Sensory nerve regulates progenitor cells via FGF-SHH axis in tooth root morphogenesis.

Nerves play important roles in organ development and tissue homeostasis. Stem/progenitor cells differentiate into different cell lineages responsible for building the craniofacial organs. The mechanism by which nerves regulate stem/progenitor cell behavior in organ morphogenesis has not yet been comprehensively explored. Here, we use tooth root development in mouse as a model to investigate how sensory nerves regulate organogenesis. We show that sensory nerve fibers are enriched in the dental papilla at the initiation of tooth root development. Through single cell RNA-sequencing analysis of the trigeminal ganglion and developing molar, we reveal several signaling pathways that connect the sensory nerve with the developing molar, of which FGF signaling appears to be one of the important regulators. Fgfr2 is expressed in the progenitor cells during tooth root development. Loss of FGF signaling leads to shortened roots with compromised proliferation and differentiation of progenitor cells. Furthermore, Hh signaling is impaired in Gli1-CreER;Fgfr2fl/fl mice. Modulation of Hh signaling rescues the tooth root defects in these mice. Collectively, our findings elucidate the nerve-progenitor crosstalk and reveal the molecular mechanism of the FGF-SHH signaling cascade during tooth root morphogenesis.

Ror2-mediated non-canonical Wnt signaling regulates Cdc42 and cell proliferation during tooth root development.

The control of size and shape is an important part of regulatory process during organogenesis. Tooth formation is a highly complex process that fine-tunes the size and shape of the tooth, which are crucial for its physiological functions. Each tooth consists of a crown and one or more roots. Despite comprehensive knowledge of the mechanism that regulates early tooth crown development, we have limited understanding of the mechanism regulating root patterning and size during development. Here, we show that Ror2-mediated non-canonical Wnt signaling in the dental mesenchyme plays a crucial role in cell proliferation, and thereby regulates root development size in mouse molars. Furthermore, Cdc42 acts as a potential downstream mediator of Ror2 signaling in root formation. Importantly, activation of Cdc42 can restore cell proliferation and partially rescue the root development size defects in Ror2 mutant mice. Collectively, our findings provide novel insights into the function of Ror2-mediated non-canonical Wnt signaling in regulating tooth morphogenesis, and suggest potential avenues for dental tissue engineering.

Lhx6 regulates canonical Wnt signaling to control the fate of mesenchymal progenitor cells during mouse molar root patterning.

Mammalian tooth crown formation has long served as a model for investigating how patterning and morphogenesis are orchestrated during development. However, the mechanism underlying root patterning and morphogenesis remains poorly understood. In this study, we find that Lhx6 labels a subpopulation of root progenitor cells in the apical dental mesenchyme, which is closely associated with furcation development. Loss of Lhx6 leads to furcation and root number defects, indicating that Lhx6 is a key root patterning regulator. Among the multiple cellular events regulated by Lhx6 is the odontoblast fate commitment of progenitor cells, which it controls in a cell-autonomous manner. Specifically, Lhx6 loss leads to elevated expression of the Wnt antagonist Sfrp2 and down-regulation of Wnt signaling in the furcation region, while overactivation of Wnt signaling in Lhx6+ progenitor cells partially restore the furcation defects in Lhx6-/- mice. Collectively, our findings have important implications for understanding organ morphogenesis and future strategies for tooth root regeneration.

A prospective, randomized clinical trial of emergency treatment of chemotherapy-induced neutropenia and febrile neutropenia by pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF).

AIMS: As one of the mainstays of breast cancer therapy, chemotherapy inevitably induces neutropenia. In this study, we explored the role of PEG-rhG-CSF (pegylated recombinant human granulocyte colony-stimulating factor) in the emergency treatment of chemotherapy-induced grades 3-4 neutropenia. METHODS: A total of 100 patients with breast cancer were randomized (1:1) into the study. Fifty patients randomized to the experimental group were treated with PEG-rhG-CSF after grades 3-4 neutropenia following the first cycle of chemotherapy, while 50 patients randomized to the control group received a daily injection of rhG-CSF (recombinant human granulocyte colony-stimulating factor). The primary endpoint was the recovery time of grades 3-4 neutropenia. RESULTS: Compared with patients in the control group, the mean ± SD recovery time of grades 3-4 neutropenia and febrile neutropenia (FN) was significantly shorter for patients in the experimental group (grades 3-4, P = .000; grade 4, P = .000; FN, P = .038). There is no significant difference in the incidence of FN for the two groups. In the experimental group, the duration of grades 3-4 neutropenia in patients aged <60 years and ≥60 years was 2.15 and 3.20 days, respectively (P = .037). Adverse events (AEs) of any grade were reported in 37 (75.5%) and 28 (59.6%) patients from the two groups, respectively. No grade ≥3 AEs were reported. CONCLUSION: This study supported that the PEG-rhG-CSF was more effective and convenient than rhG-CSF for treating grades 3-4 neutropenia and FN in patients with breast cancer and had manageable toxicity.

Micro-computed tomography analysis of root canal morphology and thickness of crown and root of mandibular incisors in Chinese population.

OBJECTIVES: The aim of this study was to investigate the root canal morphology and the thickness of crown and root of mandibular incisors in a Chinese subpopulation by micro-computed tomography (micro-CT). METHODS: In total, 208 mandibular incisors were scanned using micro-CT. The anatomical features of the canals (canal configuration, apical constriction, foramen-to-apex distance, accessory canal vertical distribution, and canal geometrical parameters) and the thickness of the crown and root 2/3 were evaluated. RESULTS: Three canal categories, labeled as Single (77.88%), Merged (15.87%), and Separated (6.25%), were summarized. The most frequent constriction type in main foramina was single constriction (42.53%). Wide and narrow diameters in a single main foramen were 0.37 ± 0.14 mm and 0.26 ± 0.07 mm, respectively. The distance from the anatomical foramen to the physiological foramen and the anatomical apex was 0.49 ± 0.20 mm and 0.36 ± 0.28 mm, respectively. During the virtual root-end resection, 97.12% of roots underwent successful resection at the 2-mm level, with the foramina visible on the resection surface. During 2-D cross-sectional analyses, the shape parameters of the root and canal showed significant positive correlation (P < 0.05). The thickest and thinnest walls were the incisal and proximal walls (P < 0.05) of the crown, respectively. The buccal walls were significantly thicker than the lingual walls on the crown (P < 0.05), whereas the lingual walls were thicker on the root 2/3 (P < 0.05). CONCLUSIONS: This study provides detailed information about the root canal morphology and thickness of the crown and root of mandibular incisors in a Chinese population. An understanding of morphology can benefit endodontic treatment. CLINICAL RELEVANCE: Adequate knowledge of the crown, root, and canal morphology, as well as the thickness distribution of the crown and root, is essential for successful root canal therapy and prevention of complications.

Coexistence of Candida albicans and Enterococcus faecalis increases biofilm virulence and periapical lesions in rats.

The present study utilized an in vitro dual-species biofilm model and an in vivo rat post-treatment endodontic disease (PTED) model to investigate whether co-infection of Candida albicans and Enterococcus faecalis would aggravate periapical lesions. The results showed that co-culturing yielded a thicker and denser biofilm more tolerant to detrimental stresses compared with the mono-species biofilm, such as a starvation-alkalinity environment, mechanical shear force and bactericidal chemicals. Consistently, co-inoculation of E. faecalis and C. albicans significantly increased the extent of in vivo periapical lesions compared with mono-species infection. Specifically, coexistence of both microorganisms increased osteoclastic bone resorption and suppressed osteoblastic bone formation. The synergistic effects also up-regulated inflammatory cytokines including TNF-α and IL-6. In summary, coexistence of C. albicans and E. faecalis increased periapical lesions by enhanced biofilm virulence.

Efficacy of Er:YAG laser irradiation for decontamination and its effect on biocompatibility of different titanium surfaces.

BACKGROUND: Erbium yttrium-aluminum-garnet (Er:YAG) laser have been shown to be suitable for decontamination of titanium surfaces at a wide range of energy settings, however, high intensity of laser irradiation destroy titanium surface and low intensity cannot remove enough microbial biofilm. The aim of this study was to investigate the optimal energy setting of Er:YAG laser for decontamination of sandblasted/acid-etched (SLA) and hydroxyapatite (HA) titanium surfaces. MATERIAL AND METHODS: After supragingival biofilm construction in vivo, SLA and HA titanium discs were divided into three groups: blank control (BC, clean discs), experimental control (EC, contaminated discs) and experimental groups (EP, contaminated discs irradiated by Er:YAG laser at 40, 70, and 100 mJ/pulse). Scanning electron microscopy (SEM), live/dead bacterial fluorescent detection, and colony counting assay were used to detect the efficacy of laser decontamination. To investigate the effect of laser decontamination on titanium surface biocompatibility, MC3T3-E1 cell adhesion and proliferation activity were examined by SEM and CCK-8 assay. RESULTS: Er:YAG laser irradiation at 100 mJ/pulse removed 84.1% of bacteria from SLA titanium surface; laser irradiation at 70 and 100 mJ/pulse removed 76.4% and 77.85% of bacteria from HA titanium surface respectively. Laser irradiation improved MC3T3-E1 cell adhesion on both titanium surfaces. For SLA titanium discs, 100 mJ/pulse group displayed excellent cellular proliferation activity higher than that in BC group (P < 0.01). For HA titanium discs, 70 mJ/pulse group showed the highest activity comparable to BC group (P > 0.05). CONCLUSIONS: With regards to efficient microbial biofilm decontamination and biocompatibility maintenance, Er:YAG laser at 100 mJ/pulse and 70 mJ/pulse are considered as the optimal energy settings for SLA titanium and HA titanium surface respectively. This study provides theoretical basis for the clinical application of Er:YAG laser in the treatment of peri-implantitis.

Mechano-chemical coupling of irrigation enhances endodontic biofilm debridement.

The complexity of the root canal system results in areas where mechanical instrumentation is impossible during endodontic treatment. To disinfect these areas, the effect of irrigation on biofilm debridement is of great significance but has not yet been well explored. Using an in vitro Enterococcus faecalis biofilm model and a biofilm reactor, the present study provides a better understanding of the relative contributions of mechanical and chemical effects of irrigation on biofilm removal, as well as the factors influencing their coupling efficiency. The results clearly demonstrate that, the mechanical effect of irrigation alone does not significantly influence the stability of biofilms. However, the mechanical effect promotes biofilm eradication by coupling with the chemical effect. In addition, both the irrigant concentration and the irrigant-biofilm contact time are among the key factors affecting the mechano-chemical coupling. This knowledge may serve to better direct endodontists in designing irrigation regimes during root canal therapy.

Constitutive activation of hedgehog signaling adversely affects epithelial cell fate during palatal fusion.

Cleft palate is one of the most common craniofacial congenital defects in humans. It is associated with multiple genetic and environmental risk factors, including mutations in the genes encoding signaling molecules in the sonic hedgehog (Shh) pathway, which are risk factors for cleft palate in both humans and mice. However, the function of Shh signaling in the palatal epithelium during palatal fusion remains largely unknown. Although components of the Shh pathway are localized in the palatal epithelium, specific inhibition of Shh signaling in palatal epithelium does not affect palatogenesis. We therefore utilized a hedgehog (Hh) signaling gain-of-function mouse model, K14-Cre;R26SmoM2, to uncover the role of Shh signaling in the palatal epithelium during palatal fusion. In this study, we discovered that constitutive activation of Hh signaling in the palatal epithelium results in submucous cleft palate and persistence of the medial edge epithelium (MEE). Further investigation revealed that precise downregulation of Shh signaling is required at a specific time point in the MEE during palatal fusion. Upregulation of Hh signaling in the palatal epithelium maintains the proliferation of MEE cells. This may be due to a dysfunctional p63/Irf6 regulatory loop. The resistance of MEE cells to apoptosis is likely conferred by enhancement of a cell adhesion network through the maintenance of p63 expression. Collectively, our data illustrate that persistent Hh signaling in the palatal epithelium contributes to the etiology and pathogenesis of submucous cleft palate through its interaction with a p63/Irf6-dependent biological regulatory loop and through a p63-induced cell adhesion network.

Taxonomic and Functional Analyses of the Supragingival Microbiome from Caries-Affected and Caries-Free Hosts.

Caries is one of the most prevalent and costly infectious diseases affecting humans of all ages. It is initiated by cariogenic supragingival dental plaques forming on saliva-coated tooth surfaces, yet the etiology remains elusive. To determine which microbial populations may predispose a patient to caries, we report here an in-depth and comprehensive view of the microbial community associated with supragingival dental plaque collected from the healthy teeth of caries patients and healthy adults. We found that microbial communities from caries patients had a higher evenness and inter-individual variations but simpler ecological networks compared to healthy controls despite the overall taxonomic structure being similar. Genera including Selenomonas, Treponema, Atopobium, and Bergeriella were distributed differently between the caries and healthy groups with disturbed co-occurrence patterns. In addition, caries and healthy subjects carried different Treponema, Atopobium, and Prevotella species. Moreover, distinct populations of 13 function genes involved in organic acid synthesis, glycan biosynthesis, complex carbohydrate degradation, amino acid synthesis and metabolism, purine and pyrimidine metabolism, isoprenoid biosynthesis, lipid metabolism, and co-factor biosynthesis were present in each of the healthy and caries groups. Our results suggested that the fundamental differences in dental plaque ecology partially explained the patients' susceptibility to caries, and could be used for caries risk prediction in the future.

l-Arginine Modifies the Exopolysaccharide Matrix and Thwarts Streptococcus mutans Outgrowth within Mixed-Species Oral Biofilms.

UNLABELLED: l-Arginine, a ubiquitous amino acid in human saliva, serves as a substrate for alkali production by arginolytic bacteria. Recently, exogenous l-arginine has been shown to enhance the alkalinogenic potential of oral biofilm and destabilize its microbial community, which might help control dental caries. However, l-arginine exposure may inflict additional changes in the biofilm milieu when bacteria are growing under cariogenic conditions. Here, we investigated how exogenous l-arginine modulates biofilm development using a mixed-species model containing both cariogenic (Streptococcus mutans) and arginolytic (Streptococcus gordonii) bacteria in the presence of sucrose. We observed that 1.5% (wt/vol) l-arginine (also a clinically effective concentration) exposure suppressed the outgrowth of S. mutans, favored S. gordonii dominance, and maintained Actinomyces naeslundii growth within biofilms (versus vehicle control). In parallel, topical l-arginine treatments substantially reduced the amounts of insoluble exopolysaccharides (EPS) by >3-fold, which significantly altered the three-dimensional (3D) architecture of the biofilm. Intriguingly, l-arginine repressed S. mutans genes associated with insoluble EPS (gtfB) and bacteriocin (SMU.150) production, while spxB expression (H2O2 production) by S. gordonii increased sharply during biofilm development, which resulted in higher H2O2 levels in arginine-treated biofilms. These modifications resulted in a markedly defective EPS matrix and areas devoid of any bacterial clusters (microcolonies) on the apatitic surface, while the in situ pH values at the biofilm-apatite interface were nearly one unit higher in arginine-treated biofilms (versus the vehicle control). Our data reveal new biological properties of l-arginine that impact biofilm matrix assembly and the dynamic microbial interactions associated with pathogenic biofilm development, indicating the multiaction potency of this promising biofilm disruptor. IMPORTANCE: Dental caries is one of the most prevalent and costly infectious diseases worldwide, caused by a biofilm formed on tooth surfaces. Novel strategies that compromise the ability of virulent species to assemble and maintain pathogenic biofilms could be an effective alternative to conventional antimicrobials that indiscriminately kill other oral species, including commensal bacteria. l-Arginine at 1.5% has been shown to be clinically effective in modulating cariogenic biofilms via alkali production by arginolytic bacteria. Using a mixed-species ecological model, we show new mechanisms by which l-arginine disrupts the process of biofilm matrix assembly and the dynamic microbial interactions that are associated with cariogenic biofilm development, without impacting the bacterial viability. These results may aid in the development of enhanced methods to control biofilms using l-arginine.

Oral cavity contains distinct niches with dynamic microbial communities.

Microbes colonize human oral surfaces within hours after delivery. During postnatal development, physiological changes, such as the eruption of primary teeth and replacement of the primary dentition with permanent dentition, greatly alter the microbial habitats, which, in return, may lead to community composition shifts at different phases in people's lives. By profiling saliva, supragingival and mucosal plaque samples from healthy volunteers at different ages and dentition stages, we observed that the oral cavity is a highly heterogeneous ecological system containing distinct niches with significantly different microbial communities. More importantly, the phylogenetic microbial structure varies with ageing. In addition, only a few taxa were present across the whole populations, indicating a core oral microbiome should be defined based on age and oral niches.

Analysis of oral microbial community and Th17-associated cytokines in saliva of patients with oral lichen planus.

Oral lichen planus (OLP) is a chronic inflammatory disorder of oral mucosa of unknown cause. Microbial infection and dysimmunity appear to play important roles in its pathogenesis. In this study, differences in genetic profiling of salivary microbial communities in two subtypes of OLP and healthy controls were evaluated by means of PCR-denaturing gradient gel electrophoresis (DGGE). Additionally, ELISA was used to investigate the possible role of Th17 in lesion formation by detecting two related cytokines IL-17 and IL-23 in the saliva of OLP patients. When the DGGE profiles were analyzed, the bacterial populations were found to be significantly less rich in subjects with reticular and erosive OLP than in healthy controls. There was significantly less microbial diversity, as denoted by the Shannon index, in saliva samples from subjects with erosive OLP than in those from healthy controls. Cluster analysis and principal component analysis showed that the DGGE profiles formed distinctly group-specific clusters. Salivary concentrations of IL-17 in subjects with erosive OLP group were significantly higher than in those with reticular OLP and healthy controls. What's more, significantly positive correlations were observed between salivary IL-17 concentrations and disease clinical scores. Microbial richness and diversity was negatively correlated with salivary IL-17 concentrations. These results suggest there is significantly less salivary bacterial diversity and complexity in subjects with OLP han in healthy controls and that the shifted community composition is closely related to an immune cytokine, IL-17.

Stem Cells from the Apical Papilla (SCAPs): Past, Present, Prospects, and Challenges.

Dental diseases occurring on young permanent teeth usually lead to the premature arrest of tooth root development. Sustained tooth root elongation is necessary to achieve the goal of long-term preservation of affected teeth. To this end, stem cell-based regenerative endodontic treatment has been regarded as one of the most promising strategies for treating young permanent teeth with pulp and periapical infections. Endogenous stem cells residing in the apical papilla, named stem cells from the apical papilla (SCAPs), have been intensively investigated due to their critical roles in pulp regeneration and root redevelopment. The present review summarizes advances in the field of SCAPs studies and discusses the challenges that need to be further addressed.

Roles of Streptococcus mutans-Candida albicans interaction in early childhood caries: a literature review.

As one of the most common oral diseases in kids, early childhood caries affects the health of children throughout the world. Clinical investigations show the copresence of Candida albicans and Streptococcus mutans in ECC lesions, and mechanistic studies reveal co-existence of C. albicans and S. mutans affects both of their cariogenicity. Clearly a comprehensive understanding of the interkingdom interaction between these two microorganisms has important implications for ECC treatment and prevention. To this end, this review summarizes advances in our understanding of the virulence of both C. albicans and S. mutans. More importantly, the synergistic and antagonistic interactions between these two microbes are discussed.

Human periodontitis-associated salivary microbiome affects the immune response of diabetic mice.

Background: The bidirectional association between periodontitis and diabetes mellitus has been well accepted; however, pathways connecting them remain unclear. Some oral bacteria are able to induce immunologic changes favoring insulin resistance individually. However, it is unclear if and how the systemic immune system responds to a disturbed oral microbial community in diabetic sufferers. Aim: This study aimed to investigate the impact of the human periodontitis-associated salivary microbiome on the splenic immune responses of diabetic mice. Methods: An in vivo diabetic animal model was established by feeding high fat food. After microbial depletion with quadruple antibiotic treatment, human saliva from healthy and periodontitis volunteers was transplanted into the mouth of these diabetic mice (N = 3), respectively. Results: Osteoclasts and expression levels of TNF-α and IL-1ß were significantly increased in periodontal tissues of mice receiving periodontitis patients donated microbiome compared to these transplanted with healthy subjects donated microbiome. The proportion of monocyte (an innate immunocyte) decreased in mice receiving periodontitis patients donated microbiome. However, the abundance of an adaptive immunocyte Th17 was up-regulated. The IL17 production of ILC3 cells in human periodontitis-associated salivary microbiome recipient mice was significantly impaired. Conclusions: A disturbed oral microbiome imposes a stress on the splenic immune responses of diabetic mice.

Effect of LongZhang Gargle on Dual-Species Biofilm of Candida albicans and Streptococcus mutans.

Bioactive natural products have become a hot spot for oral disease treatments. At the present study, LongZhang Gargle was investigated for its effects on single-species biofilms of Candida albicans and dual-species biofilms of Candida albicans and Streptococcus mutans. Two different models of single and dual-species biofilms were grown in YNBB medium under appropriate conditions. Biofilm biomass, biofilm architecture, and cell activity in biofilms were assessed using Crystal Violet Staining, MTT, scanning electron microscopy (SEM), and confocal laser scanning microscopy (CLSM). Significant reductions of biofilm biomass and fungus activity were obtained when treated with LongZhang Gargle at 2% (P < 0.05), 4% (P < 0.05), and 8% (P < 0.05) in single-species biofilms of C. albicans, and at 4% (P < 0.05) and 8% (P < 0.05) in double-species biofilms. Suppression of density, thickness, and the proportion of hyphae and fungal spores were obtained under SEM and CLSM. In conclusion, LongZhang Gargle affects single and dual-species biofilms by inhibiting biofilm biomass, cell activity, and formation of hyphae, but it does not affect the production of Extracellular polysaccharides (EPS). We speculate that LongZhang Gargle would be a promising natural drug, which can be used in treatment against C. albicans and S. mutans in oral diseases.

Broken Instrument Removal from Mandibular First Molar with Conebeam Computed Tomography based Pre-operative Computer-assisted Simulation: A Case Report.

Intracanal separation of nickel titanium files hinders complete shaping, cleaning, and filling of the root canal system and ultimately influences the endodontic treatment outcome. In this case report, we presented a successful broken instrument retrieval from the middle third of the mesiobuccal root canal of tooth #30 with the assistance of cone-beam computed tomograpgy based preoperative computer-assisted simulation, micro-trepan bur and micro-tube from Micro-Retrieve & Repair system and dental operative microscope. The involved tooth was then successfully cleaned, shaped and obturated followed by coronal restoration. At the three-year follow-up, tooth #30 was asymptomatic and functioned well without radiographic changes. The present case provides an example to show the robustness of computer-assisted technology in dental procedures and to show how the combination of advanced techniques can facilitate root canal therapy.

Candida albicans promotes tooth decay by inducing oral microbial dysbiosis.

Candida albicans has been detected in root carious lesions. The current study aimed to explore the action of this fungal species on the microbial ecology and the pathogenesis of root caries. Here, by analyzing C. albicans in supragingival dental plaque collected from root carious lesions and sound root surfaces of root-caries subjects as well as caries-free individuals, we observed significantly increased colonization of C. albicans in root carious lesions. Further in vitro and animal studies showed that C. albicans colonization increased the cariogenicity of oral biofilm by altering its microbial ecology, leading to a polymicrobial biofilm with enhanced acidogenicity, and consequently exacerbated tooth demineralization and carious lesion severity. More importantly, we demonstrated that the cariogenicity-promoting activity of C. albicans was dependent on PHR2. Deletion of PHR2 restored microbial equilibrium and led to a less cariogenic biofilm as demonstrated by in vitro artificial caries model or in vivo root-caries rat model. Our data indicate the critical role of C. albicans infection in the occurrence of root caries. PHR2 is the major factor that determines the ecological impact and caries-promoting activity of C. albicans in a mixed microbial consortium.

Reciprocal interaction between mesenchymal stem cells and transit amplifying cells regulates tissue homeostasis.

Interaction between adult stem cells and their progeny is critical for tissue homeostasis and regeneration. In multiple organs, mesenchymal stem cells (MSCs) give rise to transit amplifying cells (TACs), which then differentiate into different cell types. However, whether and how MSCs interact with TACs remains unknown. Using the adult mouse incisor as a model, we present in vivo evidence that TACs and MSCs have distinct genetic programs and engage in reciprocal signaling cross talk to maintain tissue homeostasis. Specifically, an IGF-WNT signaling cascade is involved in the feedforward from MSCs to TACs. TACs are regulated by tissue-autonomous canonical WNT signaling and can feedback to MSCs and regulate MSC maintenance via Wnt5a/Ror2-mediated non-canonical WNT signaling. Collectively, these findings highlight the importance of coordinated bidirectional signaling interaction between MSCs and TACs in instructing mesenchymal tissue homeostasis, and the mechanisms identified here have important implications for MSC-TAC interaction in other organs.