Penn Dental Medicine
Established in 1878, Penn Dental Medicine is among the oldest university-affiliated dental schools in the nation. The school's mission is to transform global oral health and well-being through exceptional clinical care, innovation, education, and research.
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Publication Accurate gingival segmentation from 3D images with artificial intelligence: an animal pilot study(Springer, 2023-12) Yang, Min; Li, Chenshuang; Yang, Wen; Chen, Chider; Chung, Chun-Hsi; Tanna, Nipul; Zheng, ZhongBackground: Gingival phenotype plays an important role in dental diagnosis and treatment planning. Traditionally, determining the gingival phenotype is done by manual probing of the gingival soft tissues, an invasive and time-consuming procedure. This study aims to evaluate the feasibility and accuracy of an alternatively novel, non-invasive technology based on the precise 3-dimension (3D) soft tissue reconstruction from intraoral scanning and cone beam computed tomography (CBCT) to predict the gingival biotype. Methods: As a proof-of-concept, Yorkshire pig mandibles were scanned, and the CBCT data were fed into a deep-learning model to reconstruct the teeth and surrounding bone structure in 3D. By overlaying the CBCT scan with the intraoral scans, an accurate superposition was created and used for virtual measurements of the soft tissue thickness. Meanwhile, gingival thicknesses were also measured by a periodontal probe and digital caliper on the buccal and lingual sides at 3 mm apical to the gingival margin of the posterior teeth and compared with the virtual assessment at the same location. The data obtained from virtual and clinical measurements were compared by Wilcoxon matched-pairs signed-rank analysis, while their correlation was determined by Pearson’s r value. The Mann–Whitney U test was used for intergroup comparisons of the amount of difference. Results: Among 108 investigated locations, the clinical and virtual measurements are strongly positively correlated (r = 0.9656, P < 0.0001), and only clinically insignificant differences (0.066 ± 0.223 mm) were observed between the two assessments. There is no difference in the agreement between the virtual and clinical measurements on sexually matured samples (0.087 ± 0.240 mm) and pre-pubertal samples (0.033 ± 0.195 mm). Noticeably, there is a greater agreement between the virtual and clinical measurements at the buccal sites (0.019 ± 0.233 mm) than at the lingual sites (0.116 ± 0.215 mm). Conclusion: In summary, the artificial intelligence-based virtual measurement proposed in this work provides an innovative technique potentially for accurately measuring soft tissue thickness using clinical routine 3D imaging systems, which will aid clinicians in generating a more comprehensive diagnosis with less invasive procedures and, in turn, optimize the treatment plans with more predictable outcomes. © 2023, The Author(s).Publication Csf1 from marrow adipogenic precursors is required for osteoclast formation and hematopoiesis in bone(eLife, 2023-02-13) Zhong, Leilei; Lu, Jiawei; Fang, Jiankang; Yao, Lutian; Yu, Wei; Gui, Tao; Duffy, Michael; Holdreith, Nicholas; Bautista, Catherine A.; Huang, Xiaobin; Bandyopadhyay, Shovik; Tan, Kai; Chen, Chider; Choi, Yongwon; Jiang, Jean X.; Yang, Shuying; Tong, Wei; Dyment, Nathanial; Qin, LingColony-stimulating factor 1 (Csf1) is an essential growth factor for osteoclast progenitors and an important regulator for bone resorption. It remains elusive which mesenchymal cells synthesize Csf1 to stimulate osteoclastogenesis. We recently identified a novel mesenchymal cell population, marrow adipogenic lineage precursors (MALPs), in bone. Compared to other mesenchymal subpopulations, MALPs expressed Csf1 at a much higher level and this expression was further increased during aging. To investigate its role, we constructed MALP-deficient Csf1 CKO mice using AdipoqCre. These mice had increased femoral trabecular bone mass, but their cortical bone appeared normal. In comparison, depletion of Csf1 in the entire mesenchymal lineage using Prrx1Cre led to a more striking high bone mass phenotype, suggesting that additional mesenchymal subpopulations secrete Csf1. TRAP staining revealed diminished osteoclasts in the femoral secondary spongiosa region of Csf1 CKOAdipoq mice, but not at the chondral-osseous junction nor at the endosteal surface of cortical bone. Moreover, Csf1 CKOAdipoq mice were resistant to LPS-induced calvarial osteolysis. Bone marrow cellularity, hematopoietic progenitors, and macrophages were also reduced in these mice. Taken together, our studies demonstrate that MALPs synthesize Csf1 to control bone remodeling and hematopoiesis. © 2023, Zhong et al.Publication Advancing collagen-based biomaterials for oral and craniofacial tissue regeneration(Springer, 2023-12) Zhang, Bo; He, Yunxiang; Liu, Jialing; Shang, Jiaojiao; Chen, Chider; Wang, Tianyi; Chen, Mei; Li, Yifei; Gong, Guidong; Fang, Jie; Zhao, Zhihe; Guo, JunlingThe oral and craniofacial region consists of various types of hard and soft tissues with the intricate organization. With the high prevalence of tissue defects in this specific region, it is highly desirable to enhance tissue regeneration through the development and use of engineered biomaterials. Collagen, the major component of tissue extracellular matrix, has come into the limelight in regenerative medicine. Although collagen has been widely used as an essential component in biomaterial engineering owing to its low immunogenicity, high biocompatibility, and convenient extraction procedures, there is a limited number of reviews on this specific clinic sector. The need for mechanical enhancement and functional engineering drives intensive efforts in collagen-based biomaterials concentrating on therapeutical outcomes and clinical translation in oral and craniofacial tissue regeneration. Herein, we highlighted the status quo of the design and applications of collagen-based biomaterials in oral and craniofacial tissue reconstruction. The discussion expanded on the inspiration from the leather tanning process on modifications of collagen-based biomaterials and the prospects of multi-tissue reconstruction in this particular dynamic microenvironment. The existing findings will lay a new foundation for the optimization of current collagen-based biomaterials for rebuilding oral and craniofacial tissues in the future. Graphical Abstract: [Figure not available: see fulltext.] © 2023, The Author(s).Publication Natural compounds and mesenchymal stem cells: implications for inflammatory-impaired tissue regeneration(Springer, 2024-12) Li, Wen; Xiang, Zichao; Yu, Wenjing; Huang, Xiaobin; Jiang, Qian; Abumansour, Arwa; Yang, Ying; Chen, ChiderInflammation is a common and important pathological process occurring in any part of the body and relating to a variety of diseases. Effective tissue repair is critical for the survival of impaired organisms. Considering the side effects of the currently used anti-inflammatory medications, new therapeutic agents are urgently needed for the improvement of regenerative capacities of inflammatory-impaired tissues. Mesenchymal stromal stem/progenitor cells (MSCs) are characterized by the capabilities of self-renewal and multipotent differentiation and exhibit immunomodulatory capacity. Due to the ability to modulate inflammatory phenotypes and immune responses, MSCs have been considered as a potential alternative therapy for autoimmune and inflammatory diseases. Natural compounds (NCs) are complex small multiple-target molecules mostly derived from plants and microorganisms, exhibiting therapeutic effects in many disorders, such as osteoporosis, diabetes, cancer, and inflammatory/autoimmune diseases. Recently, increasing studies focused on the prominent effects of NCs on MSCs, including the regulation of cell survival and inflammatory response, as well as osteogenic/adipogenic differentiation capacities, which indicate the roles of NCs on MSC-based cytotherapy in several inflammatory diseases. Their therapeutic effects and fewer side effects in numerous physiological processes, compared to chemosynthetic drugs, made them to be a new therapeutic avenue combined with MSCs for impaired tissue regeneration. Here we summarize the current understanding of the influence of NCs on MSCs and related downstream signaling pathways, specifically in pathological inflammatory conditions. In addition, the emerging concepts through the combination of NCs and MSCs to expand the therapeutic perspectives are highlighted. A promising MSC source from oral/dental tissues is also discussed, with a remarkable potential for MSC-based therapy in future clinical applications. © The Author(s) 2024.Publication ERK1-mediated immunomodulation of mesenchymal stem cells ameliorates inflammatory disorders(Elsevier, 2023-10-20) Zhang, Qing; Lei, Xiao; Wang, Fang; He, Xiaoning; Liu, Lu; Hou, Yuxia; Liu, Yuan; Jin, Fang; Chen, Chider; Li, BeiImmune system disorders, especially T cell disorders, are important therapeutic targets of mesenchymal stem cells (MSCs) in many autoimmune diseases (ADs). Although extracellular regulated protein kinases (ERKs) play a role in MSC therapy by promoting T cell apoptosis, the mechanism remains unclear. Our findings indicate that ERK1−/− bone marrow MSCs (BMMSCs), but not ERK2−/− BMMSCs, failed to promote T cell apoptosis due to incapacity to activate the ETS2/AURKA/NF-κB/Fas/MCP-1 cascade. Moreover, ERK1−/− BMMSCs were unable to upregulate regulatory T cells and suppress T helper 17 cells. Licochalcone A (LA), which promotes ERK pathway activation, enhanced the therapeutic efficacy of MSC therapy in ulcerative colitis and collagen-induced arthritis mice. Our findings suggest that ERK1, but not ERK2, plays a crucial role in regulating T cells in MSCs. LA-treated MSCs provide a strategy to improve the efficacy of MSC-based treatments for ADs. © 2023 The Author(s)Publication Nanozyme-Based Robotics Approach for Targeting Fungal Infection(Wiley, 2024-03-07) Oh, Min Jun; Yoon, Seokyoung; Babeer, Alaa; Liu, Yuan; Ren, Zhi; Xiang, Zhenting; Miao, Yilan; Cormode, David P.; Chen, Chider; Steager, Edward; Koo, HyunFungal pathogens have been designated by the World Health Organization as microbial threats of the highest priority for global health. It remains a major challenge to improve antifungal efficacy at the site of infection while avoiding off-target effects, fungal spreading, and drug tolerance. Here, a nanozyme-based microrobotic platform is developed that directs localized catalysis to the infection site with microscale precision to achieve targeted and rapid fungal killing. Using electromagnetic field frequency modulation and fine-scale spatiotemporal control, structured iron oxide nanozyme assemblies are formed that display tunable dynamic shape transformation and catalysis activation. The catalytic activity varies depending on the motion, velocity, and shape providing controllable reactive oxygen species (ROS) generation. Unexpectedly, nanozyme assemblies bind avidly to fungal (Candida albicans) surfaces to enable concentrated accumulation and targeted ROS-mediated killing in situ. By exploiting these tunable properties and selective binding to fungi, localized antifungal activity is achieved using in vivo-like cell spheroid and animal tissue infection models. Structured nanozyme assemblies are directed to Candida-infected sites using programmable algorithms to perform precisely guided spatial targeting and on-site catalysis resulting in fungal eradication within 10 min. This nanozyme-based microrobotics approach provides a uniquely effective and targeted therapeutic modality for pathogen elimination at the infection site. © 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.Publication Apoptotic vesicles rescue impaired mesenchymal stem cells and their therapeutic capacity for osteoporosis by restoring miR-145a-5p deficiency(BioMed Central, 2024-12) Zhang, Rong; Mu, Xiaodan; Liu, Dawei; Chen, Chider; Meng, Bowen; Qu, Yan; Liu, Jin; Wang, Runci; Li, Chuanjie; Mao, Xueli; Wang, Qintao; Zhang, QingbinApoptotic vesicles (apoVs) play a vital role in various physiological and pathological conditions. However, we have yet to fully understand their precise biological effects in rescuing impaired mesenchymal stem cells (MSCs). Here, we proved that systemic infusion of MSCs derived from wild-type (WT) mice rather than from ovariectomized (OVX) mice effectively improved the osteopenia phenotype and rescued the impaired recipient MSCs in osteoporotic mice. Meanwhile, apoVs derived from WT MSCs (WT apoVs) instead of OVX apoVs efficiently restored the impaired biological function of OVX MSCs and their ability to improve osteoporosis. Mechanistically, the reduced miR-145a-5p expression hindered the osteogenic differentiation and immunomodulatory capacity of OVX MSCs by affecting the TGF-β/Smad 2/3-Wnt/β-catenin signaling axis, resulting in the development of osteoporosis. WT apoVs directly transferred miR-145a-5p to OVX MSCs, which were then reused to restore their impaired biological functions. The differential expression of miR-145a-5p is responsible for the distinct efficacy between the two types of apoVs. Overall, our findings unveil the remarkable potential of apoVs, as a novel nongenetic engineering approach, in rescuing the biological function and therapeutic capability of MSCs derived from patients. This discovery offers a new avenue for exploring apoVs-based stem cell engineering and expands the application scope of stem cell therapy, contributing to the maintenance of bone homeostasis through a previously unrecognized mechanism. © The Author(s) 2024.Publication Apoptotic vesicles ameliorate lupus and arthritis via phosphatidylserine-mediated modulation of T cell receptor signaling(Elsevier, 2023-07) Wang, Runci; Hao, Meng; Kou, Xiaoxing; Sui, Bingdong; Sanmillan, Maria Laura; Zhang, Xiao; Liu, Dawei; Tian, Jun; Yu, Wenjing; Chen, Chider; Yang, Ruili; Sun, Lingyun; Liu, Yi; Giraudo, Claudio; Rao, Deepak A.; Shen, Nan; Shi, SongtaoMesenchymal stem cells (MSCs) influence T cells in health, disease and therapy through messengers of intercellular communication including extracellular vesicles (EVs). Apoptosis is a mode of cell death that tends to promote immune tolerance, and a large number of apoptotic vesicles (apoVs) are generated from MSCs during apoptosis. In an effort to characterize these apoVs and explore their immunomodulatory potential, here we show that after replenishing them systemically, the apoV deficiency in Fas mutant mice and pathological lymphoproliferation were rescued, leading to the amelioration of inflammation and lupus activity. ApoVs directly interacted with CD4+ T cells and inhibited CD25 expression and IL-2 production in a dose-dependent manner. A broad range of Th1/2/17 subsets and cytokines including IFNγ, IL17A and IL-10 were suppressed while Foxp3+ cells were maintained. Mechanistically, exposed phosphatidylserine (PtdSer/PS) on apoVs mediated the interaction with T cells to disrupt proximal T cell receptor signaling transduction. Remarkably, administration of apoVs prevented Th17 differentiation and memory formation, and ameliorated inflammation and joint erosion in murine arthritis. Collectively, our findings unveil a previously unrecognized crosstalk between MSC apoVs and CD4+ T cells and suggest a promising therapeutic use of apoVs for autoimmune diseases. © 2022 The AuthorsPublication Mapping the cellular biogeography of human bone marrow niches using single-cell transcriptomics and proteomic imaging(Elsevier, 2024-06-06) Bandyopadhyay, Shovik; Duffy, Michael P.; Ahn, Kyung Jin; Sussman, Jonathan H.; Pang, Minxing; Smith, David; Duncan, Gwendolyn; Zhang, Iris; Huang, Jeffrey; Lin, Yulieh; Xiong, Barbara; Imtiaz, Tamjid; Chen, Chia-Hui; Thadi, Anusha; Chen, Changya; Xu, Jason; Reichart, Melissa; Martinez, Zachary; Diorio, Caroline; Chen, Chider; Pillai, Vinodh; Snaith, Oraine; Oldridge, Derek; Bhattacharyya, Siddharth; Maillard, Ivan; Carroll, Martin; Nelson, Charles; Qin, Ling; Tan, KaiNon-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely uncharacterized. We used single-cell RNA sequencing (scRNA-seq) to profile 29,325 non-hematopoietic cells and discovered nine transcriptionally distinct subtypes. We simultaneously profiled 53,417 hematopoietic cells and predicted their interactions with non-hematopoietic subsets. We employed co-detection by indexing (CODEX) to spatially profile over 1.2 million cells. We integrated scRNA-seq and CODEX data to link predicted cellular signaling with spatial proximity. Our analysis revealed a hyperoxygenated arterio-endosteal neighborhood for early myelopoiesis, and an adipocytic localization for early hematopoietic stem and progenitor cells (HSPCs). We used our CODEX atlas to annotate new images and uncovered mesenchymal stromal cell (MSC) expansion and spatial neighborhoods co-enriched for leukemic blasts and MSCs in acute myeloid leukemia (AML) patient samples. This spatially resolved, multiomic atlas of human bone marrow provides a reference for investigation of cellular interactions that drive hematopoiesis. © 2024 The Author(s)Publication ZIF-8 as a pH-Responsive Nanoplatform for 5-Fluorouracil Delivery in the Chemotherapy of Oral Squamous Cell Carcinoma(MDPI, 2024-09) Hao, Jessica; Chen, Chider; Pavelic, Kresimir; Ozer, Fusun5-fluorouracil (5-FU), a chemotherapeutic agent against oral squamous cell carcinoma (OSCC), is limited by poor pharmacokinetics and toxicity. The pH-sensitive zeolite imidazolate framework-8 (ZIF-8) may increase the selectivity and length of 5-FU released into the acidic tumor microenvironment. This study examined the in vitro 5-FU absorption and release profiles of ZIF-8, and then progressed to cytotoxicity assays using the OSCC primary cell line SCC7. The 5-FU loading capacity of ZIF-8 was calculated with UV-vis spectroscopy (λ = 260 nm). 5-FU release was quantified by submerging 5-FU@ZIF-8 in pH 7.4 and 5.5 acetate buffer over 48 h. For the cytotoxicity assays, 5-FU, ZIF-8, and 5-FU@ZIF-8 were added to SCC7 cultures at 25, 50, and 100 μg/mL. Cell viability was assessed through toluidine blue staining and further quantified through transcriptomic RNA sequencing. ZIF-8 stabilized at a maximum absorption of 2.71 ± 0.22 mg 5-FU, and released 0.66 mg more 5-FU at pH 5.5 than 7.4 for at least 72 h. The cytotoxicity assays showed that 5-FU@ZIF-8 had a synergistic inhibitory effect at 50 μg/mL. The RNA sequencing analysis further revealed the molecular targets of 5-FU@ZIF-8 in SCC7. 5-FU@ZIF-8 may release 5-FU based on the pH of the surrounding microenvironments and synergistically inhibit OSCC. © 2024 by the authors.