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Translating m6A-Glycolysis Discovery into Therapy: GOQD-Based Multifunctional Bioactive Scaffolds Rejuvenates Bone
Zengguang Wang1,2, Tanjun Deng3, Hanwen Chang1,2
1Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, P. R. China.
Abstract:
Senescence-related bone regeneration failure arises from the altered fate of senescent BMSCs(s-BMSCs). This study identified glycolysis dysregulation as a key factor in this process. Mechanistically, the downregulation of METTL3 in s-BMSCs destabilized ALDH3A1 mRNA, which subsequently triggered ubiquitin-mediated degradation of c-Myc-a key regulator of glycolysis. Targeting glycolysis altered s-BMSCs fate, promoting osteogenic differentiation while inhibiting adipogenesis. Building on the glycolysis-BMSCs fate relationship, graphene oxide quantum dots (GOQDs) are engineered that demonstrate the ability to potently activate glycolytic flux in s-BMSCs while concomitantly suppressing macrophage-mediated inflammatory responses and enhancing angiogenic capacity. Then, a hierarchically porous β-TCP scaffold is fabricated via 3D printing and subsequently functionalized with GOQDs through polydopamine biointerface-mediated modification, and BMSCs are integrated into the scaffold by fluid dynamics. This multi-biofunctional construct accelerates bone regeneration in critical-sized defects within senescent rat models, evidenced by the restoration of bone tissue compared to senescence-matched controls. These findings not only establish glycolytic modulation as a key determinant of s-BMSCs fate but also demonstrate an engineered therapeutic paradigm that simultaneously addresses two critical pathological dimensions: cellular fate dysfunction, vessel-immune microenvironment disorder in senescence-related bone regeneration.
Insights
Senescent bone regeneration fails due to altered stem cell fate, linked to glycolysis issues. Targeting glycolysis with engineered GOQDs on scaffolds restores bone in aged rats.
Area of Science:
- Biomaterials Science
- Regenerative Medicine
- Cellular Biology
Background:
- Senescence impairs bone regeneration by altering mesenchymal stem cell (BMSC) fate.
- Glycolysis dysregulation is identified as a critical factor in senescent BMSCs (s-BMSCs) dysfunction.
- METTL3 downregulation in s-BMSCs affects ALDH3A1 mRNA stability and c-Myc degradation, impacting glycolysis.
Purpose of the Study:
- To investigate the role of glycolysis in senescence-related bone regeneration failure.
- To engineer a therapeutic strategy using graphene oxide quantum dots (GOQDs) to modulate s-BMSC fate and enhance bone repair.
- To develop a 3D-printed scaffold functionalized with GOQDs for accelerated bone regeneration in senescent models.
Main Methods:
- Investigated the molecular mechanism linking METTL3, ALDH3A1, c-Myc, and glycolysis in s-BMSCs.
- Engineered GOQDs to activate glycolytic flux, suppress inflammation, and promote angiogenesis in s-BMSCs.
- Fabricated a 3D-printed β-TCP scaffold, functionalized it with GOQDs via polydopamine, and integrated BMSCs.
- Evaluated the efficacy of the GOQD-functionalized scaffold in promoting bone regeneration in critical-sized defects in senescent rats.
Main Results:
- Glycolysis targeting reversed s-BMSC fate, promoting osteogenesis and inhibiting adipogenesis.
- Engineered GOQDs effectively activated glycolytic flux in s-BMSCs.
- The GOQD-functionalized scaffold significantly accelerated bone regeneration in senescent rat models compared to controls.
- The construct demonstrated simultaneous improvement in cellular fate, inflammation, and angiogenesis.
Conclusions:
- Glycolytic modulation is a key determinant of s-BMSC fate and crucial for senescence-related bone regeneration.
- Engineered GOQDs integrated into a 3D-printed scaffold offer a multi-biofunctional therapeutic approach for bone repair in aging.
- This strategy effectively addresses cellular dysfunction and the pro-inflammatory, anti-angiogenic microenvironment in senescent bone defects.
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