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Ferulic acid promotes bone defect repair after radiation by maintaining the stemness of skeletal stem cells.

ABSTRACT: The reconstruction of irradiated bone defects after settlement of skeletal tumors remains a significant challenge in clinical applications. In this study, we explored radiation-induced skeletal stem cell (SSC) stemness impairments and rescuing effects of ferulic acid (FA) on SSCs in vitro and in vivo. The immunophenotype, cell renewal, cell proliferation, and differentiation of SSCs in vitro after irradiation were investigated. Mechanistically, the changes in tissue regeneration-associated gene expression and MAPK pathway activation in irradiated SSCs were evaluated. The regenerative capacity of SSCs in the presence of FA in an irradiated bone defect mouse model was also investigated. We found that irradiation reduced CD140a- and CD105-positive cells in skeletal tissues and mouse-derived SSCs. Additionally, irradiation suppressed cell proliferation, colony formation, and osteogenic differentiation of SSCs. The RNA-Seq results showed that tissue regeneration-associated gene expression decreased, and the Western blotting results demonstrated the suppression of phosphorylated p38/MAPK and ERK/MAPK in irradiated SSCs. Notably, FA significantly rescued the radiation-induced impairment of SSCs by activating the p38/MAPK and ERK/MAPK pathways. Moreover, the results of imaging and pathological analyses demonstrated that FA enhanced the bone repair effects of SSCs in an irradiated bone defect mouse model substantially. Importantly, inhibition of the p38/MAPK and ERK/MAPK pathways in SSCs by specific chemical inhibitors partially abolished the promotive effect of FA on SSC-mediated bone regeneration. In summary, our findings reveal a novel function of FA in repairing irradiated bone defects by maintaining SSC stemness and suggest that the p38/MAPK and ERK/MAPK pathways contribute to SSC-mediated tissue regeneration postradiation.

SUBMITTER: Liang JW

PROVIDER: S-EPMC8284777 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRepairing radiation-induced bone injuries remains a significant challenge in the clinic, and few effective medicines are currently available. Psoralen is a principal bioactive component of Cullen corylifolium (L.) Medik and has been reported to have antitumor, anti-inflammatory, and pro-osteogenesis activities. However, less information is available regarding the role of psoralen in the treatment of radiation-induced bone injury. In this study, we explored the modulatory effects of psoralen on skeletal stem cells and their protective effects on radiation-induced bone injuries.MethodsThe protective effects of psoralen on radiation-induced osteoporosis and irradiated bone defects were evaluated by microCT and pathological analysis. In addition, the cell proliferation, osteogenesis, and self-renewal of SSCs were explored. Further, the underlying mechanisms of the protective of psoralen were investigated by using RNA sequencing and functional gain and loss experiments in vitro and in vivo. Statistical significance was analyzed using Student's t test. The one-way ANOVA was used in multiple group data analysis.ResultsHere, we demonstrated that psoralen, a natural herbal extract, mitigated radiation-induced bone injury (irradiation-induced osteoporosis and irradiated bone defects) in mice partially by rescuing the stemness of irradiated skeletal stem cells. Mechanistically, psoralen restored the stemness of skeletal stem cells by alleviating the radiation-induced suppression of AKT/GSK-3β and elevating NRF2 expression in skeletal stem cells. Furthermore, the expression of KEAP1 in skeletal stem cells did not significantly change in the presence of psoralen. Moreover, blockade of NRF2 in vivo partially abolished the promising effects of psoralen in a murine model of irradiation-induced osteoporosis and irradiated bone regeneration.ConclusionsIn summary, our findings identified psoralen as a potential medicine to mitigate bone radiation injury. In addition, skeletal stem cells and AKT-GSK-3β and NRF2 may thus represent therapeutic targets for treating radiation-induced bone injury.

Project description:Background:The restoration and repair method in the clinic of delayed fracture healing and non-union after comminuted fractures are urgently needed to improve the prognosis of patients. The recruitment of endogenous stem cells has been considered a promising approach in bone defect repair. Propose:The aim of this study was to generate a de novel MSCs aptamer and developed the first, feasible, economical, bio-compatible, and functional MSCs aptamer-directed nanoparticles without complex manufacture to recruit mesenchymal stem cells (MSCs) for bone defect regeneration. Methods:Whole-cell SELEX was used to generate a de novel MSCs aptamer. Flow cytometry was applied to assess the binding specificities, affinities and sorting abilities of the aptamers. Nano-Aptamer Ball (NAB) was constructed by NHS/EDC reaction. The diameter and zeta of NAB were assessed by dynamic light scattering. CCK8 assay was utilized to evaluate whether NAB could cause non-specific cytotoxicity and induce cell proliferation. To evaluate the bone repair capacity of NAB, histomorphological staining, alizarin red and micro X-ray were used to observe the repair degree of defect in vivo. ELISA was used to detect osteopontin (OPN), osteocalcin (BGP) by, and alkaline phosphatase (ALP) in peripheral blood. Results:MSCs aptamer termed as HM69 could bind with MSCs with high specificity and Kd of 9.67 nM, while has minimal cross-reactivities to other negative cells. HM69 could capture MSCs with a purity of >89%. In vitro, NAB could bind and capture MSCs effectively, whereas did not cause obvious cytotoxicity. In vivo, serum OPN, BGP, and ALP levels in the NAB group of rats were increased at both 2 and 4 weeks, indicating the repair and osteogenesis generation. The healing of bone defects in the NAB group was significantly better than control groups, the defects became blurred, and local trabecular bone growth could be observed in X-ray. The organized hematoma and cell growth in the bone marrow of the NAB group were more vigorous in bone sections staining. Conclusion:These suggested that HM69 and HM69-functionalized nanoparticles NAB exhibited the ability to recruit MSCs both in vitro and in vivo and achieved a better outcome of bone defect repair in a rat model. The findings demonstrate a promising strategy of using aptamer-functionalized bio-nanoparticles for the restoration of bone defects via aptamer-introduced homing of MSCs.

Project description:ObjectiveBone defects or atrophy may arise as a consequence of injury, inflammation of various etiologies, and neoplastic or traumatic processes or as a result of surgical procedures. Sometimes the regeneration process of bone loss is impaired, significantly slowed down, or does not occur, e.g., in congenital defects. For the bone defect reconstruction, a piece of the removed bone from ala of ilium or bone transplantation from a decedent is used. Replacement of the autologous or allogenic source of the bone-by-bone substitute could reduce the number of surgeries and time in the pharmacological coma during the reconstruction of the bone defect. Application of mesenchymal stem cells in the reconstruction surgery may have positive influence on tissue regeneration by secretion of angiogenic factors, recruitment of other MSCs, or differentiation into osteoblasts. Materials and Methods. Mesenchymal stem cells derived from the umbilical cord (Wharton's jelly (WJ-MSC)) were cultured in GMP-grade DMEM low glucose supplemented with heparin, 10% platelet lysate, glucose, and antibiotics. In vitro WJ-MSCs were seeded on the bone substitute Bio-Oss Collagen® and cultured in the StemPro® Osteogenesis Differentiation Kit. During the culture on the 1st, 7th, 14th, and 21st day (day in vitro (DIV)), we analyzed viability (confocal microscopy) and adhesion capability (electron microscopy) of WJ-MSC on Bio-Oss scaffolds, gene expression (qPCR), and secretion of proteins (Luminex). In vivo Bio-Oss® scaffolds with WJ-MSC were transplanted to trepanation holes in the cranium to obtain their overgrowth. The computed tomography was performed 7, 14, and 21 days after surgery to assess the regeneration.ResultsThe Bio-Oss® scaffold provides a favourable environment for WJ-MSC survival. WJ-MSCs in osteodifferentiation medium are able to attach and proliferate on Bio-Oss® scaffolds. Results obtained from qPCR and Luminex® indicate that WJ-MSCs possess the ability to differentiate into osteoblast-like cells and may induce osteoclastogenesis, angiogenesis, and mobilization of host MSCs. In animal studies, WJ-MSCs seeded on Bio-Oss® increased the scaffold integration with host bone and changed their morphology to osteoblast-like cells.ConclusionsThe presented construct consisted of Bio-Oss®, the scaffold with high flexibility and plasticity, approved for clinical use with seeded immunologically privileged WJ-MSC which may be considered reconstructive therapy in bone defects.

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Ferulic acid promotes bone defect repair after radiation by maintaining the stemness of skeletal stem cells.

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