Disruption of TNF-α signaling improves osteoblastic differentiation of adipose-derived mesenchymal stem cells and bone repair.

Autor: Bighetti-Trevisan RL; Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Bueno NP; School of Dentistry, University of São Paulo, São Paulo, São Paulo, Brazil., Souza ATP; Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Marques MM; Aachen Dental Laser Centre - Sigmund Freud University, Austria Campus Prater, Vienna, Austria., Rosa AL; Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Beloti MM; Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Ferraz EP; Bone Research Lab, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.; School of Dentistry, University of São Paulo, São Paulo, São Paulo, Brazil.
Jazyk: angličtina
Zdroj: Biotechnology and bioengineering [Biotechnol Bioeng] 2023 Oct; Vol. 120 (10), pp. 3067-3078. Date of Electronic Publication: 2023 Jun 15.
DOI: 10.1002/bit.28468
Abstrakt: Adipose tissue is an attractive source of mesenchymal stem cells (at-MSCs), but their low osteogenic potential limits their use in bone regeneration. Adipose tissue plays a role in pro-inflammatory diseases by releasing cytokines with a catabolic effect on bone, such as tumor necrosis factor-alpha (TNF-α). Thus, we hypothesized that endogenous TNF-α could have a negative effect on at-MSC differentiation into osteoblasts. Short interfering RNAs (siRNAs) targeting TNF-α receptors (siR1, siR2, and si1R/R2) were transfected into at-MSCs, and cell differentiation was assessed by measuring the expression of bone markers, ALP activity, and mineralized matrix. Scrambled was used as Control. Knockout at-MSCs (KOR1/R2) was injected in mice calvaria defects, and bone formation was evaluated by microtomography and histological analysis. Data were compared by Kruskal-Wallis or analysis of variance (5%). The expression of bone markers confirmed that at-MSCs differentiate less than bone marrow MSCs. In silenced cells, the expression of Alp, Runx2, and Opn was generally higher compared to Control. ALP, RUNX2, and OPN were expressed at elevated levels in silenced groups, most notably at-MSCs-siR1/R2. ALP was detected at high levels in at-MSCs-siR1/R2 and in-MSCs-siR1, followed by an increase in mineralized nodules in at-MSCs-siR1/R2. As the morphometric parameters increased, the groups treated with KOR1/R2 exhibited slight bone formation near the edges of the defects. Endogenous TNF-α inhibits osteoblast differentiation and activity in at-MSCs, and its disruption increases bone formation. While opening a path of investigation, that may lead to the development of new treatments for bone regeneration using at-MSC-based therapies.
(© 2023 Wiley Periodicals LLC.)
Databáze: MEDLINE
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