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The endoplasmic reticulum stress transducer old astrocyte specifically induced substance positively regulates glial scar formation in spinal cord injury.

ABSTRACT: To investigate the relationship between endoplasmic reticulum (ER) stress mediated by old astrocyte specifically induced substance (OASIS) and astrogliosis in spinal cord injury (SCI). SCI models were established using adult male mice deficient for OASIS and C57BL/6 (wild-type mice) mice. After SCI, recovery and astrogliosis were examined in the mice at specific time points using functional and histological methods. After SCI, functional recovery was better in the OASIS-deficient mice than in the wild-type mice. OASIS deletion did not inhibit astrocyte migration but reduced the excessive accumulation of N-cadherin-expressing reactive astrocytes that formed the glial scar around the injury site. In addition, OASIS deletion increased the number of serotonin-positive axons in spinal cord regions caudal to the injury site. These findings suggested that the OASIS-mediated ER stress response inhibits the repair of the injured spinal cord by promoting the development of N-cadherin-expressing reactive astrocytes that form glial scars following injury. OASIS deletion inhibited the development of N-cadherin-positive reactive astrocytes that form glial scars and promoted axon growth and functional recovery after SCI. These results suggest that the ER stress response mediated by OASIS could be a new target in the treatment of SCI.

SUBMITTER: Sumida Y

PROVIDER: S-EPMC6250257 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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The endoplasmic reticulum stress transducer old astrocyte specifically induced substance positively regulates glial scar formation in spinal cord injury.

Sumida Yoshikazu Y Kamei Naosuke N Suga Norifumi N Ochi Mitsuo M Adachi Nobuo N

Neuroreport 20181201 17

To investigate the relationship between endoplasmic reticulum (ER) stress mediated by old astrocyte specifically induced substance (OASIS) and astrogliosis in spinal cord injury (SCI). SCI models were established using adult male mice deficient for OASIS and C57BL/6 (wild-type mice) mice. After SCI, recovery and astrogliosis were examined in the mice at specific time points using functional and histological methods. After SCI, functional recovery was better in the OASIS-deficient mice than in th ...[more]

PMID: 30273224

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Project description:Prevention of kidney fibrosis is an essential requisite for effective therapy in preventing chronic kidney disease (CKD). Here, we identify Old astrocyte specifically induced substance (OASIS)/cAMP responsive element-binding protein 3-like 1 (CREB3l1), a CREB/ATF family transcription factor, as a candidate profibrotic gene that drives the final common pathological step along the fibrotic pathway in CKD. Although microarray data from diseased patient kidneys and fibrotic mouse model kidneys both exhibit OASIS/Creb3l1 upregulation, the pathophysiological roles of OASIS in CKD remains unknown. Immunohistochemistry revealed that OASIS protein was overexpressed in human fibrotic kidney compared with normal kidney. Moreover, OASIS was upregulated in murine fibrotic kidneys, following unilateral ureteral obstruction (UUO), resulting in an increase in the number of OASIS-expressing pathological myofibroblasts. In vitro assays revealed exogenous TGF-β1 increased OASIS expression coincident with fibroblast-to-myofibroblast transition and OASIS contributed to TGF-β1-mediated myofibroblast migration and increased proliferation. Significantly, in vivo kidney fibrosis induced via UUO or ischemia/reperfusion injury was ameliorated by systemic genetic knockout of OASIS, accompanied by reduced myofibroblast proliferation. Microarrays revealed that the transmembrane glycoprotein Bone marrow stromal antigen 2 (Bst2) expression was reduced in OASIS knockout myofibroblasts. Interestingly, a systemic anti-Bst2 blocking antibody approach attenuated kidney fibrosis in normal mice but not in OASIS knockout mice after UUO, signifying Bst2 functions downstream of OASIS. Finally, myofibroblast-restricted OASIS conditional knockouts resulted in resistance to kidney fibrosis. Taken together, OASIS in myofibroblasts promotes kidney fibrosis, at least in part, via increased Bst2 expression. Thus, we have identified and demonstrated that OASIS signaling is a novel regulator of kidney fibrosis.

Project description:Schwann cell (SC) transplantation is a promising approach for the treatment of spinal cord injury (SCI); however, SC grafts show a low migratory capacity within the astrocytic environment, which inevitably hampers their therapeutic efficacy. The purpose of this study was to explore mechanisms to modify the characteristics of SCs and astrocytes (ASs), as well as to adjust the SC-AS interface to break the SC-AS boundary, thus improving the benefits of SCI treatment. We observed that the expression levels of miR-124 in SCs and ASs were significantly lower than those in the normal spinal cord. Furthermore, overexpressing miR-124 in SCs (miR-124-SCs) significantly inhibited gene and protein expression levels of SC-specific markers, such as GFAP and Krox20. The expression of neurotrophic factors, Bdnf and Nt-3, was up-regulated in miR-124-SCs without affecting their proliferation. Further, the boundary assay showed an increased number of miR-124-SCs that had actively migrated and entered the astrocytic region to intermingle with ASs, compared with normal SCs. In addition, although Krox20 protein expression was down-regulated in miR-124-SCs, the luciferase assay showed that Krox20 is not a direct target of miR-124. RNA sequencing of miR-124-SCs revealed seven upregulated and eleven downregulated genes involved in cell migration and motility. Based on KEGG pathway and KOG functional analyses, changes in these genes corresponded to the activation of Hippo, FoxO, and TGF-beta signaling pathways, cytokine-cytokine receptor interactions, and the cell cycle. Finally, co-culturing of miR-124-SCs and ASs in a transwell system revealed that GFAP and p-STAT3 protein expression in ASs was significantly reduced. Collectively, these results show that overexpression of miR-124 in SCs promotes SC-AS integration in vitro and may attenuate the capacity of ASs to form glial scars. Thus, this study provides novel insights into modifying SCs by overexpressing miR-124 to improve their therapeutic potential in SCI.

Project description:BackgroundVascular endothelial growth factor-A (VEGFA) is the main mediator of angiogenesis. Angiogenesis plays important roles not only in many physiological processes, but also in the pathophysiology of many diseases. VEGFA is one of the therapeutic targets of treatment for ocular diseases with neovascularization. Therefore, elucidation of the regulatory mechanisms for VEGFA expression is important for the development of pharmaceutical drugs. Recent studies have demonstrated that the unfolded protein response is involved in the transcriptional regulation of VEGFA. However, the precise regulation of VEGFA in the human retina is not fully understood.Principal findingsWhen human retinal pigment epithelial cells, ARPE-19, were exposed to endoplasmic reticulum stressors, VEGFA mRNA was significantly upregulated. The unfolded protein response-related transcription factors XBP1, ATF4, ATF6, and OASIS were expressed in ARPE-19 cells. To determine which transcription factors preferentially contribute to the induction of VEGFA expression after endoplasmic reticulum stress, we carried out reporter assays using an approximately 6-kbp 5'-upstream region of the human VEGFA gene. Among these transcription factors, OASIS acted most effectively on the VEGFA promoter in ARPE-19 cells. Based on data obtained for certain deleted and mutated reporter constructs, we determined that OASIS promoted VEGFA expression by acting on a cyclic AMP-responsive element-like site located at around -500 bp relative to the VEGFA transcription start site. Furthermore, we confirmed that OASIS directly bound to the promoter region containing this site by chromatin immunoprecipitation assays.Conclusions and significanceWe have demonstrated a novel regulatory mechanism for VEGFA transcription by OASIS in human retinal pigment epithelial cells. Chemical compounds that regulate the binding of OASIS to the promoter region of the VEGFA gene may have potential as therapeutic agents for ocular diseases with neovascularization.

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The endoplasmic reticulum stress transducer old astrocyte specifically induced substance positively regulates glial scar formation in spinal cord injury.

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The endoplasmic reticulum stress transducer old astrocyte specifically induced substance positively regulates glial scar formation in spinal cord injury.

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