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.
PublicationMesenchymal Stem Cells Derived From Human Gingiva Are Capable of Immunomodulatory Functions and Ameliorate Inflammation-Related Tissue Destruction in Experimental Colitis (Journal of Immunology (2009) 183, (7787-7798))(2010-02-01) Zhang, Qunzhou; Shi, Hong; Liu, Yi; Uyanne, Jettie; Shi, Yufang; Shi, Songtao; Le, Anh D PublicationInterplay Between Mesenchymal Stem Cells and Lymphocytes Implications for Immunotherapy and Tissue Regeneration(2012-11-01) Wang, L.; Zhao, Y.; Shi, SongtaoIn addition to their potential for replacing damaged and diseased tissues by differentiating into tissue-specific cells, mesenchymal stem cells (MSCs) have been found to interact closely with immune cells, such as lymphocytes. In this review, we will discuss current research regarding the immunomodulatory properties of MSCs and the effects of lymphocytes on MSCs. We will suggest how these findings could be translated to potential clinical treatment. MSCs can regulate immune response by inducing activated T-cell apoptosis through the FAS ligand (FASL)/FAS-mediated death pathway via cell-cell contact, leading to up-regulation of regulatory T-cells (Tregs), which ultimately results in immune tolerance. Conversely, lymphocytes can impair survival and osteogenic differentiation of implanted MSCs by secreting the pro-inflammatory cytokines IFN-γ and TNF-α and/or through the FASL/FAS-mediated death pathway, thereby negatively affecting MSC-mediated tissue regeneration. One novel strategy to improve MSC-based tissue engineering involves the reduction of IFN-γ and TNF-α concentration by systemic infusion of Tregs or local application of aspirin. Further understanding of the mechanisms underlying the interplay between lymphocytes and MSCs may be helpful in the development of promising approaches to improve cell-based regenerative medicine and immune therapies. PublicationPeriodontal Ligament Stem Cell-Mediated Treatment for Periodontitis in Miniature Swine(2008-04-01) Liu, Yi; Zheng, Ying; Ding, Gang; Fang, Dianji; Zhang, Chunmei; Bartold, Peter Mark; Gronthos, Stan; Shi, Songtao; Wang, SonglinPeriodontitis is a periodontal tissue infectious disease and the most common cause for tooth loss in adults. It has been linked to many systemic disorders, such as coronary artery disease, stroke, and diabetes. At present, there is no ideal therapeutic approach to cure periodontitis and achieve optimal periodontal tissue regeneration. In this study, we explored the potential of using autologous periodontal ligament stem cells (PDLSCs) to treat periodontal defects in a porcine model of periodontitis. The periodontal lesion was generated in the first molars area of miniature pigs by the surgical removal of bone and subsequent silk ligament suture around the cervical portion of the tooth. Autologous PDLSCs were obtained from extracted teeth of the miniature pigs and then expanded ex vivo to enrich PDLSC numbers. When transplanted into the surgically created periodontal defect areas, PDLSCs were capable of regenerating periodontal tissues, leading to a favorable treatment for periodontitis. This study demonstrates the feasibility of using stem cell-mediated tissue engineering to treat periodontal diseases. PublicationHydrogen Sulfide Promotes Tet1- and Tet2-mediated Foxp3 Demethylation to Drive Regulatory T Cell Differentiation and Maintain Immune Homeostasis(2015-08-18) Yang, Ruili; Qu, Cunye; Zhou, Yu; Konkel, Joanne; Shi, Shihong; Liu, Yi; Chen, Chider; Liu, Shiyu; Liu, Dawei; Chen, Yibu; Zandi, Ebrahim; Chen, Wanjun; Zhou, Yanheng; Shi, SongtaoRegulatory T (Treg) cells are essential for maintenance of immune homeostasis. Here we found that hydrogen sulfide (H2S) was required for Foxp3+ Treg cell differentiation and function, and that H2S deficiency led to systemic autoimmune disease. H2S maintained expression of methylcytosine dioxygenases Tet1 and Tet2 by sulfhydrating nuclear transcription factor Y subunit beta (NFYB) to facilitate its binding to Tet1 and Tet2 promoters. Transforming growth factor-β (TGF-β)-activated Smad3 and interleukin-2 (IL-2)-activated Stat5 facilitated Tet1 and Tet2 binding to Foxp3. Tet1 and Tet2 catalyzed conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in Foxp3 to establish a Treg cell-specific hypomethylation pattern and stable Foxp3 expression. Consequently, Tet1 and Tet2 deletion led to Foxp3 hypermethylation, impaired Treg cell differentiation and function, and autoimmune disease. Thus, H2S promotes Tet1 and Tet2 expression, which are recruited to Foxp3 by TGF-β and IL-2 signaling to maintain Foxp3 demethylation and Treg cell-associated immune homeostasis. PublicationCell-based Immunotherapy with Mesenchymal Stem Cells Cures Bisphosphonate-related Osteonecrosis of the Jaw-like Disease in Mice(2010-07-01) Kikuiri, Takashi; Kim, Insoo; Yamaza, Takyoshi; Akiyama, Kentaro; Zhang, Qunzhou; Li, Yunsheng; Chen, Chider; Chen, Wanjun; Wang, Songlin; Le, Anh D; Shi, SongtaoPatients on high-dose bisphosphonate and immunosuppressive therapy have an increased risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ); despite the disease severity, its pathophysiology remains unknown, and appropriate therapy is not established. Here we have developed a mouse model of BRONJ-like disease that recapitulates major clinical and radiographic manifestations of the human disease, including characteristic features of an open alveolar socket, exposed necrotic bone or sequestra, increased inflammatory infiltrates, osseous sclerosis, and radiopaque alveolar bone. We show that administration of zoledronate, a potent aminobisphosphonate, and dexamethasone, an immunosuppressant drug, causes BRONJ-like disease in mice in part by suppressing the adaptive regulatory T cells, Tregs, and activating the inflammatory T-helper-producing interleukin 17 cells, Th17. Most interestingly, we demonstrate that systemic infusion with mesenchymal stem cells (MSCs) prevents and cures BRONJ-like disease possibly via induction of peripheral tolerance, shown as an inhibition of Th17 and increase in Treg cells. The suppressed Tregs/Th17 ratio in zoledronate- and dexamethasone-treated mice is restored in mice undergoing salvage therapy with Tregs. These findings provide evidence of an immunity-based mechanism of BRONJ-like disease and support the rationale for in vivo immunomodulatory therapy using Tregs or MSCs to treat BRONJ. © 2010 American Society for Bone and Mineral Research. PublicationVisible Red and Infrared Light Alters Gene Expression in Human Marrow Stromal Fibroblast Cells(2015-04-01) Guo, Jie; Wang, Qing; Wai, Daniel; Zhou, Qunzhou; Shi, Shihong; Le, Ahn D.; Shi, Songtao; Yen, Stephen L.K.Objectives This study tested whether or not gene expression in human marrow stromal fibroblast (MSF) cells depends on light wavelength and energy density. Material and Methods Primary cultures of isolated human bone marrow stem cells (hBMSC) were exposed to visible red (VR, 633 nm) and infrared (IR, 830) radiation wavelengths from a light emitting diode (LED) over a range of energy densities (0.5, 1.0, 1.5, 2.0 Joules/cm2) Cultured cells were assayed for cell proliferation, osteogenic potential, adipogenesis, mRNA and protein content. mRNA was analyzed by microarray, and compared among different wavelengths and energy densities. Mesenchymal and epithelial cell responses were compared to determine whether responses were cell-type specific. Protein array analysis was used to further analyze key pathways identified by microarrays. Result Different wavelengths and energy densities produced unique sets of genes identified by microarray analysis. Pathway analysis pointed to TGF beta 1 in the visible red and Akt 1 in the infrared wavelengths as key pathways to study. TGF beta protein arrays suggested switching from canonical to non-canonical TGF beta pathways with increases to longer IR wavelengths. Microarrays suggest RANKL and TIMP 10 followed IR energy density dose response curves. Epithelial and mesenchymal cells respond differently to stimulation by light suggesting cell-type specific response is possible. Conclusions These studies demonstrate differential gene expression with different wavelengths, energy densities and cell types. These differences in gene expression have the potential to be exploited for therapeutic purposes and can help explain contradictory results in the literature when wavelengths, energy densities and cell types differ. PublicationThe Hidden Treasure in Apical Papilla: The Potential Role in Pulp/Dentin Regeneration and BioRoot Engineering(2008-06-01) Huang, George T.J.; Sonoyama, Wataru; Liu, Yi; Liu, He; Wang, Songlin; Shi, SongtaoSome clinical case reports have shown that immature permanent teeth with periradicular periodontitis or abscess can undergo apexogenesis after conservative endodontic treatment. A call for a paradigm shift and new protocol for the clinical management of these cases has been brought to attention. Concomitantly, a new population of mesenchymal stem cells residing in the apical papilla of permanent immature teeth recently has been discovered and was termed stem cells from the apical papilla (SCAP). These stem cells appear to be the source of odontoblasts that are responsible for the formation of root dentin. Conservation of these stem cells when treating immature teeth may allow continuous formation of the root to completion. This article reviews current findings on the isolation and characterization of these stem cells. The potential role of these stem cells in the following respects will be discussed: (1) their contribution in continued root maturation in endodontically treated immature teeth with periradicular periodontitis or abscess and (2) their potential utilization for pulp/dentin regeneration and bioroot engineering. PublicationIL-17-mediated M1/M2 Macrophage Alteration Contributes to Pathogenesis of Bisphosphonate-related Osteonecrosis of the Jaws(2013-06-15) Zhang, Qunzhou; Atsuta, Ikiru; Liu, Shiyu; Chen, Chider; Shi, Shihong; Shi, Songtao; Le, Ahn DPurpose Osteonecrosis of the jaw (ONJ) is emerging as one of the important complications in cancer patients treated with antiresorptive agents. This study explored the potential role of IL-17-mediated M1/M2 macrophage alterations in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Experimental Design The expression of IL-17 and M1 and M2 macrophage markers at the local mucosal site of human BRONJ lesions was examined by immunofluorescence studies. BRONJ-like disease was induced in C57BL/6 mice and multiple myeloma (MM)-burdened mice by intravenous injection of zoledronate to evaluate the correlation of elevated IL-17 levels with changes in M1 and M2 macrophage phenotypes and the therapeutic effects of blocking IL-17 on pathogenesis of BRONJ-like disease. Results Increased Th17 cells and IL-17 cytokine correlate with an increase in M1/M2 macrophages ratio at the local mucosal site of both murine and human BRONJ lesion. Convincingly, in mice burdened with multiple myeloma, a combination of elevated suprabasal level and drug-induced IL-17 activity augmented the incidence of BRONJ; both systemic increase of IL-17 and disease severity could be reversed by adoptive transfer of ex vivo expanded M2 macrophages. Targeting IL-17 via specific neutralizing antibodies or a small inhibitory molecule, Laquinimod, significantly decreased M1/M2 ratio and concomitantly suppressed BRONJ-like condition in mice. Mechanistically, IL-17 enhanced IFN-γ-induced M1 polarization through augmenting STAT-1 phosphorylation while suppressed IL-4-mediated M2 conversion via inhibiting STAT-6 activation. Conclusions These findings have established a compelling linkage between activated IL-17-mediated polarization of M1 macrophages and the development of BRONJ-like conditions in both human disease and murine models. PublicationRegulation of the Stem Cell–Host Immune System Interplay Using Hydrogel Coencapsulation System with an Anti-Inflammatory Drug(2015-04-15) Moshaverinia, Alireza; Chen, Chider; Xu, Xingtian; Ansari, Sahar; Zadeh, Homayoun H.; Schricker, Scott R.; Paine, Michael L.; Moradian-Oldak, Janet; Khademhosseini, Ali; Snead, Malcolm L.; Shi, SongtaoThe host immune system is known to influence mesenchymal stem cell (MSC)-mediated bone tissue regeneration. However, the therapeutic capacity of hydrogel biomaterial to modulate the interplay between MSCs and T-lymphocytes is unknown. Here it is shown that encapsulating hydrogel affects this interplay when used to encapsulate MSCs for implantation by hindering the penetration of pro-inflammatory cells and/or cytokines, leading to improved viability of the encapsulated MSCs. This combats the effects of the host pro-inflammatory T-lymphocyte-induced nuclear factor kappaB pathway, which can reduce MSC viability through the CASPASE-3 and CAS-PASE-8 associated proapoptotic cascade, resulting in the apoptosis of MSCs. To corroborate rescue of engrafted MSCs from the insult of the host immune system, the incorporation of the anti-inflammatory drug indomethacin into the encapsulating alginate hydrogel further regulates the local microenvironment and prevents pro-inflammatory cytokine-induced apoptosis. These findings suggest that the encapsulating hydrogel can regulate the MSC-host immune cell interplay and direct the fate of the implanted MSCs, leading to enhanced tissue regeneration. PublicationHydrogen Sulfide Maintains Mesenchymal Stem Cell Function and Bone Homeostasis via Regulation of Ca2+ Channel Sulfhydration(2014-07-03) Liu, Yi; Yang, Ruili; Liu, Xibao; Zhou, Yu; Qu, Cunye; Kikuiri, Takashi; Wang, Songlin; Zandi, Ebrahim; Du, Junbao; Ambudkar, Indu S.; Shi, SongtaoGaseous signaling molecules such as hydrogen sulfide (H2S) are produced endogenously and mediate effects through diverse mechanisms. H2S is one such gasotrasmitter which regulates multiple signaling pathways in mammalian cells, and abnormal H2S metabolism has been linked to defects in bone homeostasis. Here, we demonstrate that bone marrow mesenchymal stem cells (BMMSCs) produce H2S to regulate their self-renewal and osteogenic differentiation, and H2S deficiency results in defects in BMMSC differentiation. H2S deficiency causes aberrant intracellular Ca2+ influx, due to reduced sulfhydration of cysteine residues on multiple Ca2+ TRP channels. This decreased Ca2+ flux downregulates PKC/Erk-mediated Wnt/β-catenin signaling which controls osteogenic differentiation of BMMSCs. Consistently, H2S-deficient mice display an osteoporotic phenotype, which can be rescued by small molecules which release H2S. These results demonstrate H2S regulates BMMSCs, and restoring H2S levels via non-toxic donors may provide treatments for diseases such as osteoporosis which can arise from H2S deficiencies.