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• W2008553572 abstract "Fibrocytes are supposed to be a circulating connective tissue cell progenitor, which consists of a novel population of peripheral blood cells. This distinct population of blood-borne cells shares markers of leukocytes as well as mesenchymal cells. Accumulating evidence indicates that fibrosis is characteristic of progressive chronic kidney diseases of any etiologies, resulting in kidney failure. We have uncovered that CCR7-positive fibrocytes migrate into the kidney in response to secondary lymphoid tissue chemokine (SLC/CCL21) and contribute to kidney fibrosis induced by unilateral ureteral obstruction in mice. In addition, the blockade of CCL21/CCR7 signaling by anti-CCL21 antibodies reduced kidney fibrosis, which was confirmed by a decrease in fibrosis in CCR7-null mice with concomitant reduction in macrophage recruitment along with reduced renal transcripts of monocyte chemoattractant protein-1 (MCP-1/CCL2). These findings suggest that fibrocytes dependent on CCL21/CCR7 signaling pathways contribute to the pathogenesis of kidney fibrosis, thereby providing that regulating fibrocytes may provide a novel therapeutic benefit for kidney fibrosis. Fibrocytes are supposed to be a circulating connective tissue cell progenitor, which consists of a novel population of peripheral blood cells. This distinct population of blood-borne cells shares markers of leukocytes as well as mesenchymal cells. Accumulating evidence indicates that fibrosis is characteristic of progressive chronic kidney diseases of any etiologies, resulting in kidney failure. We have uncovered that CCR7-positive fibrocytes migrate into the kidney in response to secondary lymphoid tissue chemokine (SLC/CCL21) and contribute to kidney fibrosis induced by unilateral ureteral obstruction in mice. In addition, the blockade of CCL21/CCR7 signaling by anti-CCL21 antibodies reduced kidney fibrosis, which was confirmed by a decrease in fibrosis in CCR7-null mice with concomitant reduction in macrophage recruitment along with reduced renal transcripts of monocyte chemoattractant protein-1 (MCP-1/CCL2). These findings suggest that fibrocytes dependent on CCL21/CCR7 signaling pathways contribute to the pathogenesis of kidney fibrosis, thereby providing that regulating fibrocytes may provide a novel therapeutic benefit for kidney fibrosis. Fibrocytes, originally identified as a circulating bone marrow-derived, CD34+ cell population of fibroblast-like cells in 1994, was reported to infiltrate from inflammatory exudates into subcutaneously implanted wound chambers.1.Bucala R. Spiegel L. Chesney J. et al.Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair.Mol Med. 1994; 1: 71-81Crossref PubMed Google Scholar Fibrocytes uniquely comprise a minor fraction of the circulating pool of leukocytes (less than 1%) and share the markers of leukocytes as well as mesenchymal cells (e.g., type I collagen).2.Chesney J. Metz C. Stavitsky A.B. et al.Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes.J Immunol. 1998; 160: 419-425PubMed Google Scholar,3.Moore B.B. Kolodsick J.E. Thannickal V.J. et al.CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury.Am J Pathol. 2005; 166: 675-684Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar As both of fibrocytes and bone marrow stroma express CD34, fibrocytes were at first thought to consist of scaffold to support normal hematopoiesis.4.Brown J. Greaves M. Molgaard H. et al.The gene encoding the stem cell antigen, CD34, is conserved in mouse and expressed in hematopoietic progenitor cell lines, brain, and embryonic fobroblasts.Int Immunol. 1991; 3: 175-184Crossref PubMed Scopus (144) Google Scholar However, accumulating evidence suggests that fibrocytes are a strong candidate for participating in organ fibrosis associated with conditions, such as pulmonary fibrosis, bronchial asthma, skin wounds, and intimal hyperplasia, even though the intracellular mechanisms leading from fibrocytes to fibrosis remain unclear5.Phillips R.J. Burdick M.D. Hong K. et al.Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.J Clin Invest. 2004; 114: 438-446Crossref PubMed Scopus (880) Google Scholar, 6.Schmidt M. Sun G. Stacey M.A. et al.Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma.J Immunol. 2003; 171: 380-389Crossref PubMed Scopus (542) Google Scholar, 7.Abe R. Donnelly S.C. Peng T. et al.Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J Immunol. 2001; 166: 7556-7562Crossref PubMed Scopus (882) Google Scholar, 8.Yang L. Scott P.G. Giuffre J. et al.Peripheral blood fibrocytes from burn patients: identification and quantification of fibrocytes in adherent cells cultured from peripheral blood mononuclear cells.Lab Invest. 2002; 82: 1183-1192Crossref PubMed Scopus (209) Google Scholar, 9.Quan T.E. Cowper S. Wu S.P. et al.Circulating fibrocytes:collagen-secreting cells of the peripheral blood.Int J Biochem Cell Biol. 2004; 36: 598-606Crossref PubMed Scopus (476) Google Scholar, 10.Bucala R. Fibrocytes: discovery of a circulating connective tissue cell progenitor.in: Bucala R. New insights into tissue repair and systemic fibroses. World Scientific, Singapore2007: 1-18Crossref Scopus (5) Google Scholar, 11.Varcoe R.L. Mikhail M. Guiffre A.K. et al.The role of the fibrocyte in intimal hyperplasia.J Thromb Haemost. 2006; 4: 1125-1133Crossref PubMed Scopus (75) Google Scholar (Table 1). In relation with human diseases, fibrocytes contribute to nephrogenic fibrosing dermopathy as well as burns.9.Quan T.E. Cowper S. Wu S.P. et al.Circulating fibrocytes:collagen-secreting cells of the peripheral blood.Int J Biochem Cell Biol. 2004; 36: 598-606Crossref PubMed Scopus (476) Google Scholar,10.Bucala R. Fibrocytes: discovery of a circulating connective tissue cell progenitor.in: Bucala R. New insights into tissue repair and systemic fibroses. World Scientific, Singapore2007: 1-18Crossref Scopus (5) Google Scholar A recent study reveals that the impairment of fibrocytes caused by the loss in otospiralin leads to abnormal cochlear physiology and auditory function.12.Delprat B. Ruel J. Guitton M.J. et al.Deafness and cochlear fibrocyte alterations in mice deficient for the inner ear protein otospiralin.Mol Cell Biol. 2005; 25: 847-853Crossref PubMed Scopus (49) Google Scholar In addition, fibrocytes are characterized as circulating adipocyte progenitors as well as fibroblasts and myofibroblasts.10.Bucala R. Fibrocytes: discovery of a circulating connective tissue cell progenitor.in: Bucala R. New insights into tissue repair and systemic fibroses. World Scientific, Singapore2007: 1-18Crossref Scopus (5) Google Scholar,13.Hong K.M. Burdick M.D. Phillips R.J. et al.Characterization of human fibrocytes as circulating adipocyte progenitors and the formation of human adipose tissue in SCID mice.FASEB J. 2005; 19: 2029-2031Crossref PubMed Scopus (108) Google Scholar Transforming growth factor (TGF)-β, serum amyloid P, and aggregated IgG influence fibrocyte function and differentiation.10.Bucala R. Fibrocytes: discovery of a circulating connective tissue cell progenitor.in: Bucala R. New insights into tissue repair and systemic fibroses. World Scientific, Singapore2007: 1-18Crossref Scopus (5) Google Scholar, 14.Pilling D. Buckley C.D. Salmon M. et al.Inhibition of fibrocyte differentiation by serum amyloid P.J Immunol. 2003; 171: 5537-5546Crossref PubMed Scopus (247) Google Scholar, 15.Pilling D. Tucker N.M. Gomer R.H. Aggregated IgG inhibits the differentiation of human fibrocytes.J Leukoc Biol. 2006; 79: 1242-1251Crossref PubMed Scopus (86) Google Scholar However, the detection and role of fibrocytes in the progressive fibrosis in the kidney remains investigated.Table 1 Characteristics of fibrocytesCell markersSecreted productsFunctional rolesα-Smooth muscle actin (α-SMA)Collagen IWound repairCollagens I and IIIMatrix metalloproteinase-9 (MMP-9)BurnProcollagen IProinflammatory cytokines/chemokinesAngiogenesisFibronectinTumor necrosis factor-α (TNF-α)Antigen presenting propertiesVimentinInterleukin-α (IL-1α)GranulomaPropyl 4-hydroxylaseIL-6Tumor biologyCD antigensIL-8/CXCL1Infection CD11a (LFA-1)Macrophage inflammatory protein 2(MIP-2)/CXCL2Chronic pancreatitis CD11b (MAC-1)Monocyte chemoattractant protein-1 (MCP-1)/CCL2Chronic cystits CD13 (aminopeptidase N)MIP-1α/CCL3Nephrogenic systemic fibrosis CD18Platelet-derived growth factor A (PDGF-A)Kidney fibrosis CD34Transforming growth factor-α (TGF-α)Scleroderma CD45ROTGF-β1Asthma CD54 (ICAM-1)Connecting tissue growth factor (CTGF)Pulmonary fibrosis CD58 (LFA-3)Macrophage-colony stimulating factor (M-CSF)Acute lung injury CD71Vascular endothelial cell growth factor (VEGF)Intimal hyperplasia CD80 (B7.1)Granulocyte-macrophage colony stimulating factor (GM-CSF)Cochlear physiology CD86 (B7.2)Basic fibroblast growth factor (bFGF)Fibrocyte differentiationMHC class IIAngiogeninMyofibroblast DPHepatocyte growth factorFibroblast DQOtospiralinAdipocyte DRFdpChemokine receptorLeukocyte specific protein 1 (LSP-1) CXCR4 (CD184) CCR2 CCR3 CCR5 (CD195) CCR7 (CDw107) Open table in a new tab Fibrosis is a characteristic pathological feature that determines the prognosis of diseases independent of their etiologies. Kidney diseases progress to end-stage failure, showing pathological characteristics including glomerulosclerosis and interstitial fibrosis.1.Bucala R. Spiegel L. Chesney J. et al.Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair.Mol Med. 1994; 1: 71-81Crossref PubMed Google Scholar,2.Chesney J. Metz C. Stavitsky A.B. et al.Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes.J Immunol. 1998; 160: 419-425PubMed Google Scholar The histological picture of interstitial fibrosis is characterized by tubular atrophy and dilation, interstitial leukocyte infiltration, accumulation of fibroblasts, and increased interstitial matrix deposition.16.Strutz F. Zeisberg M. Renal fibroblasts and myofibroblasts in chronic kidney disease.J Am Soc Nephrol. 2006; 17: 2992-2998Crossref PubMed Scopus (251) Google Scholar In this aspect, our recent study has uncovered the evidence that human peripheral CD14-positive monocytes/macrophages directly contribute to producing type I collagen, resulting in fibrogenesis, which are dependent on an amplification loop of monocyte chemoattractant protein-1 (MCP-1/CCL2)/CCR2.17.Sakai N. Wada T. Furuichi K. et al.MCP-1/CCR2-dependent loop for fibrogenesis in human peripheral CD14-positive monocytes.J Leukoc Biol. 2006; 79: 555-563Crossref PubMed Scopus (74) Google Scholar These results may provide a key role of immune-competent cells for their own promoting and escalating tissue fibrosis in addition to participating in the inflammatory cascade. Further, fibrocytes are capable of producing profibrotic molecules such as TGF-β as well as collagen.10.Bucala R. Fibrocytes: discovery of a circulating connective tissue cell progenitor.in: Bucala R. New insights into tissue repair and systemic fibroses. World Scientific, Singapore2007: 1-18Crossref Scopus (5) Google Scholar These results prompt us to investigate a distinct impact of fibrocytes on kidney tissue remodeling by secreting fibrogenic factors in the progression of kidney fibrosis. Here, we focus on the pathophysiological role of fibrocytes dependent on chemokine system in kidney fibrosis. In progressive kidney fibrosis induced by a ureteral ligation in mice, CD45- and type I collagen-dual-positive fibrocytes (CD45+/ColI+) infiltrated the interstitium, especially the corticomedullary regions (Figure 1a–c).18.Sakai N. Wada T. Yokoyama H. et al.Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis.Proc Natl Acad Sci USA. 2006; 103: 14098-14103Crossref PubMed Scopus (212) Google Scholar The number of infiltrating fibrocytes increased with the progression of fibrosis after a ureteral ligation, reaching a peak on day 7 (Figure 1d). To further verify the existence of fibrocytes, dual immunostainings of CD34 and type I collagen were also performed. The infiltration of CD34- and type I collagen-dual-positive fibrocytes was also observed in the interstitium and correlated with disease progression as determined by CD45- and type I collagen dual immunostainings.18.Sakai N. Wada T. Yokoyama H. et al.Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis.Proc Natl Acad Sci USA. 2006; 103: 14098-14103Crossref PubMed Scopus (212) Google Scholar In addition to murine-progressive interstitial fibrosis, CD45+/ColI+ fibrocytes infiltrate into human chronic kidney diseases. The number of infiltrating fibrocytes well correlates with the intensity of interstitial fibrosis in human various kidney diseases including diabetic nephropathy (manuscript in preparation). Further, CD34-positive spindle cells, detected in tubulointerstitial lesions in patients with glomerulonephritis, were closely related with interstitial volume, but not with kidney function.19.Okon K. Szumera A. Kuzniewski M. Are CD34+ cells found in renal interstitial fibrosis?.Am J Nephrol. 2003; 23: 409-414Crossref PubMed Scopus (19) Google Scholar Recent studies demonstrate that chemokine/chemokine receptor systems on fibrocytes are involved in the recruitment of circulating fibrocytes to sites of fibrosis.3.Moore B.B. Kolodsick J.E. Thannickal V.J. et al.CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury.Am J Pathol. 2005; 166: 675-684Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar, 5.Phillips R.J. Burdick M.D. Hong K. et al.Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.J Clin Invest. 2004; 114: 438-446Crossref PubMed Scopus (880) Google Scholar, 10.Bucala R. Fibrocytes: discovery of a circulating connective tissue cell progenitor.in: Bucala R. New insights into tissue repair and systemic fibroses. World Scientific, Singapore2007: 1-18Crossref Scopus (5) Google Scholar It is of note that fibrocytes, isolated from human and mice, express chemokine receptors such as CCR2, CCR3, CCR5, CCR7, and CXCR4.3.Moore B.B. Kolodsick J.E. Thannickal V.J. et al.CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury.Am J Pathol. 2005; 166: 675-684Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar, 5.Phillips R.J. Burdick M.D. Hong K. et al.Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.J Clin Invest. 2004; 114: 438-446Crossref PubMed Scopus (880) Google Scholar, 10.Bucala R. Fibrocytes: discovery of a circulating connective tissue cell progenitor.in: Bucala R. New insights into tissue repair and systemic fibroses. World Scientific, Singapore2007: 1-18Crossref Scopus (5) Google Scholar Intradermal instillation of secondary lymphoid tissue chemokine (SLC/CCL21) was firstly described to induce the recruitment of fibrocytes at the injected site.7.Abe R. Donnelly S.C. Peng T. et al.Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J Immunol. 2001; 166: 7556-7562Crossref PubMed Scopus (882) Google Scholar The migration of fibrocytes to the lung has been demonstrated to be dependent on signaling pathways of CXCL12/CXCR4 or CCR2.3.Moore B.B. Kolodsick J.E. Thannickal V.J. et al.CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury.Am J Pathol. 2005; 166: 675-684Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar,5.Phillips R.J. Burdick M.D. Hong K. et al.Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.J Clin Invest. 2004; 114: 438-446Crossref PubMed Scopus (880) Google Scholar CCR7-expressing fibrocytes, also positive for type I collagen (CCR7+/ColI+), were detected in diseased kidneys 7 days after a ureteral ligation in wild-type mice.18.Sakai N. Wada T. Yokoyama H. et al.Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis.Proc Natl Acad Sci USA. 2006; 103: 14098-14103Crossref PubMed Scopus (212) Google Scholar Infiltrating fibrocytes (37.8%) expressed CCR7 (number of CCR7+/ColI+ divided by the number of CCR7+ or CXCR4+ or CCR2+/ColI+). In wild-type mice, the ratio of CCR7+/ColI+ cells in obstructed kidneys was increased to 7.9% of the total isolated renal cells compared with that in normal kidneys (0.25%) and contralateral kidneys (0.21%). Of these CCR7-expressing fibrocytes in obstructed kidneys, 66.5% of cells were CXCR4+/CCR2+, 16.8% of cells were CXCR4+/CCR2-, 4.3% of cells were CXCR4-/CCR2+, and 12.4% of cells were CXCR4-/CCR2-. In contrast, the percentage of CCR7-negative collagen-producing cells (CCR7-/ColI+) increased to 26.7% of the total isolated renal cells from obstructed kidneys. A ligand for CCR7, secondary lymphoid tissue chemokine (SLC/CCL21), which is a member of the CC chemokine family, remains to be investigated in the progression of kidney fibrosis. CCL21 has been reported to act as a chemotactic stimulus for fibrocytes.18.Sakai N. Wada T. Yokoyama H. et al.Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis.Proc Natl Acad Sci USA. 2006; 103: 14098-14103Crossref PubMed Scopus (212) Google Scholar,20.Abe R. Donnelly S.C. Peng T. et al.Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J Immunol. 2001; 166: 7556-7562Crossref PubMed Google Scholar In humans as well as in mice, CCL21 is constitutively abundant in lymphoid tissues, particularly in the lymph nodes and spleen. It is of note that CCL21 is also expressed at lower levels in some non-lymphoid tissues, including the lung.21.Gunn M.D. Tangemann D.K. Tam C. et al.A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naïve T lymphocytes.Proc Natl Acad Sci USA. 1998; 95: 258-263Crossref PubMed Scopus (836) Google Scholar CCL21 expression is relatively localized in high endothelial venules (HEVs) in lymph nodes under physiological conditions21.Gunn M.D. Tangemann D.K. Tam C. et al.A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naïve T lymphocytes.Proc Natl Acad Sci USA. 1998; 95: 258-263Crossref PubMed Scopus (836) Google Scholar as well as in non-lymphoid tissues under inflammatory conditions.22.Kraal G. Mebius R.E. High endothelial venules: lymphatic traffic control and controlled traffic.Adv Immunol. 1997; 65: 347-395Crossref PubMed Google Scholar In fact, CCL21- and MECA79-dual-positive vessels were found in synovial tissues from patients with rheumatoid arthritis.23.Drayton D.L. Bonizzi G. Ying X. et al.I kappa B kinase complex alpha kinase activity controls chemokine and high endothelial venule gene expression in lymph nodes and nasal-associated lymphoid tissue.J Immunol. 2004; 173: 6161-6168Crossref PubMed Scopus (58) Google Scholar The number of CCL21- and MECA79-dual-positive HEV-like vessels as well as in situ expression of CCL21 mRNA increased with disease progression after ureteral ligation.18.Sakai N. Wada T. Yokoyama H. et al.Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis.Proc Natl Acad Sci USA. 2006; 103: 14098-14103Crossref PubMed Scopus (212) Google Scholar HEVs express certain chemokines, such as EBI1-ligand chemokine/CCL1924.Weninger W. Carlsen H.S. Goodarzi M. et al.Naïve T cell recruitment to nonlymphoid tissues: a role for endothelium-expressed CC chemokine ligand 21 in autoimmune disease and lymphoid neogenesis.J Immunol. 2003; 170: 4638-4648Crossref PubMed Scopus (170) Google Scholar as well as CCL21, that can activate CCR7-expressing cells, even though CCL19 expression remained investigated in the previous report.18.Sakai N. Wada T. Yokoyama H. et al.Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis.Proc Natl Acad Sci USA. 2006; 103: 14098-14103Crossref PubMed Scopus (212) Google Scholar Concomitantly, MECA79-positive HEV-like vessels located at the corticomedullary junction were detected and associated with interstitial leukocyte infiltration in human glomerulonephritis.25.Segawa C. Wada T. Takaeda M. et al.In situ expression and soluble form of P-selectin in human glomerulonephritis.Kidney Int. 1997; 52: 1054-1063Abstract Full Text PDF PubMed Scopus (50) Google Scholar These findings suggest that CCR7-expressing circulating fibrocytes infiltrate the kidney via CCL21-positive HEV-like vessels, resulting in the contribution to kidney fibrosis. The impact of CCL21/CCR7 signaling on progressive kidney interstitial fibrosis was further examined. Mean interstitial fibrosis as well as the amount of hydroxyproline was reduced by almost 50% in mice treated with anti-CCL21 antibodies compared with that in wild-type mice 7 days after an ureteral ligation, which was confirmed by the similar reduction in CCR7-null mice (Figure 2).18.Sakai N. Wada T. Yokoyama H. et al.Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis.Proc Natl Acad Sci USA. 2006; 103: 14098-14103Crossref PubMed Scopus (212) Google Scholar Accordingly, on the basis of finding that treatment with anti-CCL21 antibodies or CCR7 deficiency resulted in over 50% reduction in the number of CD45- and type I collagen-dual-positive fibrocytes, thereby CCL21/CCR7 signaling is thought to be the major pathway attracting fibrocytes into the kidney in this particular model. In addition, ureteral ligation enhanced the pro-α1 chain of type I collagen mRNA expression as well as transcripts of TGF-β1, which was also downregulated by the inhibition of CCL21/CCR7 signaling. Moreover, blockade of CCL21/CCR7 signaling reduced the number of CCR7-expressing fibrocytes as well as CCR2-expressing fibrocytes in immunohistochemical studies. A recent study reported that CCL2/CCR2 signaling mediated recruitment of CCR2-expressing fibrocytes to the alveolar space after administration of fluorescein isothiocyanate, resulting in pulmonary fibrosis.3.Moore B.B. Kolodsick J.E. Thannickal V.J. et al.CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury.Am J Pathol. 2005; 166: 675-684Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar Fibrocytes have been considered to be capable of producing MCP-1/CCL2 under pathological fibrotic conditions.10.Bucala R. Fibrocytes: discovery of a circulating connective tissue cell progenitor.in: Bucala R. New insights into tissue repair and systemic fibroses. World Scientific, Singapore2007: 1-18Crossref Scopus (5) Google Scholar Therefore, inhibiting the infiltration of CCR7-expressing fibrocytes appears to decrease the infiltration of CCR2-expressing fibrocytes through suppression of MCP-1/CCL2 production, thereby contributing to more effective protection from kidney fibrosis (Figure 3).26.Wada T. Furuichi K. Sakai N. et al.Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis.J Am Soc Nephrol. 2004; 15: 940-948Crossref PubMed Scopus (147) Google Scholar,27.Wada T. Yokoyama H. Furuichi K. et al.Intervention of crescentic glomerulonephritis by antibodies to monocyte chemotactic and activating factor (MCAF/MCP-1).FASEB J. 1996; 12: 1418-1425Google Scholar In contrast, the infiltration of CXCR4-positive fibrocytes was not reduced by the blockade of CCL21/CCR7. Therefore, further studies will be required to elucidate the precise mechanisms that other chemokine/chemokine receptor pathways may also be involved in the recruitment and activation of fibrocytes, resulting in progressive fibrosis. Detailed molecular mechanisms involved in progressive organ fibrosis are not fully uncovered. Currently, resident fibroblasts, epithelial–mesenchymal transition-derived fibroblasts/myofibroblasts, and monocytes/macrophages are thought to be participants in the pathogenesis of kidney fibrosis.17.Sakai N. Wada T. Furuichi K. et al.MCP-1/CCR2-dependent loop for fibrogenesis in human peripheral CD14-positive monocytes.J Leukoc Biol. 2006; 79: 555-563Crossref PubMed Scopus (74) Google Scholar, 28.Iwano M. Plieth D. Danoff T.M. et al.Evidence that fibroblast derive from epithelium during tissue fibrosis.J Clin Invest. 2002; 110: 341-350Crossref PubMed Scopus (1612) Google Scholar, 29.Kitagawa K. Wada T. Furuichi K. et al.Blockade of CCR2 ameliorates progressive fibrosis in kidney.Am J Pathol. 2004; 165: 237-246Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar In addition, Iwano et al.28.Iwano M. Plieth D. Danoff T.M. et al.Evidence that fibroblast derive from epithelium during tissue fibrosis.J Clin Invest. 2002; 110: 341-350Crossref PubMed Scopus (1612) Google Scholar reported that 15% were derived from CD34-negative fibroblasts in bone marrow, whereas 36% of renal fibroblasts found in a UUO model were derived from epithelial–mesenchymal transition. Interestingly, circulating fibrocytes express CD34; however, fibrocytes reduce the expression of CD34 on the surface as they become more specialized.10.Bucala R. Fibrocytes: discovery of a circulating connective tissue cell progenitor.in: Bucala R. New insights into tissue repair and systemic fibroses. World Scientific, Singapore2007: 1-18Crossref Scopus (5) Google Scholar Moreover, the stimulation of TGF-β1 decreases the expression of cell surface CD34. However, the relation of fibrocytes with epithelial–mesenchymal transition-derived fibloblasts and CD34-negative fibroblasts remains investigated. Recent reports raise the possibility that these participants may interact with each other. TGF-β1 may play a key role in this aspect. TGF-β1, which could be produced by fibrocytes,2.Chesney J. Metz C. Stavitsky A.B. et al.Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes.J Immunol. 1998; 160: 419-425PubMed Google Scholar is a well-characterized inducer of epithelial–mesenchymal transition in tubular epithelial cells.30.Zeisberg M. Hanai J. Sugimoto H. et al.BMP-7 counteracts TGF-β1-induced epithelial-to-mesenchymal transition and reverse chronic renal injury.Nat Med. 2003; 9: 964-968Crossref PubMed Scopus (1107) Google Scholar Concomitantly, fibrocytes further differentiate to contractile myofibroblasts co-existant with TGF-β1.10.Bucala R. Fibrocytes: discovery of a circulating connective tissue cell progenitor.in: Bucala R. New insights into tissue repair and systemic fibroses. World Scientific, Singapore2007: 1-18Crossref Scopus (5) Google Scholar Alternatively, a very recent study revealed that an average of 32% of all interstitial α-smooth muscle actin-positive myofibroblasts were derived from the bone marrow. Functional bone marrow-derived myofibroblasts infiltrate in the post-ischemic renal interstitium and are involved in extracellular matrix.31.Martine B. Harmsen M.C. van Luyn M.J.A. et al.Bone-marrow derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after ischemia/reperfusion in rats.Am J Soc Nephrol. 2007; 18: 165-175Crossref PubMed Scopus (142) Google Scholar Therefore, further study would be required to examine the fundamental properties, differentiation potential, and mutual interactions of participants in progressive organ fibrosis in depth (Figure 3). Fibrocytes are now considered to be involved in various conditions including tumor biology, immunostimulatory properties, infection, and scleroderma (Table 1).10.Bucala R. Fibrocytes: discovery of a circulating connective tissue cell progenitor.in: Bucala R. New insights into tissue repair and systemic fibroses. World Scientific, Singapore2007: 1-18Crossref Scopus (5) Google Scholar Dual-positive spindle-shaped cells for CD34 and procollagen are present at a thickened dermins in a patient with nephrogenic systemic fibrosis, which is closely related to renal insufficiency.32.Cowper S.E. Bucala R. Nephrogenic fibrosing dermopathy: suspect identified, motive unclear.Am J Dermatopathol. 2003; 25: 358Crossref PubMed Scopus (151) Google Scholar A more recent study revealed a population of small spindle-shaped fibroblasts that were highly proliferative and expressed collagen I and α-smooth muscle actin (myofibroblast markers), CD34 (a precursor marker), and CD45 (a hematopoietic marker) in ischemic cardiomyopathy in mice. Importantly, serum amyloid P may be an important regulator in the linkage between inflammation and nonadaptive fibrosis through the modulation of proliferative spindle-shaped fibroblasts in the heart.33.Haudek S.B. Huebener P. Lee J.M. et al.Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice.Proc Natl Acad Sci USA. 2006; 103: 18284-18289Crossref PubMed Scopus (272) Google Scholar An insight of fibrocytes dependent on CCL21/CCR7 signaling pathways through HEV-like vessels has shed light on the novel pathogenesis of progressive organ fibrosis including kidney fibrosis. The most compelling part in our previous study was that the inhibition of CCL21/CCR7 signaling ameliorated progressive kidney fibrosis by almost 50%.18.Sakai N. Wada T. Yokoyama H. et al.Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis.Proc Natl Acad Sci USA. 2006; 103: 14098-14103Crossref PubMed Scopus (212) Google Scholar In addition to inhibiting chemokine system, our recent unpublished data suggest that renin–angiotensin aldosterone system plays a role in the activation of fibrocytes, suggesting the blockade of renin–angiotensin aldosterone system might provide a beneficial therapeutic approach, at least in part, via the inhibition of fibrocyte activation. Deeper knowledge of signals for the recruitment and activation of fibrocytes during the progression of fibrosis may provide a key to better therapeutic benefit for combating fibrosis in humans." @default.
• W2008553572 created "2016-06-24" @default.
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• W2008553572 date "2007-08-01" @default.
• W2008553572 modified "2023-10-15" @default.
• W2008553572 title "Fibrocytes: A new insight into kidney fibrosis" @default.
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