Faculty Bibliography
Searched for:
person:alum01 or dabovb01 or mezzav01 or dbh274 or loomic01 or selvas05 or dewanz01
Total Results:
171
Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis
OBJECTIVE: Netrin-1 is a chemorepulsant and matrix protein expressed during and required for osteoclast differentiation, which also plays a role in inflammation by preventing macrophage egress. Because wear particle-induced osteolysis requires osteoclast-mediated destruction of bone, we hypothesised that blockade of Netrin-1 or Unc5b, a receptor for Netrin-1, may diminish this pathological condition. METHODS: C57BL/6 mice, 6-8 weeks old, had 3 mg of ultrahigh-molecular-weight polyethylene particles implanted over the calvaria and then received 10 microg of monoclonal antibodies for Netrin-1 or its receptors, Unc5b and deleted in colon cancer (DCC), injected intraperitoneally on a weekly basis. After 2 weeks, micro-computed tomography and histology analysis were performed. Netrin-1 expression was analysed in human tissue obtained following primary prosthesis implantation or after prosthesis revision for peri-implant osteolysis and aseptic implant loosening. RESULTS: Weekly injection of anti-Netrin-1 or anti-Unc5b-antibodies significantly reduced particle-induced bone pitting in calvaria exposed to wear particles (46+/-4% and 49+/-3% of control bone pitting, respectively, p<0.001) but anti-DCC antibody did not affect inflammatory osteolysis (80+/-7% of control bone pitting, p=ns). Anti-Netrin-1 or anti-Unc5b, but not anti-DCC, antibody treatment markedly reduced the inflammatory infiltrate and the number of tartrate resistance acid phosphatase (TRAP)-positive osteoclasts (7+/-1, 4+/-1 and 14+/-1 cells/high power field (hpf), respectively, vs 12+/-1 cells/hpf for control, p<0.001), with no significant changes in alkaline phosphatase-positive osteoblasts on bone-forming surfaces in any antibody-treated group. Netrin-1 immunostaining colocalised with CD68 staining for macrophages. The peri-implant tissues of patients undergoing prosthesis revision surgery showed an increase in Netrin-1 expression, whereas there was little Netrin-1 expression in soft tissues removed at the time of primary joint replacement. CONCLUSIONS: These results demonstrate a unique role for Netrin-1 in osteoclast biology and inflammation and may be a novel target for prevention/treatment of inflammatory osteolysis.
PMCID:5349296
PMID: 26452536
ISSN: 1468-2060
CID: 1794812
Desmosomal Junctions Are Necessary for Adult Sinus Node Function
AIMS: Current mechanisms driving cardiac pacemaker function have focused on ion channel and gap junction channel function, which are essential for action potential generation and propagation between pacemaker cells. However, pacemaker cells also harbor desmosomes that structurally anchor pacemaker cells to each other in tissue, but their role in pacemaker function remains unknown. METHODS AND RESULTS: To determine the role of desmosomes in pacemaker function, we generated a novel mouse model harboring cardiac conduction-specific ablation (csKO) of the central desmosomal protein, desmoplakin (DSP) using the Hcn4-Cre-ERT2 mouse line. Hcn4-Cre targets cells of the adult mouse sinoatrial node (SAN) and can ablate DSP expression in the adult DSP csKO SAN resulting in specific loss of desmosomal proteins and structures. Dysregulation of DSP via loss-of-function (adult DSP csKO mice) and mutation (clinical case of a patient harboring a pathogenic DSP variant) in mice and man, respectively, revealed that desmosomal dysregulation is associated with a primary phenotype of increased sinus pauses/dysfunction in the absence of cardiomyopathy. Underlying defects in beat-to-beat regulation were also observed in DSP csKO mice in vivo and intact atria ex vivo. DSP csKO SAN exhibited migrating lead pacemaker sites associated with connexin 45 loss. In vitro studies exploiting ventricular cardiomyocytes that harbor DSP loss and concurrent early connexin loss phenocopied the loss of beat-to-beat regulation observed in DSP csKO mice and atria, extending the importance of DSP-associated mechanisms in driving beat-to-beat regulation of working cardiomyocytes. CONCLUSIONS: We provide evidence of a mechanism that implicates an essential role for desmosomes in cardiac pacemaker function, which has broad implications in better understanding mechanisms underlying beat-to-beat regulation as well as sinus node disease and dysfunction.
PMCID:4957488
PMID: 27097650
ISSN: 1755-3245
CID: 2080092
Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart
Studies have demonstrated non-myocytes, including fibroblasts, can electrically couple to myocytes in culture. However, evidence demonstrating current can passively spread across scar tissue in the intact heart remains elusive. We hypothesize electrotonic conduction occurs across non-myocyte gaps in the heart and is partly mediated by Connexin43 (Cx43). We investigated whether non-myocytes in ventricular scar tissue are electrically connected to surrounding myocardial tissue in wild type and fibroblast-specific protein-1 driven conditional Cx43 knock-out mice (Cx43fsp1KO). Electrical coupling between the scar and uninjured myocardium was demonstrated by injecting current into the myocardium and recording depolarization in the scar through optical mapping. Coupling was significantly reduced in Cx43fsp1KO hearts. Voltage signals were recorded using microelectrodes from control scars but no signals were obtained from Cx43fsp1KO hearts. Recordings showed significantly decreased amplitude, depolarized resting membrane potential, increased duration and reduced upstroke velocity compared to surrounding myocytes, suggesting that the non-excitable cells in the scar closely follow myocyte action potentials. These results were further validated by mathematical simulations. Optical mapping demonstrated that current delivered within the scar could induce activation of the surrounding myocardium. These data demonstrate non-myocytes in the scar are electrically coupled to myocytes, and coupling depends on Cx43 expression.
PMCID:4886689
PMID: 27244564
ISSN: 2045-2322
CID: 2124772
Bone marrow derived cells populate post-ablation scar tissue and couple to surrounding myocardium [Meeting Abstract]
Introduction: Post-ablation scarring is used as a method to uncouple and/or silence pro-arrhythmic circuits. It has been previously suggested that circulating bone marrow derived cells (BMDC) are capable of homing into myocardial infarction scars. It is possible that intercellular junctions form between myocytes and BMDCs and may contribute to ablation failure and recurrence of arrhythmias. Methods: We tested whether BMDCs populate an ablation scars and contribute to functional coupling between the scar and surrounding myocardium. Wild type C57BI/6 mice (n=17) underwent radiation-induced myeloablation and subsequent transplantation with bone marrow progenitors obtained from fetal Cx43 WT (bmcWT) or Cx43 deficient (bmcKO) mice. Results: All donor cells constitutively expressed mCherry protein. Right ventricular ablation was carried out thirty days post transplantation and hearts were studied 30 day post ablation. Cells expressing mCherry and vimentin were observed throughout the scar suggesting donor cells differentiated into a mesenchymal lineage. Coupling between the uninjured myocardium and the scar was assayed with optical mapping. Suction electrode was placed on uninjured myocardium next to the scar to deliver current pulses. Conclusions: Changes in membrane voltage were measured optically at three different sites: Uninjured myocardium, Scar and Remote area (see figure). These data demonstrate that BMDCs can couple to the surrounding myocardium and contribute to the electrophysiological properties of ablation scar tissue. Delivery of modified BMDCs could be used to modifythe post-ablation scar electrophysiological properties. (Figure Presented)
EMBASE:72283867
ISSN: 1556-3871
CID: 2150962
Sonic Hedgehog (shh) Signaling Regulates Myofibroblast Function During Alveolar Septum Formation In Postnatal Lung [Meeting Abstract]
ISI:000390749601588
ISSN: 1535-4970
CID: 2414542
Progress in biophysics & molecular biology. 2016:120(1-3):128-33.DOI: 10.1016/j.pbiomolbio.2015.12.006
A review of the literature on cardiac electrical activity between fibroblasts and myocytes
Myocardial injuries often lead to fibrotic deposition. This review presents evidence supporting the concept that fibroblasts in the heart electrically couple to myocytes.
PMCID:4808420
PMID: 26713556
ISSN: 1873-1732
CID: 1895142
Methylation profiling of locally advanced rectal cancer (LARC): Exploration of potential predictive markers for neoadjuvant chemoradiation (NACR). [Meeting Abstract]
ISI:000378109600591
ISSN: 1527-7755
CID: 2169652
Implementation of tissue clearing, fluorescence labeling, and imaging via lightsheet as a cross-core collaborative service [Meeting Abstract]
Recent developments in tissue clearing methods have provided investigators with an invaluable tool for visualizing and mapping three dimensional macromolecular structures and processes. By implementing a routine protocol, based on the passive clarity technique (PACT) method, for tissue clearing, the Research Histopathology Core at NYU Langone Medical Center seeks to provide investigators with a reliable, customizable service in conjunction with the immunohistochemistry (IHC) and Microscopy Cores in order to produce results in the most efficient way possible for both the investigators and the cores. The PACT method of clearing allows visualization of endogenous fluorescence and immunofluorescence labeling performed by the Core, or both. Stabilization through transparent hydrogel cross-linking, followed by delipidation in an sodium dodecyl sulfate buffer, results in a clear tissue sample that remains structurally sound with proteins, nucleic acids, and any associated labels in place. The clearing buffer can also be modified to allow simultaneous decalcification of bone specimens. Final clearing is achieved in a refractive index matching solution (RIMS buffer) which also serves as the microscopy medium. Cleared and labeled tissue can then be imaged on the Microscopy Core's Zeiss lightsheet microscope, allowing multichannel fluorescence from a range of angles and Z-stacking. The lightsheet microscope excites and detects only one thin optical section of the specimen at a time, making three dimensional imaging exceptionally light efficient. By honing proficiency in tissue clearing via the PACT method and working in close collaboration with neighboring core labs, the Histopathology Core can increase its breadth of expertise while relieving investigators of the time and cost intensive burden of protocol development and training.
EMBASE:613792615
ISSN: 0147-8885
CID: 2396962
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2015:112(45):14012-7.DOI: 10.1073/pnas.1507652112
Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome
Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFbeta signaling. TGFbeta is secreted from cells as a latent complex consisting of TGFbeta, the TGFbeta propeptide, and a molecule of latent TGFbeta binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGFbeta levels, and has been hypothesized as an explanation for enhanced TGFbeta signaling observed in MFS. We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that perturbed TGFbeta signaling in MFS might be due to defective interaction of latent TGFbeta complexes containing LTBP-3 with mutant fibrillin-1 microfibrils. To test this hypothesis, we genetically suppressed Ltbp3 expression in a mouse model of progressively severe MFS. Here, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms, reduced disruption and fragmentation of medial elastic fibers, and decreased Smad2/3 and Erk1/2 activation in their aortas. These data suggest that, in MFS, improper localization of latent TGFbeta complexes composed of LTBP-3 and TGFbeta contributes to aortic disease progression.
PMCID:4653215
PMID: 26494287
ISSN: 1091-6490
CID: 1810602
Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF
PMCID:4755714
PMID: 26367794
ISSN: 1476-4687
CID: 1779142
