Multiple Differentiation Capacity of STRO-1+/CD146+ PDL Mesenchymal Progenitor Cells

Although mesenchymal progenitor cells can be isolated from periodontal ligament (PDL) tissues using stem cell markers STRO-1 and CD146, the proportion of these cells that have the capacity to differentiate into multiple cell lineages remains to be determined. This study was designed to quantify the proportions of primary human PDL cells that can undergo multilineage differentiation and to compare the magnitude of these capabilities relative to bone marrow-derived mesenchymal stem cells (MSCs) and parental PDL (PPDL) cells. PDL mesenchymal progenitor (PMP) cells were isolated from PPDL cells using the markers STRO-1 and CD146. The colony-forming efficiency and multilineage differentiation potential of PMP, PPDL, and MSCs under chondrogenic, osteogenic, and adipogenic conditions were determined. Flow cytometry revealed that on average 2.6% of PPDL cells were STRO-1+/CD146+, whereas more than 63% were STRO-1/CD146. Colony-forming efficiency of STRO-1+/CD146+ PMP cells (19.3%) and MSCs (16.7%) was significantly higher than that of PPDL cells (6.8%). Cartilage-specific genes, early markers of osteoblastic differentiation, and adipogenic markers were significantly upregulated under appropriate conditions in PMP cells and MSCs compared to either their noninduced counterparts or induced PPDL cells. Consistent with these findings, immunohistochemistry revealed substantial accumulation of cartilaginous macromolecules, mineralized calcium nodules, and lipid vacuoles under chondrogenic, osteogenic, or adipogenic conditions in PMP and MSC cultures, respectively, compared to noninduced controls or induced PPDL cells. Thus STRO-1+/CD146+ PMP cells demonstrate multilineage differentiation capacity comparable in magnitude to MSCs and could potentially be utilized for regeneration of the periodontium and other tissues.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78113/1/scd.2008.0113.pd

SIRT3 and cancer: Tumor promoter or suppressor?

AbstractSirtuins (SIRT1–7), the mammalian homologues of the Sir2 gene in yeast, have emerging roles in age-related diseases, such as cardiac hypertrophy, diabetes, obesity, and cancer. However, the role of several sirtuin family members, including SIRT1 and SIRT3, in cancer has been controversial. The aim of this review is to explore and discuss the seemingly dichotomous role of SIRT3 in cancer biology with particular emphasis on its potential role as a tumor promoter and tumor suppressor. This review will also discuss the potential role of SIRT3 as a novel therapeutic target to treat cancer

Incidental Findings From Cone‐Beam Computed Tomography During Implant Therapy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141737/1/cap0094.pd

Nisin, an apoptogenic bacteriocin and food preservative, attenuates HNSCC tumorigenesis via CHAC 1

Nisin, a bacteriocin and commonly used food preservative, may serve as a novel potential therapeutic for treating head and neck squamous cell carcinoma ( HNSCC ), as it induces preferential apoptosis, cell cycle arrest, and reduces cell proliferation in HNSCC cells, compared with primary keratinocytes. Nisin also reduces HNSCC tumorigenesis in vivo. Mechanistically, nisin exerts these effects on HNSCC , in part, through CHAC 1, a proapoptotic cation transport regulator, and through a concomitant CHAC 1‐independent influx of extracellular calcium. In addition, although CHAC 1 is known as an apoptotic mediator, its effects on cancer cell apoptosis have not been examined. Our studies are the first to report CHAC 1's new role in promoting cancer cell apoptosis under nisin treatment. These data support the concept that nisin decreases HNSCC tumorigenesis in vitro and in vivo by inducing increased cell apoptosis and decreased cell proliferation; effects that are mediated by activation of CHAC 1, increased calcium influxes, and induction of cell cycle arrest. These findings support the use of nisin as a potentially novel therapeutic for HNSCC , and as nisin is safe for human consumption and currently used in food preservation, its translation into a clinical setting may be facilitated. Nisin decreases HNSCC tumorigenesis in vitro and in vivo by inducing increased cell apoptosis and decreased cell proliferation; effects that are mediated by activation of CHAC1, increased calcium influxes, and induction of cell cycle arrest. These findings support the use of nisin as a potentially novel therapeutic for HNSCC , and as nisin is safe for human consumption and currently used in food preservation, its translation into a clinical setting may be facilitated.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94527/1/cam435.pd

Shedding of NG2 by MMP-13 Attenuates Anoikis

Disruption of cell?matrix interactions can lead to anoikis?apoptosis due to loss of matrix contacts. We previously showed that Nerve/glial antigen 2 (NG2) is a novel anoikis receptor. Specifically, overexpression of NG2 leads to anoikis propagation, whereas its suppression leads to anoikis attenuation. Interestingly, NG2 expression decreases in late anoikis, suggesting that NG2 reduction is also critical to this process. Thus, we hypothesized that NG2 undergoes cleavage to curtail anoikis propagation. Further, since matrix metalloproteinases (MMPs) cleave cell surface receptors, play a major role in modulating apoptosis, and are associated with death receptor cleavage during apoptosis, we further hypothesized that cleavage of NG2 could be mediated by MMPs to regulate anoikis. Indeed, anoikis conditions triggered release of the NG2 extracellular domain into condition media during late apoptosis, and this coincided with increased MMP-13 expression. Treatment with an MMP-13 inhibitor and MMP-13 siRNA increased anoikis, since these treatments blocked NG2 release. Further, NG2-positive cells exhibited increased anoikis upon MMP-13 inhibition, whereas MMP-13 inhibition did not increase anoikis in NG2-null cells, corroborating that retention of NG2 on the cell membrane is critical for sustaining anoikis, and its cleavage for mediating anoikis attenuation. Similarly, NG2 suppression with siRNA inhibited NG2 release and anoikis. In contrast, MMP-13 overexpression or exogenous MMP-13 reduced anoikis by more effectively shedding NG2. In conclusion, maintenance of NG2 on the cell surface promotes anoikis propagation, whereas its shedding by MMP-13 actions attenuates anoikis. Given that these findings are derived in the context of periodontal ligament fibroblasts, these data have implications for periodontal inflammation and periodontal disease pathogenesis.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140362/1/dna.2014.2399.pd

Implant success remains high despite grafting voids in the maxillary sinus

ObjectivesGiven that the nature and presence of voids present within grafted sinuses following maxillary sinus elevation procedures were not known, nor was the contribution of these factors to implant success, the purpose of this study was to investigate these parameters and their relationship to implant success.Materials and MethodsThis study evaluated data from 25 subjects who had a lateral window maxillary sinus augmentation procedure. Cone‐beam computed tomography (CBCT) was performed at baseline and 4 months after surgery. CBCT images were used to evaluate grafted sites prior to implant placement. Using CBCT images, three examiners independently measured bone‐grafted areas (BG), void areas (V), and percentage of void areas (V%) from six different sections within grafted sites. The six sections were defined as a cross‐sectional (CS) midpoint, CS mesial point, CS distal point, horizontal section (HS) low point, HS midpoint, and HS high point. Implant success was also determined.ResultsThe calculated V% (V/BG) for the CS midpoint, CS mesial point, CS distal point, HS low point, HS midpoint, and HS high point were 5.30 ± 6.67%, 5.79 ± 8.51%, 6.67 ± 7.12%, 2.07 ± 2.56%, 5.30 ± 6.62%, and 4.92 ± 5.17% respectively. Implant success after 6 months of follow‐up approximated 100%.ConclusionsAlthough voids within grafts varied in terms of distribution and size, the V% within the HS low point were significantly smaller compared to those within the CS midpoint and CS distal point, which had the most intra‐subject V%. Thus, more attention should be given to the distal aspect of the sinus when compacting graft materials in the lateral wall sinus augmentation procedure. Implant success was not influenced by the existence of voids as implant success remained high.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110843/1/clr12386.pd

Effect of membrane exposure on guided bone regeneration: A systematic review and metaâ analysis

AimsThis review aimed at investigating the effect of membrane exposure on guided bone regeneration (GBR) outcomes at periâ implant sites and edentulous ridges.Material and MethodsElectronic and manual literature searches were conducted by two independent reviewers using four databases, including MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials, for articles up to February 2017. Articles were included if they were human clinical trials or case series reporting outcomes of GBR procedures with and without membrane exposure. A randomâ effects metaâ analysis was conducted, and the weighted mean difference (WMD) between the two groups and 95% confidence interval (CI) were reported.ResultsOverall, eight articles were included in the quantitative analysis. The WMD of the horizontal bone gain at edentulous ridges was â 76.24% (95% CI = â 137.52% to â 14.97%, p = .01) between sites with membrane exposure and without exposure. In addition, the WMD of the dehiscence reduction at periâ implant sites was â 27.27% (95% CI of â 45.87% to â 8.68%, p = .004). Both analyses showed significantly favorable outcomes at the sites without membrane exposure.ConclusionBased on the findings of this study, membrane exposure after GBR procedures has a significant detrimental influence on the outcome of bone augmentation. For the edentulous ridges, the sites without membrane exposure achieved 74% more horizontal bone gain than the sites with exposure. For periâ implant dehiscence defects, the sites without membrane exposure had 27% more defect reduction than the sites with exposure.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142961/1/clr13121.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142961/2/clr13121_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142961/3/clr13121-sup-0003-checklist.pd

Polymicrobial periodontal disease triggers a wide radius of effect and unique virome.

Periodontal disease is a microbially-mediated inflammatory disease of tooth-supporting tissues that leads to bone and tissue loss around teeth. Although bacterially-mediated mechanisms of alveolar bone destruction have been widely studied, the effects of a polymicrobial infection on the periodontal ligament and microbiome/virome have not been well explored. Therefore, the current investigation introduced a new mouse model of periodontal disease to examine the effects of a polymicrobial infection on periodontal ligament (PDL) properties, changes in bone loss, the host immune response, and the microbiome/virome using shotgun sequencing. Periodontal pathogens, namely Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum were used as the polymicrobial oral inoculum in BALB/cByJ mice. The polymicrobial infection triggered significant alveolar bone loss, a heightened antibody response, an elevated cytokine immune response, a significant shift in viral diversity and virome composition, and a widening of the PDL space; the latter two findings have not been previously reported in periodontal disease models. Changes in the PDL space were present at sites far away from the site of insult, indicating that the polymicrobial radius of effect extends beyond the bone loss areas and site of initial infection and wider than previously appreciated. Associations were found between bone loss, specific viral and bacterial species, immune genes, and PDL space changes. These findings may have significant implications for the pathogenesis of periodontal disease and biomechanical properties of the periodontium. This new polymicrobial mouse model of periodontal disease in a common mouse strain is useful for evaluating the features of periodontal disease

Treponema denticola increases MMP‐2 expression and activation in the periodontium via reversible DNA and histone modifications

Host‐derived matrix metalloproteinases (MMPs) and bacterial proteases mediate destruction of extracellular matrices and supporting alveolar bone in periodontitis. The Treponema denticola dentilisin protease induces MMP‐2 expression and activation in periodontal ligament (PDL) cells, and dentilisin‐mediated activation of pro‐MMP‐2 is required for cellular fibronectin degradation. Here, we report that T. denticola regulates MMP‐2 expression through epigenetic modifications in the periodontium. PDL cells were treated with epigenetic enzyme inhibitors before or after T. denticola challenge. Fibronectin fragmentation, MMP‐2 expression, and activation were assessed by immunoblot, zymography, and qRT‐PCR, respectively. Chromatin modification enzyme expression in T. denticola‐challenged PDL cells and periodontal tissues were evaluated using gene arrays. Several classes of epigenetic enzymes showed significant alterations in transcription in diseased tissue and T. denticola‐challenged PDL cells. T. denticola‐mediated MMP‐2 expression and activation were significantly reduced in PDL cells treated with inhibitors of aurora kinases and histone deacetylases. In contrast, DNA methyltransferase inhibitors had little effect, and inhibitors of histone acetyltransferases, methyltransferases, and demethylases exacerbated T. denticola‐mediated MMP‐2 expression and activation. Chronic epigenetic changes in periodontal tissues mediated by T. denticola or other oral microbes may contribute to the limited success of conventional treatment of chronic periodontitis and may be amenable to therapeutic reversal.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142926/1/cmi12815.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142926/2/cmi12815_am.pd

The significance of surgically modifying soft tissue phenotype around fixed dental prostheses: An American Academy of Periodontology best evidence review

BackgroundThis systematic review endeavored to investigate the effect of soft tissue phenotype modification therapy (PhMT- s) at sites with a tooth or an implant supported fixed dental prosthesis.MethodsA comprehensive literature search was conducted by two independent examiners to identify relevant studies reporting differences in clinical, esthetic, or radiographic outcomes of interest between sites underwent PhMT- s and sites that remained untreated. Risk of bias assessment was calculated for all included studies. Meta- analyses involving endpoints of interest were performed when feasible.ResultsNo controlled studies pertaining to tooth sites were identified. A total of six articles reporting on the outcomes of buccal soft tissue phenotype modification around implants were selected, of which, five were included in the meta- analyses. Quantitative analyses showed a weighted mean difference (WMD) of 0.98 mm (95% CI = 0.25 to 1.72 mm, P = 0.009) for change of tissue thickness; a WMD of - 4.87% (95% CI = - 34.27 to 24.53%, P = 0.75) for bleeding on probing (BOP); a WMD of 0.36 mm (95% CI = 0.12 to 0.59 mm, P = 0.003) for mucosal recession (MR); a WMD of 0.13 mm (95% CI = - 0.11 to 0.36 mm, P = 0.30 for probing depth (PD); a WMD of 1.08 (95% CI = - 0.39 to 2.55, P = 0.15) for pink esthetic score (PES), and a WMD of 0.40 mm (95% CI = - 0.34 to 1.14 mm, P = 0.28) for marginal bone loss (MBL).ConclusionsSurgical modification of peri- implant soft tissue phenotype via PhMT- s may decrease the amount of MR. Future clinical trials are needed to warrant the clinical benefits of modifying soft tissue phenotype around tooth- supported restorations.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154660/1/jper10458-sup-0006-figureS1F.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154660/2/jper10458_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154660/3/jper10458-sup-0001-figureS1A.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154660/4/jper10458-sup-0005-figureS1E.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154660/5/jper10458-sup-0004-figureS1D.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154660/6/jper10458-sup-0003-figureS1C.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154660/7/jper10458-sup-0002-figureS1B.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154660/8/jper10458.pd