International Journal of Oral Science · Published 2026-07-23 · DOI 10.1038/s41368-026-00452-5
Tiankai Di, Yuhan Liu, Zhili Li, Lulu Wang, Peiyi Li, Meng Nian, Dezhong Zhou, Lina Niu, Yujiang Chen
Abstract The age-related decline in the pro-angiogenic capacity of mature dental pulp stem cells (DPSCs) severely limits pulp regeneration. We identify impaired glycolytic metabolism, driven by reduced glucose transporter type 1 (GLUT1) and hexokinase 2 (HK2) expression, as the key mechanism, as its inhibition diminished endothelial tube formation. To reverse this, we developed an aminolyzed highly branched poly(β-amino ester) (HBPA) as a vector for GLUT1/HK2 mRNA co-delivery, achieving >90% transfection efficiency with excellent biocompatibility. In vitro, conditioned medium from reprogrammed mature DPSCs resulted in a 2.0-fold increase in capillary length and a 2.3-fold increase in branch points, restoring angiogenic potential to levels equivalent to those of immature DPSCs. This efficacy translated robustly in vivo, where a tooth root slice model showed reprogrammed cells generated tissue with a vessel density of 10.2 vessels per mm2, 2.5-fold higher than that of untreated controls. Crucially, this level of vascularization was statistically indistinguishable from that achieved by the benchmark immature DPSCs. Our study demonstrates that HBPA-mediated metabolic reprogramming effectively rejuvenates mature DPSCs by restoring the “Metabolic-ECM-Angiogenesis Axis”, offering a translatable strategy for predictable, vascularized pulp regeneration.
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Di, T., Liu, Y., Li, Z., et al. (2026). Enhancing pulp regeneration through metabolic reprogramming of mature dental pulp stem cells mediated by GLUT1/HK2 mRNA delivery. International Journal of Oral Science. https://doi.org/10.1038/s41368-026-00452-5