Mesenchymal stem cell-mediated tissue regeneration is a promising approach for regenerative medicine for a wide range of applications. Here we report a new population of stem cells isolated from the root apical papilla of human teeth (SCAP, stem cells from apical papilla). Using a minipig model, we transplanted both human SCAP and periodontal ligament stem cells (PDLSCs) to generate a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This work integrates a stem cell-mediated tissue regeneration strategy, engineered materials for structure, and current dental crown technologies. This hybridized tissue engineering approach led to recovery of tooth strength and appearance.
Some 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. KeywordsApexogenesis; apical papilla; bioroot engineering; dental pulp stem cells; immature teeth; periodontal ligament stem cells; pulp regeneration; stem cells from human exfoliated deciduous teeth; stem cells from the apical papilla A number of recent clinical case reports have revealed the possibilities that many teeth that traditionally would receive apexification may be treated for apexogenesis. A call for a paradigm shift and new protocol for the clinical management of these cases has been made by the authors (1-3). A recent scientific finding, which may explain in part why apexogenesis can occur in these infected immature permanent teeth, is the discovery and isolation of a new population of mesenchymal stem cells (MSCs) residing in the apical papilla of incompletely developed teeth (4,5). These cells are termed stem cells from the apical papilla (SCAP), and they differentiate
The scrapie prion protein (PrP Sc ) is the major, and possibly the only, component of the infectious prion; it is generated from the cellular isoform (PrP C ) by a conformational change. N-terminal truncation of PrP Sc by limited proteolysis produces a protein of Ϸ142 residues designated PrP 27-30, which retains infectivity. A recombinant protein (rPrP) corresponding to Syrian hamster PrP 27-30 was expressed in Escherichia coli and purified. After refolding rPrP into an ␣-helical form resembling PrP C , the structure was solved by multidimensional heteronuclear NMR, revealing many structural features of rPrP that were not found in two shorter PrP fragments studied previously. Extensive side-chain interactions for residues 113-125 characterize a hydrophobic cluster, which packs against an irregular -sheet, whereas residues 90-112 exhibit little defined structure. Although identifiable secondary structure is largely lacking in the N terminus of rPrP, paradoxically this N terminus increases the amount of secondary structure in the remainder of rPrP. The surface of a long helix (residues 200-227) and a structured loop (residues 165-171) form a discontinuous epitope for binding of a protein that facilitates PrP Sc formation. Polymorphic residues within this epitope seem to modulate susceptibility of sheep and humans to prion disease. Conformational heterogeneity of rPrP at the N terminus may be key to the transformation of PrP C into PrP Sc , whereas the discontinuous epitope near the C terminus controls this transition.
Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome.
Alteration of the surface glycosylation pattern on malignant cells potentially affects tumor immunity by directly influencing interactions with glycan-binding proteins (lectins) on the surface of immunomodulatory cells. The sialic acid-binding Ig-like lectins Siglec-7 and -9 are MHC class I-independent inhibitory receptors on human NK cells that recognize sialic acid-containing carbohydrates. Here, we found that the presence of Siglec-9 defined a subset of cytotoxic NK cells with a mature phenotype and enhanced chemotactic potential. Interestingly, this Siglec-9 + NK cell population was reduced in the peripheral blood of cancer patients. Broad analysis of primary tumor samples revealed that ligands of Siglec-7 and -9 were expressed on human cancer cells of different histological types. Expression of Siglec-7 and -9 ligands was associated with susceptibility of NK cell-sensitive tumor cells and, unexpectedly, of presumably NK cell-resistant tumor cells to NK cellmediated cytotoxicity. Together, these observations have direct implications for NK cell-based therapies and highlight the requirement to consider both MHC class I haplotype and tumor-specific glycosylation.
Geometrically-enhanced differential immunocapture (GEDI) and an antibody for prostate-specific membrane antigen (PSMA) are used for high-efficiency and high-purity capture of prostate circulating tumor cells from peripheral whole blood samples of castrate-resistant prostate cancer patients.Prostate circulating tumor cells (PCTCs) are often found in the blood of patients suffering from metastatic prostate cancer 1, 2. While these PCTCs are rare, as few as one cell per 10 9 hematologic cells in blood 3,4 , they are theorized to contribute to metastatic progression 3,5 . Currently, the enumeration of PCTCs is used clinically as a prognostic indicator of patient survival 2,6,7 . Capture of peripheral blood PCTCs may enable early clinical assessment of metastatic process and chemotherapeutic response, as well as genetic and pharmacological evaluation of cancer cells.Current approaches to isolate circulating tumor cells are complex and produce low yields and purity 5 . Existing commercial and research devices for the immunocapture of rare cancer cells use EpCAM antibodies 2,8,9 , which capture many circulating endothelial cells and large numbers of leukocytes. As a result, purity of captured cells is widely variable and often below 50%. In addition, while previous devices use 3D antibody-coated surfaces for immunocapture 8,9 , these devices are not designed to induce a size-dependent collision frequency. Devices focused on size-dependent particle transport are typically focused on sorting 10 , separation 11,12 , or filtration 13 .In this communication, we demonstrate high-efficient and high-purity capture of PCTCs from peripheral blood samples of castrate-resistant prostate cancer patients using an antibody for prostate-specific membrane antigen (PSMA), a highly prostate-specific cellsurface antigen 14 . In addition, we describe a theoretical framework for the use of staggered § To whom correspondence should be addressed: The GEDI µdevice geometry was designed to maximize streamline distortion and thus bring desired cells in contact with the immunocoated obstacle walls for capture. Blood is a dense heterogeneous cell suspension consisting of cells of various sizes ranging from approximately 4 to 18 µm in size16. PCTCs, in contrast, are larger and range from 15 to 25 µm in diameter 16 . Relative obstacle alignment was chosen so that the displacement caused by cell impact with obstacles (which ranges from zero to one cell radius) increases the likelihood of future cell impacts for large cells more than for small cells. Thus when cellobstacle impact does not lead to capture, larger cells are displaced onto streamlines that impinge onto the next obstacle, while smaller cells are displaced onto streamlines that do not impinge ( Figure 1A). Cell advection was modeled in silico (computational details in supplementary information) to determine obstacle array geometries that optimize PCTCwall interactions and minimize wall shear forces to maximize PCTC capture. For a given obstacle geometry, the frequency of cell-wall...
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