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Hummitzsch K.,University of Adelaide | Irving-Rodgers H.F.,University of Adelaide | Irving-Rodgers H.F.,Queensland University of Technology | Irving-Rodgers H.F.,Griffith University | And 8 more authors.
PLoS ONE | Year: 2013

Ovarian follicular granulosa cells surround and nurture oocytes, and produce sex steroid hormones. It is believed that during development the ovarian surface epithelial cells penetrate into the ovary and develop into granulosa cells when associating with oogonia to form follicles. Using bovine fetal ovaries (n = 80) we identified a novel cell type, termed GREL for Gonadal Ridge Epithelial-Like. Using 26 markers for GREL and other cells and extracellular matrix we conducted immunohistochemistry and electron microscopy and chronologically tracked all somatic cell types during development. Before 70 days of gestation the gonadal ridge/ovarian primordium is formed by proliferation of GREL cells at the surface epithelium of the mesonephros. Primordial germ cells (PGCs) migrate into the ovarian primordium. After 70 days, stroma from the underlying mesonephros begins to penetrate the primordium, partitioning the developing ovary into irregularly-shaped ovigerous cords composed of GREL cells and PGCs/oogonia. Importantly we identified that the cords are always separated from the stroma by a basal lamina. Around 130 days of gestation the stroma expands laterally below the outermost layers of GREL cells forming a sub-epithelial basal lamina and establishing an epithelial-stromal interface. It is at this stage that a mature surface epithelium develops from the GREL cells on the surface of the ovary primordium. Expansion of the stroma continues to partition the ovigerous cords into smaller groups of cells eventually forming follicles containing an oogonium/oocyte surrounded by GREL cells, which become granulosa cells, all enclosed by a basal lamina. Thus in contrast to the prevailing theory, the ovarian surface epithelial cells do not penetrate into the ovary to form the granulosa cells of follicles, instead ovarian surface epithelial cells and granulosa cells have a common precursor, the GREL cell. © 2013 Hummitzsch et al.

Tamamura R.,Okayama University | Nagatsuka H.,Okayama University | Siar C.H.,University of Malaya | Katase N.,Okayama University | And 3 more authors.
Acta Histochemica | Year: 2013

The aim of this study was to compare the expressions of basal lamina (BL) collagen IV α chains and matrix metalloproteinases (MMP)-2 and MMP-9 in oral dysplasia (OED) and invasive carcinoma. Ten cases each of OEDs, carcinomas-in situ and oral squamous cell carcinomas (OSCCs) were examined by immunohistochemistry. Another 5 cases, each of normal and hyperplastic oral mucosa, served as controls. Results showed that α1(IV)/α2(IV) and α5(IV)/α6(IV) chains were intact in BLs of control and OEDs. In BLs of carcinoma-in situ, α1(IV)/α2(IV) chains preceded α5(IV)/α6(IV) chains in showing incipient signs of disruption. OSCCs exhibited varying degrees of collagen α(IV) chain degradation. MMP-2 and MMP-9 were absent in controls and OED, but weakly detectable in carcinoma-in situ. In OSCC, these proteolytic enzymes were expressed in areas corresponding to collagen α(IV) chain loss. Enzymatic activity was enhanced in higher grade OSCC, and along the tumor advancing front. Overall the present findings suggest that loss of BL collagen α(IV) chains coincided with gain of expression for MMP-2 and MMP-9, and that these protein alterations are crucial events during progression from OED to OSCC. © 2012 Elsevier GmbH.

Assadian S.,McGill University | El-Assaad W.,McGill University | Wang X.Q.D.,McGill University | Gannon P.O.,University of Montreal | And 7 more authors.
Cancer Research | Year: 2012

Several types of collagen contain cryptic antiangiogenic noncollagenous domains that are released upon proteolysis of extracellular matrix (ECM). Among those is Arresten, a collagen-derived antiangiogenic factor (CDAF) that is processed from α1 collagen IV. However, the conditions under which Arresten is released from collagen IV in vivo or whether the protein functions in tumor suppressor pathways remain unknown. Here, we show that p53 induces the expression of α1 collagen IV and release of Arresten-containing fragments from the ECM. Comparison of the transcriptional activation of COL4A1 with other CDAF-containing genes revealed that COL4A1 is a major antiangiogenic gene induced by p53 in human adenocarinoma cells. p53 directly activated transcription of the COL4A1 gene by binding to an enhancer region 26 kbp downstream of its 3′ end. p53 also stabilized the expression of full-length α1 collagen IV by upregulation of α(II) prolyl-hydroxylase and increased the release of Arresten in the ECM through a matrix metalloproteinase (MMP)-dependent mechanism. The resulting upregulation of α1 collagen IV and production of Arresten by the tumor cells significantly inhibited angiogenesis and limited tumor growth in vivo. Furthermore, we show that immunostaining of Arresten correlated with p53 status in human prostate cancer specimens. Our findings, therefore, link the production of Arresten to the p53 tumor suppressor pathway and show a novel mechanism through which p53 can inhibit angiogenesis. ©2012 AACR.

Furuhashi K.,Nagoya University | Tsuboi N.,Nagoya University | Shimizu A.,Nagoya University | Katsuno T.,Nagoya University | And 7 more authors.
Journal of the American Society of Nephrology | Year: 2013

Mesenchymal stromal cells (MSCs) derived from adipose tissue have immunomodulatory effects, suggesting that they may have therapeutic potential for crescentic GN. Here, we systemically administered adipose-derived stromal cells (ASCs) in a rat model of anti-glomerular basement membrane (anti-GBM) disease and found that this treatment protected against renal injury and decreased proteinuria, crescent formation, and infiltration by glomerular leukocytes, including neutrophils, CD8+ T cells, and CD68+ macrophages. Interestingly, ASCs cultured under low-serum conditions (LASCs), but not bone marrow-derived MSCs (BM-MSCs), increased the number of immunoregulatory CD163+ macrophages in diseased glomeruli. Macrophages cocultured with ASCs, but not with BM-MSCs, adopted an immunoregulatory phenotype. Notably, LASCs polarized macrophages into CD163 + immunoregulatory cells associated with IL-10 production more efficiently than ASCs cultured under high-serum conditions. Pharmaceutical ablation of PGE2 production, blocking the EP4 receptor, or neutralizing IL-6 in the coculture medium all significantly reversed this LASC-induced conversion of macrophages. Furthermore, pretreating LASCs with aspirin or cyclooxygenase-2 inhibitors impaired the ability of LASCs toameliorate nephritogenic IgG-mediated renal injury. Taken together, these results suggest thatLASCs exert renoprotective effects in anti-GBM GN by promoting the phenotypic conversion of macrophages to immunoregulatory cells, suggesting that LASCtransfermay represent a therapeutic strategy for crescentic GN. Copyright © 2013 by the American Society of Nephrology.

Takigawa T.,Okayama University of Science | Yonezawa T.,Okayama University of Science | Yoshitaka T.,Okayama University of Science | Minaguchi J.,Okayama University of Science | And 6 more authors.
Journal of Neurotrauma | Year: 2010

Spinal cord injury results in disruption of the cord microstructure, which is followed by inflammation leading to additional deterioration. Perivascular basement membranes are a component of the spinal cord microstructure that lies between blood vessels and astrocytes. The impact of disrupting the basement membrane structure on the expansion of inflammation has not been fully examined. The objective of this study was to clarify the relationship between damage to basement membranes and inflammation after spinal cord injury. Immunohistochemical analyses of the perivascular extracellular matrix were performed in a mouse spinal cord injury model. In normal tissue, the perivascular basement membrane was a single-layer structure produced by both endothelial cells and surrounding astrocytes. After spinal cord injury, however, the perivascular basement membrane often separated into an inner endothelial basement membrane and an outer parenchymal basement membrane. The altered basement membranes formed during the acute phase (within 7 days after spinal cord injury). During the subacute phase of injury, numerous monocytes and macrophages accumulated in the space between the separated basement membranes and infiltrated into the parenchyma where astrocytic endfeet were displaced. Infiltration of inflammatory cells from the injury core was attenuated coincident with the appearance of the glia limitans and glial scar. Furthermore, the outer parenchymal basement membrane was connected to the basement membrane of the glia limitans surrounding the injury core. Our data suggest that structurally altered basement membranes facilitate expansion of secondary inflammation during the subacute phase of spinal cord injury. © 2010, Mary Ann Liebert, Inc.

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