The role of circulating mesenchymal progenitor cells (fibrocytes) in the pathogenesis of fibrotic disorders

Summary

Fibrocytes are bone marrow-derived mesenchymal progenitor cells that express markers of leukocytes, haematopoietic progenitor cells, and fibroblasts. They play a pivotal role in tissue remodelling and fibrosis in both physiologic and pathologic settings. Fibrocytes are unique in that they are capable of differentiating into fibroblasts and myofibroblasts, as well as adipocytes. In this review we will present data supporting the critical role they play in the pathogenesis of chronic inflammatory fibrotic diseases of the lungs, heart and vasculature.

Keywords

Chemokines - collagens - wound healing

• References

• 1 Bucala R, Spiegel LA, Chesney J. et al. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1994; 1: 71-81.
• 2 Ebihara Y, Masuya M, Larue AC. et al. Haematopoietic origins of fibroblasts: II. In vitro studies of fibroblasts, CFU-F, and fibrocytes. Exp Haematol 2006; 34: 219-229.
• 3 Metz CN. Fibrocytes: a unique cell population implicated in wound healing. Cell Mol Life Sci 2003; 60: 1342-1350.
• 4 Quan TE, Cowper S, Wu SP. et al. Circulating fibrocytes: collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol 2004; 36: 598-606.
• 5 Chesney J, Metz C, Stavitsky AB. et al. Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. J Immunol 1998; 160: 419-425.
• 6 Hong KM, Burdick MD, Phillips RJ. et al. Characterization of human fibrocytes as circulating adipocyte progenitors and the formation of human adipose tissue in SCID mice. Faseb J 2005; 19: 2029-2031.
• 7 Hong KM, Belperio JA, Keane MP. et al. Differentiation of human circulating fibrocytes as mediated by transforming growth factor-beta and peroxisome proliferator-activated receptor gamma. J Biol Chem 2007; 282: 22910-22920.
• 8 Chesney J, Bacher M, Bender A. et al. The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ. Proc Natl Acad Sci USA 1997; 94: 6307-6312.
• 9 Phillips RJ, Burdick MD, Hong K. et al. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 2004; 114: 438-446.
• 10 Santucci M, Borgognoni L, Reali UM. et al. Keloids and hypertrophic scars of Caucasians show distinctive morphologic and immunophenotypic profiles. Virchows Arch 2001; 438: 457-463.
• 11 Mehrad B, Burdick MD, Zisman DA. et al. Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease. Biochem Biophys Res Commun 2007; 353: 104-108.
• 12 Barth PJ, Ebrahimsade S, Hellinger A. et al. CD34+ fibrocytes in neoplastic and inflammatory pancreatic lesions. Virchows Arch 2002; 440: 128-133.
• 13 Bucala R. Circulating fibrocytes: cellular basis for NSF. J Am Coll Radiol 2008; 5: 36-39.
• 14 Nimphius W, Moll R, Olbert P. et al. CD34+ fibrocytes in chronic cystitis and noninvasive and invasive urothelial carcinomas of the urinary bladder. Virchows Arch 2007; 450: 179-185.
• 15 Varcoe RL, Mikhail M, Guiffre AK. et al. The role of the fibrocyte in intimal hyperplasia. J Thromb Haemost 2006; 4: 1125-1133.
• 16 Medbury HJ, Tarran SL, Guiffre AK. et al. Monocytes contribute to the atherosclerotic cap by transformation into fibrocytes. Int Angiol 2008; 27: 114-123.
• 17 Zulli A, Buxton BF, Black MJ. et al. CD34 Class III positive cells are present in atherosclerotic plaques of the rabbit model of atherosclerosis. Histochem Cell Biol 2005; 124: 517-522.
• 18 Hartlapp I, Abe R, Saeed RW. et al. Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo. Faseb J 2001; 15: 2215-2224.
• 19 Fukuda Y, Ishizaki M, Masuda Y. et al. The role of intraalveolar fibrosis in the process of pulmonary structural remodelling in patients with diffuse alveolar damage. Am J Pathol 1987; 126: 171-182.
• 20 Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003; 112: 1776-1784.
• 21 Marshall R, Bellingan G, Laurent G. The acute respiratory distress syndrome: fibrosis in the fast lane. Thorax 1998; 53: 815-817.
• 22 Iwano M, Plieth D, Danoff TM. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002; 110: 341-350.
• 23 Abe R, Donnelly SC, Peng T. et al. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 2001; 166: 7556-7562.
• 24 Aiba S, Tagami H. Inverse correlation between CD34 expression and proline-4-hydroxylase immuno-reactivity on spindle cells noted in hypertrophic scars and keloids. J Cutan Pathol 1997; 24: 65-69.
• 25 Strieter RM, Gomperts BN, Keane MP. The role of CXC chemokines in pulmonary fibrosis. J Clin Invest 2007; 117: 549-556.
• 26 Yang L, Scott PG, 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: 1183-1192.
• 27 Pilling D, Buckley CD, Salmon M. et al. Inhibition of fibrocyte differentiation by serum amyloid P. J Immunol 2003; 171: 5537-5546.
• 28 Pilling D, Tucker NM, Gomer RH. Aggregated IgG inhibits the differentiation of human fibrocytes. J Leukoc Biol 2006; 79: 1242-1251.
• 29 Schmidt M, Sun G, Stacey MA. et al. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 2003; 171: 380-389.
• 30 Chauhan H, Abraham A, Phillips JR. et al. There is more than one kind of myofibroblast: analysis of CD34 expression in benign, in situ, and invasive breast lesions. J Clin Pathol 2003; 56: 271-276.
• 31 Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5: 953-964.
• 32 Tacke F, Randolph GJ. Migratory fate and differentiation of blood monocyte subsets. Immunobiology 2006; 211: 609-618.
• 33 Bellini A, Mattoli S. The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses. Lab Invest 2007; 87: 858-870.
• 34 Balmelli C, Ruggli N, McCullough K. et al. Fibrocytes are potent stimulators of anti-virus cytotoxic T cells. J Leukoc Biol 2005; 77: 923-933.
• 35 Kuwana M, Okazaki Y, Kodama H. et al. Human circulating CD14+ monocytes as a source of progenitors that exhibit mesenchymal cell differentiation. J Leukoc Biol 2003; 74: 833-845.
• 36 Mori L, Bellini A, Stacey MA. et al. Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res 2005; 304: 81-90.
• 37 Shao DD, Suresh R, Vakil V. et al. Pivotal Advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J Leukoc Biol 2008; 83: 1323-1333.
• 38 Moore BB, Kolodsick JE, Thannickal VJ. et al. CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. Am J Pathol 2005; 166: 675-684.
• 39 Murdoch C. CXCR4: chemokine receptor extra-ordinaire. Immunol Rev 2000; 177: 175-184.
• 40 Andersson-Sjoland A, de Alba CG, Nihlberg K. et al. Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis. Int J Biochem Cell Biol 2008; 40: 2129-2140.
• 41 Ortiz LA, Gambelli F, McBride C. et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA 2003; 100: 8407-8411.
• 42 Rojas M, Xu J, Woods CR. et al. Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 2005; 33: 145-152.
• 43 Epperly MW, Guo H, Gretton JE. et al. Bone marrow origin of myofibroblasts in irradiation pulmonary fibrosis. Am J Respir Cell Mol Biol 2003; 29: 213-224.
• 44 Hashimoto N, Jin H, Liu T. et al. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest 2004; 113: 243-252.
• 45 Haudek SB, Xia Y, Huebener P. et al. Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Proc Natl Acad Sci USA 2006; 103: 18284-18289.
• 46 Kuhn C, 3rd Boldt J, King Jr TE. et al. An immunohistochemical study of architectural remodelling and connective tissue synthesis in pulmonary fibrosis. Am Rev Respir Dis 1989; 140: 1693-1703.
• 47 Lama VN, Smith L, Badri L. et al. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest 2007; 117: 989-996.
• 48 Kim KK, Kugler MC, Wolters PJ. et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA 2006; 103: 13180-13185.
• 49 American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias.. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002; 165: 277-304.
• 50 Gomperts BN, Strieter RM. Fibrocytes in lung disease. J Leukoc Biol 2007; 82: 449-456.
• 51 Moore BB, Murray L, Das A. et al. The role of CCL12 in the recruitment of fibrocytes and lung fibrosis. Am J Respir Cell Mol Biol 2006; 35: 175-181.
• 52 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: 14098-14103.
• 53 Nihlberg K, Larsen K, Hultgardh-Nilsson A. et al. Tissue fibrocytes in patients with mild asthma: a possible link to thickness of reticular basement membrane?. Respir Res 2006; 7: 50.
• 54 Kaur D, Saunders R, Berger P. et al. Airway smooth muscle and mast cell-derived CC chemokine ligand 19 mediate airway smooth muscle migration in asthma. Am J Respir Crit Care Med 2006; 174: 1179-1188.
• 55 Wang CH, Huang CD, Lin HC. et al. Increased circulating fibrocytes in asthma with chronic airflow obstruction. Am J Respir Crit Care Med 2008; 178: 583-591.
• 56 Dewald O, Frangogiannis NG, Zoerlein M. et al. Development of murine ischemic cardiomyopathy is associated with a transient inflammatory reaction and depends on reactive oxygen species. Proc Natl Acad Sci USA 2003; 100: 2700-2705.
• 57 Dewald O, Zymek P, Winkelmann K. et al. CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res 2005; 96: 881-889.
• 58 Mold C, Baca R, Du Clos TW. Serum amyloid P component and C-reactive protein opsonize apoptotic cells for phagocytosis through Fcgamma receptors. J Autoimmun 2002; 19: 147-154.