Graduation Date

Summer 8-15-2026

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Richard Reinhardt

Second Advisor

Amy Killeen

Third Advisor

Thomas Petro

Fourth Advisor

Ali Nawshad

Abstract

Tooth extraction triggers a wound-healing cascade that is critical for preserving alveolar ridge architecture and supporting future implant therapy. However, aging is associated with delayed and dysregulated healing, the mechanisms of which remain incompletely understood at the tissue level. This pilot study used spatial transcriptomics to characterize age-related differences in human extraction socket healing, with a particular focus on macrophage, dendritic cell, and fibroblast populations.

Gingival tissue biopsies were collected from three older patients (56–87 years) and three younger patients (41–49 years) 14 days after posterior tooth extraction. Samples were profiled using the Visium HD Spatial Gene Expression platform. Cell and mediator densities, differential gene expression, pathway enrichment, and Cell Chat-based communication analyses were conducted within defined regions of interest adjacent to the healing socket.

Aged tissue showed approximately fivefold higher densities of monocytes and an inflammation-associated fibroblast subcluster (Fib 1.1). Elevated densities of IL-6, TNF-α, MMP-9, BMP-2, and TNFSF11 (RANKL) were also observed. In addition, both monocytes and Fib 1.1 fibroblasts exhibited upregulation of a shared neutrophil-recruiting chemokine program, including CXCL1, CXCL5, CXCL6, and CXCL8. Fib 1.1 fibroblasts further showed increased expression of MMP1, TNC, and PPIA, consistent with a shift toward an inflammatory, matrix-remodeling phenotype.

Cell-cell communication analysis revealed a marked age-related restructuring of intercellular signaling. In young tissue, communication was dominated by a single Fib 1.1-to-dendritic cell signaling axis. In contrast, aged tissue exhibited convergent signaling from monocytes, dendritic cells, and Fib 1.1 fibroblasts onto the Fib 1.1 population. These interactions were mediated predominantly through CD44- and CD74-dependent ligand-receptor signaling.

Although derived from a small, hypothesis-generating cohort, these findings were internally consistent across four independent analytical approaches. Collectively, the results support the central hypothesis that aging is associated with persistent pro-inflammatory signaling, dysregulated macrophage-fibroblast communication, and altered bone-remodeling signaling during extraction socket healing. Furthermore, this work identifies Fib 1.1 fibroblasts as a potential convergent signaling hub linking innate immune and stromal compartments in aged healing tissue. These findings provide biologically plausible therapeutic targets and establish a testable framework for a larger study aimed at improving extraction socket healing and implant outcomes in older patients.

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