Cytoglobin/STAP, its unique localization in splanchnic fibroblast-like cells and function in organ fibrogenesis

Abstract

Cytoglobin/stellate cell activation-associated protein (Cygb/STAP) consists of a new class of hexacoordinate globin superfamily, which was recently discovered by a proteome analysis on the rat hepatic stellate cells. Unlike haemoglobin, myoglobin, and neuroglobin, Cygb/STAP is ubiquitously expressed in several organs, although its detailed localization has not been clarified. Immunohistochemistry and immunoelectron microscopy revealed that Cygb/STAP is uniquely localized in fibroblast-like cells in splanchnic organs, namely the vitamin A-storing cell lineage, but neither in epithelial cells, endothelial cells, muscle cells, blood cells, macrophages, nor dermal fibroblasts. The expression of Cygb/STAP was upregulated in fibrotic lesions of the pancreas and kidney in which activated fibroblast-like cells or myofibroblasts are known to increase in number. In cultured hepatic stellate cells, Cygb/STAP expression was augmented by the stimulation with sera, platelet-derived growth factor-BB, and transforming growth factor-beta 1. Overexpression of Cygb/STAP in NIH 3T3 cells induced the cells to lessen migratory activities and increase the expression of collagen alpha1(I) mRNA. These results indicate that Cygb/STAP is a tissue globin uniquely localized in splanchnic fibroblastic cell lineage and may play a role in fibrotic organ disorder.

Cytoglobin, a Novel Member of the Globin Family, Protects Kidney Fibroblasts against Oxidative Stress under Ischemic Conditions

“…The localization of Cygb was consistent with previous reports that identified Cygb in splanchnic fibroblasts of various organs. 6,7 Given the status of fibroblasts as one of the most important and episodically active cell types in the kidney, providing delicate collagenous matrices and remodeling of the interstitium, this localization may suggest a crucial role for Cygb in the pathogenesis of kidney injury. 31,32 An antibody-dependent difference was observed in the Cygb staining pattern in the glomeruli; whereas one antibody demonstrated positive staining in the mesangial area, a second antibody demonstrated positive staining only after antigen retrieval in the mesangial area.…”

“…3,6 In the normal rat, findings at immunohistochemical analysis suggested that Cygb-positive cells are positive for HSP47, a collagen-specific molecular chaperone of the kidney and intestine, and also for CD73, a marker of renal cortical fibroblast-like cells, in the normal rat kidney interstitium. 7 Whereas hemoglobin and myoglobin share the pentacoordinated heme, Cygb and neuroglobin are endowed with hexa-coordinated heme-iron atoms in their ferrous and ferric forms. 8 The importance of the biological role of Cygb is emphasized by the high degree of sequence conservation among vertebrate globins, with mouse and human Cygb differing in only 4.7% of amino acids.…”

“…8 The importance of the biological role of Cygb is emphasized by the high degree of sequence conservation among vertebrate globins, with mouse and human Cygb differing in only 4.7% of amino acids. 5 Although various functions have been proposed, including oxygen storage, 8 radical scavenging, 9 -11 collagen synthesis, 7,12 tumor suppression, 13 and cell respiration, 14 these were derived from in vitro studies, and no Cygb gene-manipulated animal experiments have been reported. Therefore, the biological role of Cygb in vivo remains elusive.…”

Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect

“…Collagen type I has been hypothesized to be a signal for invasion, and its intratumoral expression level has been associated with increased tumor invasiveness (16,17). The association of collagen type I with stellate cell activation -associated protein, also known as cytoglobin (Cygb/STAP), which has been hypothesized to regulate collagen synthesis under the control of TGF-h, is characteristic of cells that exhibit an activated phenotype (18,19).…”

“…Monoclonal antibodies to aSMA were from DAKO A/S (Glostrup, Denmark). Antibodies to Cygb/STAP were prepared as previously described (18). Dactinomycin (Cosmegen) was from Merck & Co., Inc. (West Point, PA); vincristine was from Pharmachemie BV (Haarlem, the Netherlands), and docetaxel (Taxotere) was from Aventis Pharma (Surrey, United Kingdom).…”