
- Decellularized extracellular matrix (dECM) shows promise as an instructive biomaterial for bone repair.
- dECM can enhance the osteogenic potential and reduce the detrimental SASP of senescent MSCs.
- This approach could improve autologous bone repair strategies for older patients by rejuvenating MSC function.
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