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A single-cell transcriptional atlas reveals resident progenitor cell niche functions in TMJ disc development and injury.

ABSTRACT: The biological characteristics of the temporomandibular joint disc involve complex cellular network in cell identity and extracellular matrix composition to modulate jaw function. The lack of a detailed characterization of the network severely limits the development of targeted therapies for temporomandibular joint-related diseases. Here we profiled single-cell transcriptomes of disc cells from mice at different postnatal stages, finding that the fibroblast population could be divided into chondrogenic and non-chondrogenic clusters. We also find that the resident mural cell population is the source of disc progenitors, characterized by ubiquitously active expression of the NOTCH3 and THY1 pathways. Lineage tracing reveals that Myh11⁺ mural cells coordinate angiogenesis during disc injury but lost their progenitor characteristics and ultimately become Sfrp2⁺ non-chondrogenic fibroblasts instead of Chad⁺ chondrogenic fibroblasts. Overall, we reveal multiple insights into the coordinated development of disc cells and are the first to describe the resident mural cell progenitor during disc injury.

SUBMITTER: Bi R

PROVIDER: S-EPMC9929076 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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A single-cell transcriptional atlas reveals resident progenitor cell niche functions in TMJ disc development and injury.

Bi Ruiye R Yin Qing Q Li Haohan H Yang Xianni X Wang Yiru Y Li Qianli Q Fang Han H Li Peiran P Lyu Ping P Fan Yi Y Ying Binbin B Zhu Songsong S

Nature communications 20230214 1

The biological characteristics of the temporomandibular joint disc involve complex cellular network in cell identity and extracellular matrix composition to modulate jaw function. The lack of a detailed characterization of the network severely limits the development of targeted therapies for temporomandibular joint-related diseases. Here we profiled single-cell transcriptomes of disc cells from mice at different postnatal stages, finding that the fibroblast population could be divided into chond ...[more]

PMID: 36788226

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Project description:The biological characteristics of the temporomandibular joint (TMJ) disc involve complex changes in cell identity and extracellular matrix (ECM) composition to modulate jaw function during postnatal growth and aging. To better understand this process, we profiled and analyzed 39111 single-cell transcriptomes of TMJ disc cells from mice at different postnatal stages. Our data showed that TMJ disc cells are composed of 9 distinct clusters that can be divided into 4 principal cell types: fibroblasts (FBs), which were the most abundant, endothelial cells (ECs), macrophages (MPhs) and mural cells (MCs). FBs were found to exhibit heterogeneity in terms of biological processes related to ECM secretion and metabolic functions. The ECs and MPhs mainly clustered together in the junction of the anterior disc band and anterior attachment, indicating the potential importance of the inflammatory response in this region in the pathological process of disc diseases. Notably, we found for the first time that resident MCs are the source of the progenitor niche in TMJ discs. The pseudotime trajectory showed that MCs have 2 lineage fates: self-renewal or multidirectional differentiation toward functional cells. In MCs, the NOTCH3 and THY1 signaling pathways were ubiquitously active at all stages, coupled with specific gene expression of Notch3 and Thy1 in MCs, indicating the critical role of these molecules in MC characteristics. As an example, THY1+ cells in TMJ discs showed markedly stronger stem cell characteristics than THY1- disc cells in vitro and ex vivo. In addition, lineage tracing in vivo showed that the Myh11-CreER+ MC lineage proliferated and migrated to coordinate angiogenesis during disc injury but gradually lost its progenitor characteristics and ultimately became a functional cell for disc repair. Overall, we reveal multiple insights into the coordinated and temporal development of TMJ disc cells at different postnatal stages and are the first to describe the resident MC progenitor cell niche during TMJ disc growth and injury.

Project description:Various interventions have been used for the management of patients with temporomandibular joint (TMJ) disc displacement without reduction (DDwoR), but their clinical effectiveness remains unclear. This systematic review investigated the effects of these interventions and is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic and manual searches up to November 1, 2013, were conducted for English-language, peer-reviewed, publications of randomized clinical trials comparing any form of conservative or surgical interventions for patients with clinical and/or radiologic diagnosis of acute or chronic DDwoR. Two primary outcomes (TMJ pain intensity and maximum mouth opening) and a number of secondary outcomes were examined. Two reviewers performed data extraction and risk of bias assessment. Data collection and analysis were performed according to Cochrane recommendations. Twenty studies involving 1,305 patients were included. Data analysis involved 21 comparisons between a variety of interventions, either between interventions, or between intervention and placebo or no intervention. Meta-analysis on homogenous groups was conducted in 4 comparisons. In most comparisons made, there were no statistically significant differences between interventions relative to primary outcomes at short- or long-term follow-up (p > .05). In a separate analysis, however, the majority of reviewed interventions reported significantly improved primary outcome measures from their baseline levels over time (p < .05). Evidence levels, however, are currently insufficient for definitive conclusions, because the included studies were too heterogeneous and at an unclear to high risk of bias. In view of the comparable therapeutic effects, paucity of high-quality evidence, and the greater risks and costs associated with more complex interventions, patients with symptomatic DDwoR should be initially treated by the simplest and least invasive intervention.

Project description:The temporomandibular joint (TMJ) disc nutrient environment profoundly affects cell energy metabolism, proliferation, and biosynthesis. Due to technical challenges of in vivo measurements, the human TMJ disc extracellular nutrient environment under load, which depends on metabolic rates, solute diffusion, and disc morphometry, remains unknown. Therefore, the study objective was to predict the TMJ disc nutrient environment under loading conditions using combined experimental and computational modeling approaches. Specifically, glucose consumption and lactate production rates of porcine TMJ discs were measured under varying tissue culture conditions (n = 40 discs), and mechanical strain-dependent glucose and lactate diffusivities were measured using a custom diffusion chamber (n = 6 discs). TMJ anatomy and loading area were obtained from magnetic resonance imaging of healthy human volunteers (n = 11, male, 30 ± 9 y). Using experimentally determined nutrient metabolic rates, solute diffusivities, TMJ anatomy, and loading areas, subject-specific finite element (FE) models were developed to predict the 3-dimensional nutrient profiles in unloaded and loaded TMJ discs (unloaded, 0% strain, 20% strain). From the FE models, glucose, lactate, and oxygen concentration ranges for unloaded healthy human TMJ discs were 0.6 to 4.0 mM, 0.9 to 5.0 mM, and 0% to 6%, respectively, with steep gradients in the anterior and posterior bands. Sustained mechanical loading significantly reduced nutrient levels (P < 0.001), with a critical zone in which cells may die representing approximately 13.5% of the total disc volume. In conclusion, this study experimentally determined TMJ disc metabolic rates, solute diffusivities, and disc morphometry, and through subject-specific FE modeling, revealed critical interactions between mechanical loading and nutrient supply and metabolism for the in vivo human TMJ disc. The results suggest that TMJ disc homeostasis may be vulnerable to pathological loading (e.g., clenching, bruxism), which impedes nutrient supply. Given difficulties associated with direct in vivo measurements, this study provides a new approach to systematically investigate homeostatic and degenerative mechanisms associated with the TMJ disc.

Project description:Cartilage fatigue may be a factor in the precocious development of degenerative changes in the temporomandibular joint (TMJ). This cross-sectional study estimated potential for cartilage fatigue via TMJ energy densities (ED) and jaw muscle duty factors (DF), which were combined to calculate mechanobehavioral scores (MBS) in women with (+) and without (-) bilateral TMJ disc displacement (DD). All subjects gave informed consent to participate and were examined using Diagnostic Criteria (DC) for Temporomandibular Disorders (TMD) and magnetic resonance (MR) and computed tomography (CT) images. Forty-seven subjects were categorized into +DD ( n = 29) and -DD ( n = 18) groups. Dynamic stereometry (MR images combined with jaw-tracking data) characterized individual-specific data of TMJ stress-field mechanics to determine ED (ED = W/ Q mJ/mm3, where W = work done, Q = volume of cartilage) during 10 symmetrical jaw-closing cycles with a 20-N mandibular right canine load. Subjects were trained to record masseter and temporalis electromyography over 3 days and 3 nights. Root mean square electromyography/bite-force calibrations determined subject-specific masseter and temporalis muscle activities per 20-N bite-force (T20 N, µV), which defined thresholds. Muscle DF (DF = % duration of muscle activity/total recording time) were determined for a range of thresholds, and MBS (ED2 × DF) were calculated. Intergroup differences in ED, DF, and MBS were assessed via analyses of variance with Bonferroni and Tukey honest significant difference post hoc tests. Average ED for contralateral TMJs was significantly larger ( P = 0.012) by 1.4-fold in +DD compared to -DD subjects. Average DF were significantly larger (all P < 0.01) for +DD compared to -DD subjects by 1.7-, 2.5-, and 1.9-fold for day, night, and overall, respectively. Daytime MBS were significantly larger (all P < 0.04) by up to 8.5-fold in +DD compared to -DD subjects. Significantly larger ED, DF, and MBS were shown in women with compared to women without bilateral TMJ DD.

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A single-cell transcriptional atlas reveals resident progenitor cell niche functions in TMJ disc development and injury.

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A single-cell transcriptional atlas reveals resident progenitor cell niche functions in TMJ disc development and injury.

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