RESUMEN
Fibrocartilage enthesis is the junction between bone and tendon with a typical characteristics of fibrocartilage transition zones. The regeneration of this transition zone is the bottleneck for functional restoration of bone tendon junction (BTJ). Biomimetic approaches, especially decellularized extracellular matrix (ECM) materials, are strategies which aim to mimic the components of tissues to the utmost extent, and are becoming popular in BTJ healing because of their ability not only to provide scaffolds to allow cells to attach and migrate, but also to provide a microenvironment to guide stem/progenitor cells lineage-specific differentiation. However, the cellular and molecular mechanisms of those approaches, especially the ECM proteins, remain unclear. For BTJ reconstruction, fibrocartilage regeneration is the key for good integrity of bone and tendon as well as its mechanical recovery, so the components which can guide stem cells to a chondrogenic commitment in biomimetic approaches might well be the key for fibrocartilage regeneration and eventually for the better BTJ healing. In this review, we firstly discuss the importance of cartilage-like formation in the healing process of BTJ. Next, we explore the possibility of tendon-derived stem/progenitor cells as cell sources for BTJ regeneration due to their multi-differentiation potential. Finally, we summarize the role of extracellular matrix components of BTJ in guiding stem cell fate to a chondrogenic commitment, so as to provide cues for understanding the mechanisms of lineage-specific potential of biomimetic approaches as well as to inspire researchers to incorporate unique ECM components that facilitate BTJ repair into design.
Asunto(s)
Huesos , Tendones , Matriz Extracelular , Fibrocartílago , Células Madre , Ingeniería de Tejidos , Andamios del TejidoRESUMEN
Asparagine synthetase (ASNS) is a gene on the long arm of chromosome 7 that is copy-number amplified in the majority of glioblastomas. ASNS copy-number amplification is associated with a significantly decreased survival. Using patient-derived glioma stem cells (GSC), we showed that significant metabolic alterations occur in gliomas when perturbing the expression of ASNS, which is not merely restricted to amino acid homeostasis. ASNS-high GSCs maintained a slower basal metabolic profile yet readily shifted to a greatly increased capacity for glycolysis and oxidative phosphorylation when needed. This led ASNS-high cells to a greater ability to proliferate and spread into brain tissue. Finally, we demonstrate that these changes confer resistance to cellular stress, notably oxidative stress, through adaptive redox homeostasis that led to radiotherapy resistance. Furthermore, ASNS overexpression led to modifications of the one-carbon metabolism to promote a more antioxidant tumor environment revealing a metabolic vulnerability that may be therapeutically exploited. IMPLICATIONS: This study reveals a new role for ASNS in metabolic control and redox homeostasis in glioma stem cells and proposes a new treatment strategy that attempts to exploit one vulnerable metabolic node within the larger multilayered tumor network.
Asunto(s)
Asparagina/biosíntesis , Neoplasias del Tronco Encefálico/metabolismo , Encéfalo/metabolismo , Glioma/metabolismo , Células Madre Neoplásicas/metabolismo , Estrés Oxidativo/fisiología , Animales , Aspartatoamoníaco Ligasa/metabolismo , Células HEK293 , Humanos , Ratones , Estudios RetrospectivosRESUMEN
OBJECTIVE: To investigate the role of three genetic polymorphisms of ABC proteins in response to chemotherapy and overall survival of osteosarcoma patients. METHODS: A prospective study was conducted. Genotyping analyses of ABCB1 C3435T, ABCG2 C421A, and ABCC3 C-211T were conducted using the TaqMan methodology. Multivariate Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% CI of effect of each genotype of ABCB1 C3435T, ABCG2 c421A, and ABCC3 C-211T on PFS and OS. RESULTS: During the follow-up period, 135 patients (74.18%) were alive and 47 died (25.82). The median follow-up periods were 36.7 months. Individuals carrying with ABCB1 3435TT genotype and T allele showed less likely to have a poor response to chemotherapy. Cox regression analysis showed that individuals with ABCB1 TT genotype and T allele were associated with high risk of death from osteosarcoma when compared with wide-type genotype. However, we did not find significant association between ABCG2 C421A and ABCC3 C-211T polymorphisms and overall survival of osteosarcoma. CONCLUSION: ABCB1 C3435T polymorphism may be used as a genetic predictor of clinical outcome in osteosarcoma patients treated with chemotherapy. However, no association was found between polymorphisms in ABCG2 C421A and ABCC3 C-211T and clinical outcome of osteosarcoma.