Mapping the immune microenvironment for mandibular alveolar bone homeostasis at single-cell resolution

Lin, Weimin; Li, Qiwen; Zhang, Danting; Zhang, Xiaohan; Qi, Xu; Wang, Qian; Chen, Yaqian; Liu, Caojie; Li, Hanwen; Zhang, Shiwen; Wang, Yuan; Shao, Bin; Zhang, Li; Yuan, Quan

doi:10.1038/s41413-021-00141-5

Cited by 70 publications

(84 citation statements)

References 52 publications

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“…For osteogenic differentiation, rBMSCs were induced with medium containing 10 mM β-glycerophosphate, 10 –8 M dexamethasone and 50 μg/ml L-2-ascorbic acid (Sigma-Aldrich, St. Louis, MO, USA) [ 33 ]. The culture cells were randomized into normal-glucose (NG) group (5.6 mM) and high-glucose (HG) group (30 mM).…”

Section: Methodsmentioning

confidence: 99%

“…The optical density (OD) was evaluated by measuring the absorbance at 405 nm spectrophotometrically. The total protein content was measured at OD 562nm , and the concentration was calculated according to the standard BSA curve using the enhanced BCA protein assay (Beyotime, P0010) [ 33 ]. ALP activity was represented by the OD 405nm value after normalization to the total cellular protein.…”

Section: Methodsmentioning

confidence: 99%

“…After 21 days of osteogenic induction, calcium deposition was determined by alizarin red S (ARS) staining and semi-quantitative analysis [ 33 ]. The cells were fixed with 4% paraformaldehyde for 15 min and then stained with 0.1% ARS (pH 4.2, Sigma-Aldrich) for 30 min.…”

Section: Methodsmentioning

confidence: 99%

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PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

et al. 2021

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Background Diabetic patients are more vulnerable to skeletal complications. Peroxisome proliferators-activated receptor (PPAR) β/δ has a positive regulatory effect on bone turnover under physiologic glucose concentration; however, the regulatory effect in diabetes mellitus has not been investigated yet. Herein, we explored the effects of PPARβ/δ agonist on the regeneration of diabetic bone defects and the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) under a pathological high-glucose condition. Methods We detected the effect of PPARβ/δ agonist on osteogenic differentiation of rBMSCs in vitro and investigated the bone healing process in diabetic rats after PPARβ/δ agonist treatment in vivo. RNA sequencing was performed to detect the differentially expressed genes and enriched pathways. Western blot was performed to detect the autophagy-related protein level. Laser confocal microscope (LSCM) and transmission electron microscope (TEM) were used to observe the formation of autophagosomes. Results Our results demonstrated that the activation of PPARβ/δ can improve the osteogenic differentiation of rBMSCs in high-glucose condition and promote the bone regeneration of calvarial defects in diabetic rats, while the inhibition of PPARβ/δ alleviated the osteogenic differentiation of rBMSCs. Mechanistically, the activation of PPARβ/δ up-regulates AMPK phosphorylation, yielding mTOR suppression and resulting in enhanced autophagy activity, which further promotes the osteogenic differentiation of rBMSCs in high-glucose condition. The addition of AMPK inhibitor Compound C or autophagy inhibitor 3-MA inhibited the osteogenesis of rBMSCs in high-glucose condition, suggesting that PPARβ/δ agonist promotes osteogenic differentiation of rBMSCs through AMPK/mTOR-regulated autophagy. Conclusion In conclusion, our study demonstrates the potential role of PPARβ/δ as a molecular target for the treatment of impaired bone quality and delayed bone healing in diabetic patients for the first time.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

et al. 2021

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“…Although the mandibular bone is not a pathological condition per se , it is closer to a pathological condition than the femoral bone since the oral cavity is frequently exposed to foreign substances. As alveolar bone is bearing mechanical loads, whose force is two times higher than that of long bones ( Ehrlich and Lanyon, 2002 ), coupled with a recent data indicating that mechanical stimulation promotes activation of myeloid-derived monocytes ( Lin et al, 2021 ), implies that occlusal forces might lead to the difference of the immune microenvironment between alveolar bone and long bone. Thus, it is likely that M-MDSCs from mandibular bone are more activated and participating in immune surveillance, which may explain why M-MDSCs from mandible shows higher immunosuppressive capabilities than M-MDSCs from long bone.…”

Section: Discussionmentioning

confidence: 99%

Discovering Myeloid Cell Heterogeneity in Mandibular Bone – Cell by Cell Analysis

et al. 2021

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The myeloid-derived bone marrow progenitor populations from different anatomical locations are known to have diverse osteoclastogenesis potential. Specifically, myeloid progenitors from the tibia and femur have increased osteoclast differentiation potential compared to myeloid progenitors from the alveolar process. In this study, we explored the differences in the myeloid lineage progenitor cell populations in alveolar (mandibular) bone versus long (femur) bone using flow cytometry and high-throughput single cell RNA sequencing (scRNA-seq) to provide a comprehensive transcriptional landscape. Results indicate that mandibular bone marrow-derived cells exhibit consistent deficits in myeloid differentiation, including significantly fewer myeloid-derived suppressor cell (MDSC)-like populations (CD11b+Ly6C+, CD11b+Ly6G+), as well as macrophages (CD11b+F4/80+). Although significantly fewer in number, MDSCs from mandibular bone exhibited increased immunosuppressive activity compared to MDSCs isolated from long bone. Using flow cytometry panels specific for bone marrow progenitors, analysis of hematopoietic stem cells showed no defects in mandibular bone marrow in LSK (Lin–Sca1+cKit+) cell and LK (Lin–Sca1–cKit+) cell populations. While there was no significant difference in granulocyte progenitors, the granulocyte-monocyte progenitors and monocyte progenitor population were significantly decreased in the mandibular bone marrow. T-lymphocyte subsets were not significantly different between mandibular and femoral bone, except for CD4+CD25+Foxp3+ regulatory T lymphocytes, which were significantly increased in the mandible. In addition, B lymphocytes were significantly increased in mandible. Single cell RNA sequencing from mandible and femur BM revealed distinct differences in transcriptomic profiles in myeloid populations establishing previously unappreciated aspects of mandibular bone marrow populations. These analyses reveal site-specific differences in the myeloid progenitor cellular composition and transcriptional programs providing a deeper appreciation of the complex differences in myeloid cell heterogeneity from different anatomical bone marrow sites.

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“…And its roles in autoimmunity and inflammation are also widely reported [ 3 , 4 ]. Our previous study indicated that OSM was highly expressed in jaw bone marrow, serving as an important inflammatory factor that regulated the homeostasis of jaw bone [ 5 ]. In particular, OSM presents pleiotropic functions on cancers.…”

Section: Introductionmentioning

confidence: 99%

Exploring the oncostatin M (OSM) feed-forward signaling of glioblastoma via STAT3 in pan-cancer analysis

et al. 2021

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Background Oncostatin M (OSM) has been reported to be a key regulating factor in the process of tumor development. Previous studies have demonstrated both the promotion and inhibition effects of OSM in tumors, therefore inspiring controversies. However, no systematic assessment of OSM across various cancers is available, and the mechanisms behind OSM-related cancer progression remain to be elucidated. Methods Based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, we conducted a pan-cancer analysis on OSM to explore its tumor-related functions across cancers as well as its correlations with specific molecules, cells in the tumor microenvironment. Considering the results of pan-cancer analysis, we chose the specific tumor glioblastoma multiforme (GBM) to screen out the OSM-induced signaling pathways and intercellular communications in tumor progression. Wound scratch assay, invasion assay and qRT-PCR were performed to verify the biological effects of OSM on glioblastoma cells. Results Higher OSM level was found in most tumor tissues compared with corresponding normal tissues, and the enhanced OSM expression was observed to be strongly related to patients’ poor prognosis in several cancers. Moreover, the expression of OSM was associated with stromal and immune cell infiltration in the tumor microenvironment, and OSM-related immune checkpoint and chemokine co-expression were also observed. Our results suggested that OSM could communicate extensively with the tumor microenvironment. Taking GBM as an example, our study found that two critical signaling pathways in OSM-related tumor progression by KEGG enrichment analysis: Jak-STAT and NF-κB pathways. Single-cell RNA sequencing data analysis of GBM revealed that OSM was mainly secreted by microglia, and cell–cell interaction analysis proved that OSM-OSMR is an important pathway for OSM to stimulate malignant cells. In vitro, OSM treatment could facilitate the migration and invasion of glioblastoma cells, meanwhile promote the proneural-mesenchymal transition. The administration of STAT3 inhibitors effectively suppressed the OSM-mediated biological effects, which proved the key role of STAT3 in OSM signaling. Conclusion Taken together, our study provides a comprehensive understanding with regard to the tumor progression under the regulation of OSM. OSM seems to be closely related to chronic inflammation and tumor development in the tumor microenvironment. As an important inflammatory factor in the tumor microenvironment, OSM may serve as a potential immunotherapeutic target for cancer treatment, especially for GBM.

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Mapping the immune microenvironment for mandibular alveolar bone homeostasis at single-cell resolution

Cited by 70 publications

References 52 publications

PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

PPARβ/δ accelerates bone regeneration in diabetic mellitus by enhancing AMPK/mTOR pathway-mediated autophagy

Discovering Myeloid Cell Heterogeneity in Mandibular Bone – Cell by Cell Analysis

Exploring the oncostatin M (OSM) feed-forward signaling of glioblastoma via STAT3 in pan-cancer analysis

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