Tanshinone IIA Loaded Inhaled Polymer Nanoparticles Alleviate Established Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by chronic, progressive scarring of the lung parenchyma, leading to an irreversible decline in lung function. Apart from supportive care, there is currently no specific treatment available to reverse the disease. Based on the fact that tanshinone IIA (TAN) had an effect on protecting against TGF-ß1-induced fibrosis through the inhibition of Smad and non-Smad signal pathways to avoid myofibroblasts activation, this study reported the development of the inhalable tanshinone IIA-loaded chitosan-oligosaccharides-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CPN@TAN) for enhancing the pulmonary delivery of tanshinone IIA to treat pulmonary fibrosis. The CPN@TAN with a size of 206.5 nm exhibited excellent in vitro aerosol delivery characteristics, featuring a mass median aerodynamic diameter (MMAD) of 3.967 ± 0.025 µm and a fine particle fraction (FPF) of 70.516 ± 0.929%. Moreover, the nanoparticles showed good stability during atomization and enhanced the mucosal penetration capabilities. The results of confocal spectroscopy confirmed the potential of the nanoparticles as carriers that facilitated the uptake of drugs by NIH3T3, A549, and MH-S cells. Additionally, the nanoparticles demonstrated good in vitro biocompatibility. In a mouse model of bleomycin-induced pulmonary fibrosis, noninvasive inhalation of aerosol CPN@TAN greatly suppressed collagen formation and facilitated re-epithelialization of the destroyed alveolar epithelium without causing systemic toxicity compared with intravenous administration. Consequently, our noninvasive inhalation drug delivery technology based on polymers may represent a promising paradigm and open the door to overcoming the difficulties associated with managing pulmonary fibrosis.

Synergistic optimization of baffles and aeration to improve the Light/Dark cycle of microalgae photobioreactor for enhanced nitrogen removal performance: Computational fluid dynamics and experimental verification.

Microalgae photobioreactor (PBR) is a kind of efficient wastewater treatment system for nitrogen removal. However, there is still an urgent need for process optimization of PBR. Especially, the synergistic effect and optimization of light and flow state poses a challenge. In this study, the computational fluid dynamics is employed for simulating the optimization of the number and length of the internal baffles, as well as the aeration rate of PBR, which in turn leads to the optimal growth of microalgae and efficient nitrogen removal. After optimization, the Light/Dark cycle of the reactor B is shortened by 51.6 %, and the biomass increases from 0.06 g/L to 3.94 g/L. In addition, the removal rate of NH4+-N increased by 106.0 % to 1.56 mg L-1 h-1. This work provides a feasible method for optimizing the design and operational parameters of PBR aiming the engineering application.

Identification of characteristic flavor quality of ceramic-pot sealed meat after reheating based on HS-GC-IMS, bionic sensory combined chemometrics.

This study investigated the impacts of microwave reheating (MR), boil reheating (BR), and steam reheating (SR) on the flavor profile of Ceramic-Pot Sealed Meat (CPSM). Electronic nose and tongue revealed that the microwaving was superior in preserving the original olfactory and gustatory profiles of CPSM compared to the other methods. Headspace- Gas chromatography- ion mobility spectrometry (HS-GC-IMS) detected 48 compounds, encompassing 15 alcohols, 11 aldehydes, 9 ketones, 7 esters, 2 alkenes, and 2 others, 1 acid. Spectral and clustering analysis revealed a significant rise in the content of Warmed-over flavor compounds after boil reheating, culminating in pronounced flavor distortion and a decline in sensory scores. Relative odor activity value (ROAV) and chemometrics identified nine substances as the principal flavor compounds responsible to flavor distortion. In conclusion, all reheating methods induce changes in the original flavor characteristics profiles of CPSM. However, microwave reheating offers superior preservation of the flavor characteristics of CPSM.

A new microalgal negative carbon technology for landfill leachate treatment: Simultaneous removal of nitrogen and phosphorus.

Replete with ammonia nitrogen and organic pollutants, landfill leachate typically undergoes treatment employing expensive and carbon-intensive integrated techniques. We propose a novel microalgae technology for efficient, low-carbon simultaneous treatment of carbon, nitrogen, and phosphorus in landfill leachate (LL). The microbial composition comprises a mixed microalgae culture with Chlorella accounting for 82.58%. After seven days, the process with an N/P ratio of approximately 14:1 removed 98.81% of NH4+-N, 88.62 % of TN, and 99.55% of TP. Notably, the concentrations of NH4+-N and TP met the discharge standards, while the removal rate of NH4+-N was nearly three times higher than previously reported in relevant studies. The microalgae achieved a removal efficiency of 64.27% for Total Organic Carbon (TOC) and 99.26% for Inorganic Carbon (IC) under mixotrophic cultivation, yielding a biomass of 1.18 g/L. The treatment process employed in this study results in a carbon emissions equivalent of -8.25 kgCO2/kgNremoved, representing a reduction of 33.56 kgCO2 compared to the 2AO + MBR process. In addition, shake flask experiments were conducted to evaluate the biodegradability of leachate after microalgae treatment. After microalgae treatment, the TOCB (Biodegradable Total Organic Carbon)/TOC ratio decreased from 56.54% to 27.71%, with no significant improvement in biodegradability. It establishes a fundamental foundation for further applied research in microalgae treatment of leachate.

Softening the tumor matrix through cholesterol depletion breaks the physical barrier for enhanced antitumor therapy.

The tumor develops defense tactics, including conversing the mechanical characteristics of tumor cells and their surrounding environment. A recent study reported that cholesterol depletion stiffens tumor cells, which could enhance adaptive T-cell immunotherapy. However, it remains unclear whether reducing the cholesterol in tumor cells contributes to re-educating the stiff tumor matrix, which serves as a physical barrier against drug penetration. Herein, we found that depleting cholesterol from tumor cells can demolish the intratumor physical barrier by disrupting the mechanical signal transduction between tumor cells and the extracellular matrix through the destruction of lipid rafts. This disruption allows nanoparticles (H/S@hNP) to penetrate deeply, resulting in improved photodynamic treatment. Our research also indicates that cholesterol depletion can inhibit the epithelial-mesenchymal transition and repolarize tumor-associated macrophages from M2 to M1, demonstrating the essential role of cholesterol in tumor progression. Overall, this study reveals that a cholesterol-depleted, softened tumor matrix reduces the difficulty of drug penetration, leading to enhanced antitumor therapeutics.

Electrifying Energy and Chemical Transformations with Single-Atom Alloy Nanoparticle Catalysts.

Single-atom alloys (SAAs) have attracted considerable attention as promising electrocatalysts in reactions central to energy conversion and chemical transformation. In contrast to monometallic nanocrystals and metal alloys, SAAs possess unique and intriguing physicochemical properties, positioning them as ideal model systems for studying structure-property relationships. However, the field is still in its early stages. In this Perspective, we first review and summarize rational synthesis methods and advanced characterization techniques for SAA nanoparticle catalysts. We then emphasize the extensive applications of SAAs in a range of electrocatalytic reactions, including fuel cell reactions, water splitting, and carbon dioxide and nitrate reductions. Finally, we provide insights into existing challenges and prospects associated with the controlled synthesis, characterization, and design of SAA catalysts.

Bidirectional Enhancement of Nitrogen Removal by Indigenous Synergetic Microalgal-Bacterial Consortia in Harsh Low-C/N Wastewater.

Conventional microalgal-bacterial consortia have limited capacity to treat low-C/N wastewater due to carbon limitation and single nitrogen (N) removal mode. In this work, indigenous synergetic microalgal-bacterial consortia with high N removal performance and bidirectional interaction were successful in treating rare earth tailing wastewaters with low-C/N. Ammonia removal reached 0.89 mg N L-1 h-1, 1.84-fold more efficient than a common microalgal-bacterial system. Metagenomics-based metabolic reconstruction revealed bidirectional microalgal-bacterial interactions. The presence of microalgae increased the abundance of bacterial N-related genes by 1.5- to 57-fold. Similarly, the presence of bacteria increased the abundance of microalgal N assimilation by 2.5- to 15.8-fold. Furthermore, nine bacterial species were isolated, and the bidirectional promotion of N removal by the microalgal-bacterial system was verified. The mechanism of microalgal N assimilation enhanced by indole-3-acetic acid was revealed. In addition, the bidirectional mode of the system ensured the scavenging of toxic byproducts from nitrate metabolism to maintain the stability of the system. Collectively, the bidirectional enhancement system of synergetic microalgae-bacteria was established as an effective N removal strategy to broaden the stable application of this system for the effective treatment of low C/N ratio wastewater.

Occlusal force orchestrates alveolar bone homeostasis via Piezo1 in female mice.

Healthy alveolar bone is the cornerstone of oral function and oral treatment. Alveolar bone is highly dynamic during the entire lifespan and is affected by both systemic and local factors. Importantly, alveolar bone is subjected to unique occlusal force in daily life, and mechanical force is a powerful trigger of bone remodeling, but the effect of occlusal force in maintaining alveolar bone mass remains ambiguous. In this study, the Piezo1 channel is identified as an occlusal force sensor. Activation of Piezo1 rescues alveolar bone loss caused by a loss of occlusal force. Moreover, we identify Piezo1 as the mediator of occlusal force in osteoblasts, maintaining alveolar bone homeostasis by directly promoting osteogenesis and by sequentially regulating catabolic metabolism through Fas ligand (FasL)-induced osteoclastic apoptosis. Interestingly, Piezo1 activation also exhibits remarkable efficacy in the treatment of alveolar bone osteoporosis caused by estrogen deficiency, which is highly prevalent among middle-aged and elderly women. Promisingly, Piezo1 may serve not only as a treatment target for occlusal force loss-induced alveolar bone loss but also as a potential target for metabolic bone loss, especially in older patients.

Daily occlusal force and estrogen synergistically maintain alveolar bone homeostasis. PIEZO1 in osteoblasts plays a critical role in sensing occlusal force and maintaining bone mass. PIEZO1 may promote osteoclastic apoptosis through osteoblast-secreted FasL through a PIEZO1-STAT3/ESR1-FasL pathway. Restoration of occlusal force with dental therapies as early as possible to prevent alveolar bone loss is the major priority in oral health care. PIEZO1 may serve as a potential target for bone metabolism disorders.

Resourceful application and mechanism of oyster shell-microalgae synergistic system：Sustainable treatment of harsh low carbon nitrogen ratio actual wastewater.

Microalgal technology holds great promise for both low C/N wastewater treatment and resource recovery simultaneously. Nevertheless, the advancement of microalgal technology is hindered by its reduced nitrogen removal efficiency in low C/N ratio wastewater. In this work, microalgae and waste oyster shells were combined to achieve a total inorganic nitrogen removal efficiency of 93.85% at a rate of 2.05 mg L-1 h-1 in low C/N wastewater. Notably, over four cycles of oyster shell reuse, the reactor achieved an average 85% ammonia nitrogen removal extent, with a wastewater treatment cost of only $0.092/ton. Moreover, microbial community analysis during the reuse of oyster shells revealed the critical importance of timely replacement in inhibiting the growth of non-functional bacteria (Poterioochromonas_malhamensi). The work demonstrated that the oyster shell - microalgae system provides a time- and cost-saving, environmental approach for the resourceful treatment of harsh low C/N wastewater.

Mitochondrial-Targeting Nanotrapper Captured Copper Ions to Alleviate Tumor Hypoxia for Amplified Photoimmunotherapy in Breast Cancer.

Hypoxia is a pervasive feature of solid tumors, which significantly limits the therapeutic effect of photodynamic therapy (PDT) and further influences the immunotherapy efficiency in breast cancer. However, the transient alleviation of tumor hypoxia fails to address the underlying issue of increased oxygen consumption, resulting from the rapid proliferation of tumor cells. At present, studies have found that the reduction of the oxygen consumption rate (OCR) by cytochrome C oxidase (COX) inhibition that induced oxidative phosphorylation (OXHPOS) suppression was able to solve the proposed problem. Herein, we developed a specific mitochondrial-targeting nanotrapper (I@MSN-Im-PEG), which exhibited good copper chelating ability to inhibit COX for reducing the OCR. The results proved that the nanotrapper significantly alleviated the hypoxic tumor microenvironment by copper chelation in mitochondria and enhanced the PDT effect in vitro and in vivo. Meanwhile, the nanotrapper improved photoimmunotherapy through both enhancing PDT-induced immunogenetic cell death (ICD) effects and reversing Treg-mediated immune suppression on 4T1 tumor-bearing mice. The mitochondrial-targeting nanotrapper provided a novel and efficacious strategy to enhance the PDT effect and amplify photoimmunotherapy in breast cancer.

Biodegradable and Efficient Charge-Migrated Z-Scheme Heterojunction Amplifies Cancer Ferroptosis by Blocking Defensive Redox System.

Ferroptosis is an emerging non-apoptotic death process, mainly involving lipid peroxidation (LPO) caused by iron accumulation, which is potentially lethal to the intrinsically apoptotic-resistant malignant tumor. However, it is still restricted by the inherent antioxidant systems of tumor cells and the poor efficacy of traditional iron-based ferroptosis initiators. Herein, the study develops a novel ferroptosis-inducing agent based on PEGylated Cu+/Cu2+-doped black phosphorus@polypyrrole heterojunction (BP@CPP), which is constructed by utilizing the phosphate on the surface of BP to chelate Cu ions and initiating subsequent in situ polymerization of pyrrole. As a novel Z-scheme heterojunction, BP@CPP possesses an excellent photocatalytic activity in which the separated electron-hole pairs under laser irradiation endow it with powerful oxidizing and reducing capacities, which synergy with Cu+/Cu2+ self-cycling catalyzing Fenton-like reaction to further strengthen reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) inactivation, ultimately leading to efficient ferroptosis. Systematic in vitro and in vivo evaluations demonstrate that BP@CPP effectively inhibit tumor growth by inducing desired ferroptosis while maintaining a favorable biosafety in the body. Therefore, the developed BP@CPP-based ferroptosis initiator provides a promising strategy for ferroptosis-like cancer therapy.

Early-Responsive Immunoregulation Therapy Improved Microenvironment for Bone Regeneration Via Engineered Extracellular Vesicles.

Overactivated inflammatory reactions hinder the bone regeneration process. Timely transformation of microenvironment from pro-inflammatory to anti-inflammatory after acute immune response is favorable for osteogenesis. Macrophages play an important role in the immune response to inflammation. Therefore, this study adopts TIM3 high expression extracellular vesicles (EVs) with immunosuppressive function to reshape the early immune microenvironment of bone injury, mainly by targeting macrophages. These EVs can be phagocytosed by macrophages, thereby increasing the infiltration of TIM3-positive macrophages (TIM3+ macrophages) and M2 subtypes. The TIM3+ macrophage group has some characteristics of M2 macrophages and secretes cytokines, such as IL-10 and TGF-ß1 to regulate inflammation. TIM3, which is highly expressed in the engineered EVs, mediates the release of anti-inflammatory cytokines by inhibiting the p38/MAPK pathway and promotes osseointegration by activating the Bmp2 promoter to enhance macrophage BMP2 secretion. After evenly loading the engineered EVs into the hydrogel, the continuous and slow release of EVsTIM3OE recruits more anti-inflammatory macrophages during the early stages of bone defect repair, regulating the immune microenvironment and eliminating the adverse effects of excessive inflammation. In summary, this study provides a new strategy for the treatment of refractory wounds through early inflammation control.

Recent Advances in NIR or X-ray Excited Persistent Luminescent Materials for Deep Bioimaging.

Due to their persistent luminescence, persistent luminescent (PersL) materials have attracted great interest. In the biomedical field, the use of persistent luminescent nanoparticles (PLNPs) eliminates the need for continuous in situ excitation, thereby avoiding interference from tissue autofluorescence and significantly improving the signal-to-noise ratio (SNR). Although persistent luminescence materials can emit light continuously, the luminescence intensity of small-sized nanoparticles in vivo decays quickly. Early persistent luminescent nanoparticles were mostly excited by ultraviolet (UV) or visible light and were administered for imaging purposes through ex vivo charging followed by injection into the body. Limited by the low in vivo penetration depth, UV light cannot secondary charge PLNPs that have decayed in vivo, and visible light does not penetrate deep enough to reach deep tissues, which greatly limits the imaging time of persistent luminescent materials. In order to address this issue, the development of PLNPs that can be activated by light sources with superior tissue penetration capabilities is essential. Near-infrared (NIR) light and X-rays are widely recognized as ideal excitation sources, making persistent luminescent materials stimulated by these two sources a prominent area of research in recent years. This review describes NIR and X-ray excitable persistent luminescence materials and their recent advances in bioimaging.

The odontoblastic differentiation of dental mesenchymal stem cells: molecular regulation mechanism and related genetic syndromes.

Dental mesenchymal stem cells (DMSCs) are multipotent progenitor cells that can differentiate into multiple lineages including odontoblasts, osteoblasts, chondrocytes, neural cells, myocytes, cardiomyocytes, adipocytes, endothelial cells, melanocytes, and hepatocytes. Odontoblastic differentiation of DMSCs is pivotal in dentinogenesis, a delicate and dynamic process regulated at the molecular level by signaling pathways, transcription factors, and posttranscriptional and epigenetic regulation. Mutations or dysregulation of related genes may contribute to genetic diseases with dentin defects caused by impaired odontoblastic differentiation, including tricho-dento-osseous (TDO) syndrome, X-linked hypophosphatemic rickets (XLH), Raine syndrome (RS), hypophosphatasia (HPP), Schimke immuno-osseous dysplasia (SIOD), and Elsahy-Waters syndrome (EWS). Herein, recent progress in the molecular regulation of the odontoblastic differentiation of DMSCs is summarized. In addition, genetic syndromes associated with disorders of odontoblastic differentiation of DMSCs are discussed. An improved understanding of the molecular regulation and related genetic syndromes may help clinicians better understand the etiology and pathogenesis of dentin lesions in systematic diseases and identify novel treatment targets.

Using Inducible Osteoblastic Lineage-Specific Stat3 Knockout Mice to Study Alveolar Bone Remodeling During Orthodontic Tooth Movement.

The alveolar bone, with a high turnover rate, is the most actively-remodeling bone in the body. Orthodontic tooth movement (OTM) is a common artificial process of alveolar bone remodeling in response to mechanical force, but the underlying mechanism remains elusive. Previous studies have been unable to reveal the precise mechanism of bone remodeling in any time and space due to animal model-related restrictions. The signal transducer and activator of transcription 3 (STAT3) is important in bone metabolism, but its role in osteoblasts during OTM is unclear. To provide in vivo evidence that STAT3 participates in OTM at specific time points and in particular cells during OTM, we generated a tamoxifen-inducible osteoblast lineage-specific Stat3 knockout mouse model, applied orthodontic force, and analyzed the alveolar bone phenotype. Micro-computed tomography (Micro-CT) and stereo microscopy were used to access OTM distance. Histological analysis selected the area located within three roots of the first molar (M1) in the cross-section of the maxillary bone as the region of interest (ROI) to evaluate the metabolic activity of osteoblasts and osteoclasts, indicating the effect of orthodontic force on alveolar bone. In short, we provide a protocol for using inducible osteoblast lineage-specific Stat3 knockout mice to study bone remodeling under orthodontic force and describe methods for analyzing alveolar bone remodeling during OTM, thus shedding new light on skeletal mechanical biology.

Atomic Layers of B2 CuPd on Cu Nanocubes as Catalysts for Selective Hydrogenation.

The search for highly active and selective catalysts with high precious metal atom utilization efficiency has attracted increasing interest in both the fundamental synthesis of materials and important industrial reactions. Here, we report the synthesis of Pd-Cu nanocubes with a Cu core and an ordered B2 intermetallic CuPd shell with controllable atomic layers on the surface (denoted as Cu/B2 CuPd), which can efficiently and robustly catalyze the selective hydrogenation of acetylene (C2H2) to ethylene (C2H4) under mild conditions. The optimized Cu/B2 CuPd with a Pd loading of 9.5 at. % exhibited outstanding performance in the C2H2 semi-hydrogenation with 100% C2H2 conversion and 95.2% C2H4 selectivity at 90 °C. We attributed this outstanding performance to the core/shell structure with a high surface density of active Pd sites isolated by Cu in the B2 intermetallic matrix, representing a structural motif of single-atom alloys (SAAs) on the surface. The combined experimental and computational studies further revealed that the electronic states of Pd and Cu are modulated by SAAs from the synergistic effect between Pd and Cu, leading to enhanced performance compared with pristine Pd and Cu catalysts. This study provides a new synthetic methodology for making single-atom catalysts with high precious metal atom utilization efficiency, enabling simultaneous tuning of both geometric and electronic structures of Pd active sites for enhanced catalysis.

Hyperthermia-triggered NO release based on Cu-doped polypyrrole for synergistic catalytic/gas cancer therapy.

Nitric oxide (NO) is a crucial gaseous medium for tumor growth and progression, but it may also cause mitochondrial disorder and DNA damage by drastically increasing its concentration in tumor. Due to its challenging administration and unpredictable release, NO based gas therapy is difficult to eliminate malignant tumor at low safe doses. To address these issues, herein, we develop a multifunctional nanocatalyst called Cu-doped polypyrrole (CuP) as an intelligent nanoplatform (CuP-B@P) to deliver the NO precursor BNN6 and specifically release NO in tumors. Under the aberrant metabolic environment of tumors, CuP-B@P catalyzes the conversion of antioxidant GSH into GSSG and excess H2O2 into ·OH through Cu+/Cu2+ cycle, which results in oxidative damage to tumor cells and the concomitant release of cargo BNN6. More importantly, after laser exposure, nanocatalyst CuP can absorb and convert photons into hyperthermia, which in turn, accelerates the aforesaid catalytic efficiency and pyrolyzes BNN6 into NO. Under the synergistic effect of hyperthermia, oxidative damage, and NO burst, almost complete tumor elimination is achieved in vivo with negligible toxicity to body. Such an ingenious combination of NO prodrug and nanocatalytic medicine provides a new insight into the development of NO based therapeutic strategies. STATEMENT OF SIGNIFICANCE: A hyperthermia-responsive NO delivery nanoplatform (CuP-B@P) based on Cu-doped polypyrrole was designed and fabricated, in which CuP catalyzed the conversion of H2O2 and GSH into ·OH and GSSG to induce intratumoral oxidative damage. After laser irradiation, hyperthermia ablation and responsive release of NO further coupled with oxidative damage to eliminate malignant tumors. This versatile nanoplatform provides new insights into the combined application of catalytic medicine and gas therapy.

Exercise maintains bone homeostasis by promoting osteogenesis through STAT3.

Bone exhibits changes in density, strength, and microarchitecture in relation to mechanical loading mediated by exercise. Appropriate exercise maintains bone homeostasis, while the absence of exercise leads to disuse bone loss. However, the acting mechanism of mechanotransduction in bone remains unclear. We performed the running-wheel exercise and tail suspension model to study the effects of exercise on bone metabolism, and found that osteoblastic Signal transducer and activator of transcription 3 (STAT3) activity was closely related to exercise-induced bone mass and metabolism changes. With the Flexcell tension-loading system in vitro, mechanical force promoted STAT3 activity, which was accompanied by increased osteoblastic differentiation of the bone marrow mesenchymal stem cells (BMSCs). In contrast, the inhibition of STAT3 phosphorylation blocked force-induced osteoblastic differentiation. Furthermore, pharmacological inactivation of STAT3 impaired the increase in exercise-induced bone mass and osteogenesis. With an inducible conditional deletion mouse model, we found that the osteoblast lineage-specific Stat3 deletion could also block force-induced osteoblastic differentiation in vitro and impair exercise-promoted bone mass and osteogenesis in vivo. This confirmed the crucial role of osteoblastic STAT3 in exercise-mediated bone metabolism. Finally, colivelin, a STAT3 agonist, promoted osteoblastic differentiation in vitro and partly rescued exercise loss-induced disuse bone loss by improving osteogenesis in the tail suspension model. Taken together, our study revealed the essential role of STAT3 in maintaining exercise-mediated bone homeostasis. In addition, STAT3 might act as a potential target for osteoporosis caused by exercise loss.

ScRNA-seq links dental fibroblasts heterogeneity with mechanoresponsiveness.

BACKGROUND AND OBJECTIVE: Periodontal ligament (PDL) and dental pulp (DP) share a common origin but have distinct biological and mechanical functions. To what extent the mechanoresponsive property of PDL can be attributed to its unique transcriptional profiles of cellular heterogeneity is unclear. This study aims to decipher cellular heterogeneity and distinct mechanoresponsive characteristics of odontogenic soft tissues and their underlying molecular mechanisms. MATERIALS AND METHODS: A single-cell comparison of digested human periodontal ligament (PDL) and dental pulp (DP) was performed using scRNA-seq. An in vitro loading model was constructed to measure mechanoresponsive ability. Dual-luciferase assay, overexpression, and shRNA knockdown were used to investigate the molecular mechanism. RESULTS: Our results demonstrate striking fibroblast heterogeneity across and within human PDL and DP. We demonstrated that a tissue-specific subset of fibroblasts existed in PDL exhibiting high expression of mechanoresponsive extracellular matrix (ECM) genes, which was verified by an in vitro loading model. ScRNA-seq analysis indicated a particularly enriched regulator in PDL-specific fibroblast subtype, Jun Dimerization Protein 2 (JDP2). Overexpression and knockdown of JDP2 extensively regulated the downstream mechanoresponsive ECM genes in human PDL cells. The force loading model demonstrated that JDP2 responded to tension and that knockdown of JDP2 effectively inhibited the mechanical force-induced ECM remodeling. CONCLUSIONS: Our study constructed the PDL and DP ScRNA-seq atlas to demonstrate PDL and DP fibroblast cellular heterogeneity and identify a PDL-specific mechanoresponsive fibroblast subtype and its underlying mechanism.