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By combining volumetric imaging and single\u2010cell analysis at various stages of the disease in human samples, the natural history of how dental pulp responds to decay is uncovered. During the early phases, an arterialization of capillary networks and a progressive outward remodeling of larger vessels are observed. Additionally, neurogenesis of nerve endings and the reprogramming of perivascular progenitor cells into fibroblasts, initiating the physiological reparative response of the stromal tissue, is identified. Vascular and nerve regression, along with a shift in immune response and dental pulp fibrosis, contribute to irreversible pulpitis. These findings establish a foundation for a more comprehensive understanding of how dental tissues respond to injury, thereby prompting a paradigm shift in patient management strategies. 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