Mechanomedicine-guided mechanical preconditioning of dental-derived stromal cells for tissue regeneration

Abstract

Dental-derived stromal cells (DSCs), including periodontal ligament stem cells, dental pulp stem cells, stem cells from the apical papilla, and stem cells from human exfoliated deciduous teeth, are promising candidates for oral and craniofacial regeneration because of their accessibility, expandability, and functional relevance to periodontal, dentin–pulp, bone, and neurovascular repair. However, the therapeutic performance of DSC-based products remains inconsistent, partly because conventionally expanded cells may be insufficiently adapted to the mechanical cues encountered in vivo. In this Review, we present mechanical preconditioning as a mechanomedicine-guided strategy for ex vivo functional priming of DSCs. We summarize how major DSC populations respond to defined biophysical cues such as tensile and compressive forces, fluid shear stress, hydrostatic pressure, matrix stiffness, and surface topography, and we discuss the principal mechanotransduction pathways involved. We further outline representative quantitative loading windows and consider how these may support subtype-specific and indication-specific preconditioning design. Finally, we highlight key translational barriers, including stromal cell heterogeneity, donor variability, senescence, uncertain persistence of mechanically induced states, safety concerns, and the lack of standardized manufacturing workflows. Overall, clinical translation will require a shift from descriptive mechanobiology toward parameter-defined, indication-specific, and good manufacturing practice-compatible preconditioning strategies for DSC-based regeneration.

1. Introduction

Mesenchymal stromal cells (MSCs) are heterogeneous adherent stromal cell populations in which bona fide stem cells constitute only a subset. Standard isolation and expansion procedures generally yield non-clonal mixtures that also include lineage-committed progenitors and more differentiated stromal cells [1, 2]. Among them, dental-derived stromal cells (DSCs) originate from oral tissues and include periodontal ligament stem cells (PDLSCs), dental pulp stem cells (DPSCs), stem cells from the apical papilla (SCAP), and stem cells from human exfoliated deciduous teeth (SHED) [3]. Although these populations are conventionally referred to as “stem cells” in the dental literature, they are more accurately regarded as heterogeneous, non-clonal stromal/progenitor mixtures rather than uniformly defined stem-cell entities [4, 5]. Nevertheless, DSCs remain highly attractive for regenerative applications because they are relatively accessible, can be obtained across multiple developmental stages, expand efficiently ex vivo, and are functionally relevant to periodontal, dentin–pulp, craniofacial, and neurovascular repair [6]. Their generally favorable immunological profile further supports their therapeutic potential [7, 8]. However, despite encouraging preclinical findings, the performance of DSC-based therapies remains inconsistent. One plausible explanation is that conventional expansion is typically performed under mechanically simplified culture conditions that do not recapitulate key biophysical features of the target tissue, potentially limiting subsequent adaptation after implantation [9, 10].

DSCs operate within microenvironments shaped by both biochemical and biophysical cues. A landmark study by Engler et al. established matrix elasticity as a determinant of lineage bias in MSCs, providing a conceptual foundation for mechanical regulation in regenerative biology [11]. This principle is directly relevant to DSCs, whose tissues of origin are embedded in mechanically dynamic oral environments. However, the biomechanical context of oral tissues should be distinguished from the actual biophysical inputs experienced by cells during ex vivo conditioning. Processes such as tooth eruption, occlusion, implantation, and orthodontic tooth movement underscore the mechanically active nature of oral tissues. However, isolated DSCs in experimental systems do not directly experience these macroscopic mechanical events. Rather, they respond to defined physical cues such as tensile and compressive forces, fluid shear stress (FSS), hydrostatic pressure, matrix stiffness, and surface topography [9, 10, 12, 13]. These inputs are sensed through mechanotransduction systems involving integrins, ion channels, focal adhesion complexes, and cytoskeletal–nuclear coupling, and can induce downstream changes in gene expression and cell state that regulate lineage bias and cellular function [14, 15]. Through these processes, mechanical regulation contributes to tissue homeostasis, adaptive remodeling, and regenerative behavior [16].