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Role of Circulating Fibrocytes in Cardiac Fibrosis.

Byline: Rong-Jie. Lin, Zi-Zhuo. Su, Shu-Min. Liang, Yu-Yang. Chen, Xiao-Rong. Shu, Ru-Qiong. Nie, Jing-Feng. Wang, Shuang-Lun. Xie

Objective: It is revealed that circulating fibrocytes are elevated in patients/animals with cardiac fibrosis, and this review aims to provide an introduction to circulating fibrocytes and their role in cardiac fibrosis. Data Sources: This review is based on the data from 1994 to present obtained from PubMed. The search terms were “circulating fibrocytes “ and “cardiac fibrosis “. Study Selection: Articles and critical reviews, which are related to circulating fibrocytes and cardiac fibrosis, were selected. Results: Circulating fibrocytes, which are derived from hematopoietic stem cells, represent a subset of peripheral blood mononuclear cells exhibiting mixed morphological and molecular characteristics of hematopoietic and mesenchymal cells (CD34[sup]+/CD45[sup]+/collagen I[sup]+). They can produce extracellular matrix and many cytokines. It is shown that circulating fibrocytes participate in many fibrotic diseases, including cardiac fibrosis. Evidence accumulated in recent years shows that aging individuals and patients with hypertension, heart failure, coronary heart disease, and atrial fibrillation have more circulating fibrocytes in peripheral blood and/or heart tissue, and this elevation of circulating fibrocytes is correlated with the degree of fibrosis in the hearts. Conclusions: Circulating fibrocytes are effector cells in cardiac fibrosis.


Cardiac fibrosis is present in many pathological conditions, including hypertension, coronary heart disease (CHD), and heart failure.[sup][1] Cardiac fibrosis has adverse effects on cardiac function. It culminates in increased stiffness of the heart, impairing diastolic function of the heart. It is also a mechanism involved in cardiac arrhythmia: (a) fibrous tissue can cause conduction slowing, leading to increased conduction heterogeneity, conduction block, or reentry,[sup][2] (b) inappropriate cardiomyocyte-fibroblast couplings may form in fibrous hearts, predisposing individuals to cardiac arrhythmia.[sup][3] Cardiac fibrosis is characterized by excessive deposition of extracellular matrix (ECM) and is now considered a result of exaggerated activity of fibroblasts, therefore researchers have done substantial work to inhibit the proliferation, differentiation, and oxidative stress of fibroblasts.[sup][4],[5] Previously, this deposition is thought to be produced by resident fibroblasts. New evidence suggests that other cells are also involved in this process. These cells include endothelial cells (undergoing endothelial-to-mesenchymal transition),[sup][6] mesenchymal stem cells (differentiating into fibroblasts),[sup][7] and circulating fibrocytes. “Circulating fibrocytes “ were first described in 1994 as a subpopulation of leukocytes. They are derived from hematopoietic cells and can further differentiate into cells such as fibroblasts and adipocytes.[sup][8],[9] They are spindle-shaped cells co-expressing hematopoietic and mesenchymal markers, such as CD34, CD45, [micro]-smooth muscle actin ([micro]-SMA), and collagen I.[sup][10],[11] Circulating fibrocytes, producers of ECM, have been extensively reported to contribute to the development of pulmonary fibrosis and renal fibrosis.[sup][12],[13] Evidence accumulated in recent years shows that circulating fibrocytes also play important roles in cardiac fibrosis. They are significantly increased in the hearts when the hosts are subject to cardiac ischemia,[sup][14] hypertension,[sup][15] heart failure,[sup][16] and atrial fibrillation (AF) [Table 1].[sup][17] Similar results were obtained when compared the number of circulating fibrocytes in aging heart to that of younger individuals [Table 1].[sup][23] This novel insight into the pathogenesis of cardiac fibrosis suggests that circulating fibrocyte may be a potential target for treatment of cardiac fibrosis. The remainder of this article describes the features of circulating fibrocytes and their contribution to cardiac fibrosis.{Table 1}

Features of Circulating Fibrocytes

Circulating fibrocytes are of hematopoietic origin

It was reported more than 150 years ago that there were a population of fibroblast-like cells in peripheral blood. However, it was not until 1994 when the term fibrocyte was used for the first time to define these blood-borne fibroblast-like cells.[sup][10] Nevertheless, this term is not specifically used to describe these cells, and it also refers to quiescent fibroblast and a cell in inner ear. Therefore, circulating fibrocyte or CD34 + fibrocyte is preferred. In the initial report, using wound-healing models, it was found that an unexpectedly large number of fibroblast-like cells were present in wound chambers.[sup][10] Further examinations of these cells revealed that they co-expressed CD34, CD45, vimentin, and collagen I, which were reminiscent of leukocytes and fibroblasts.[sup][10] In addition, cells expressing the same markers were found in peripheral blood.[sup][10] Combining these findings together, researchers defined these blood-borne fibroblast-like cells as circulating fibrocytes and supposed that these cells circulated in the blood stream, mobilized to wound sites, and contributed to wound healing.[sup][10] It was initially thought that circulating fibrocytes were derived from hematopoietic stem cells (HSCs). However, chimera studies conducted by the same group failed to prove that circulating fibrocytes were of hematopoietic origin, which may be associated with the inability of irradiation with 800 rads (1 rad = 0.01 Gy) to kill all the HSCs.[sup][10] Later, in vivo and in vitro experiments with different methods to trace circulating fibrocytes confirmed that these cells originate from HSCs.[sup][37],[38],[39]

In vitro experiments suggested that fibrocytes differentiated from monocytes.[sup][40] In this monocyte to fibrocyte differentiation, monocytes first differentiate into M1 macrophages, the latter become M2 macrophages, and finally M2 macrophages give rise to fibrocytes. This transition can be modulated by many factors. T-cells are indispensable in monocyte to fibrocyte differentiation, and deficiency in T-cells impairs this process as can be seen in a study that nude rats undergoing myocardial infarction (MI) showed few circulating fibrocytes within the myocardium.[sup][40],[41] Many cytokines are involved in this differentiation. For example, Th1 cytokines (interferon-a and interleukin-12 [IL-12]) suppress this process while Th2 cytokines (IL-4 and IL-13) promote this differentiation.[sup][42] In addition, epigenic modulation can also be a way to regulate this differentiation. Inhibition of Class I histone deacetylases was shown to suppress differentiation of monocytes to circulating fibrocytes.[sup][35]

Of note, circulating fibrocytes represent a part of stromal cells in embryos,[sup][43] therefore although circulating fibrocytes are recruited to certain sites in disease state, their presence in normal tissues was also reported.[sup][44],[45]

Identification of circulating fibrocytes

Morphologically, circulating fibrocytes are 50–200[micro]m long spindle-shaped cells with ellipsoid nuclei, and there are prominent projections on the surface of them.[sup][10] They express markers of both hematopoietic cells (CD34, CD45, and leukocyte-specific protein 1) and mesenchymal cells (collagen I, procollagen-I).[sup][40],[46] Therefore, a combination of hematopoietic and mesenchymal markers is widely used in identifying circulating fibrocytes [Table 1]. To confirm the hematopoietic origin of circulating fibrocytes, green fluorescent protein (GFP)-transgenic mice are frequently used in the tracing of circulating fibrocytes [Table 1]. Bone marrow cells of these GFP-transgenic mice are injected into experimental mice. Then, double staining of mesenchymal markers with GFP indicates the existence of circulating fibrocytes.

Functions of circulating fibrocytes

In general, circulating fibrocytes are polyfunctional. They can produce ECM [sup][33] and a variety of cytokines, such as tumor necrosis factor-[micro], platelet-derived growth factor-A, transforming growth factor-[sz]1 (TGF-[sz]1), macrophage colony-stimulating factor, and matrix metalloproteinases.[sup][45],[47] Circulating fibrocytes are regarded as precursors of fibroblasts/myofibroblasts. Once differentiated into fibroblasts/myofibroblasts, the production of ECM can even be enhanced.[sup][48] During this process, circulating fibrocytes will lose their expression of CD34 and CD45, and express [micro]-SMA, a marker of myofibroblasts.[sup][49],[50] This differentiation can be spontaneous when isolated fibrocytes are cultured in vitro [sup][51] and will be enhanced when cytokines such as endothelin-1, TGF-[sz]1, and connective tissue growth factor are added to the culture medium.[sup][33],[48],[52] In addition to tissue remodeling, circulating fibrocytes also participate in a variety of processes, including antigen presentation and angiogenesis,[sup][53],[54] which will not be extensively discussed here.

Recruitment of circulating fibrocytes

It is estimated that circulating fibrocytes comprise 0.1–1% of nonerythrocytes in peripheral blood,[sup][55] and this proportion is relatively stable unless injuries such as inflammation and hypoxia occur. For example, in patients with interstitial lung disease (ILD), the proportion of circulating fibrocytes goes up to 6–10%,[sup][56] and during exacerbation of ILD, up to 15% of nonerythrocytes in the blood are circulating fibrocytes.[sup][57] The alteration of the amount of circulating fibrocytes is probably mediated by chemokine ligand/chemokine receptor axis. Chemokines are chemotactic cytokines that control the migratory patterns and positioning of cells expressing chemokine receptors, which are G protein-coupled receptors and are expressed on the surfaces of circulating fibrocytes.[sup][46] The binding of chemokines to chemokine receptors directs the mobilization of circulating fibrocytes according to the gradient of chemokines.[sup][58] In response to injuries such as inflammation and hypoxia, the concentrations of chemokines in both peripheral blood and organs are elevated, and this elevation leads to accumulation of circulating fibrocytes in blood stream and injured organs.[sup][59],[60] This has been shown in many studies. For example, CXC-chemokine ligand 16 (CXCL16) (a transmembrane CXC chemokine) knockout mice administrated with angiotensin II (Ang II) were found to have significantly less circulating fibrocytes in injured kidney compared with these in wild-type mice,[sup][61] indicating CXCL16 is one of the mediators involved in circulating fibrocyte recruitment.

Circulating Fibrocytes in Cardiac Fibrosis

Accumulating evidence has indicated that circulating fibrocytes are involved cardiac fibrosis, when hosts are subject to hypertension, aging, cardiac ischemia, AF, and heart failure.

Circulating fibrocytes in hypertensive heart disease

Hypertension, defined as a usual blood pressure of 140/90 mmHg (1 mmHg = 0.133 kPa), is now a leading cause of death and is recognized as a risking factor for MI, aortic dissection, and cardiac fibrosis. In hypertension-induced cardiac fibrosis, circulating fibrocytes may play a role. It has been shown that patients with hypertensive heart disease had more circulating fibrocytes in peripheral blood, which is also correlated with left ventricular mass.[sup][26] In experimental models, it was found that Ang II infusion or transverse aortic constriction which resulted in a significant increase of blood pressure, causes a significant increase of fibrocytes in the hearts, resulting in enhanced deposition of collagen in the affected hearts.[sup][24],[25],[31],[62] Interestingly, it was shown in a study that NaCl, an excessive intake of which will lead to hypertension, can potentiate monocyte to fibrocyte differentiation, enhancing ECM production.[sup][63]

Circulating fibrocytes in heart failure

Heart failure is one of the most common and costly disabling diseases worldwide. It is a heterogeneous syndrome caused by the inability of the heart to pump sufficient blood to meet the requirement of metabolizing tissues. Cardiac fibrosis is commonly seen in patients with heart failure,[sup][64] and circulating fibrocytes may be involved in this process. Using Mst1 mice, which are animal models of chronic heart failure without acute ischemia (a common cause of fibrocyte recruitment), it was found that cardiomyocytes in chronic heart failure can secrete chemotactic factor, stromal-derived factor-1, recruiting circulating fibrocytes to the myocardium, and contributing to the fibrosis of affected hearts.[sup][16]

Circulating fibrocytes in coronary heart disease

CHD, causing 50% of death in developed countries, appears to rank number one in prevalence at present.[sup][65] Typically, CHD is characterized by atherosclerotic plaques presented in coronary arterial walls. These plaques narrow the lumen of coronary arteries, limiting blood supply to the hearts. Partial or complete coronary artery narrowing leads to acute myocardial infarction (AMI), which is characterized by sudden loss of cardiomyocytes and overwhelming inflammatory response. Thereafter, the infarcted areas are replaced by collagen-rich scars because of the limited regeneration ability of cardiomyocytes.[sup][66] The scar was thought to be the production of resident myofibroblasts.[sup][67] This paradigm is now challenged by many reports. It was shown in a study that a significant circulating fibrocytes were present within the myocardium on day 7 post-MI. Examination of the heart tissue revealed that 24% of myofibroblasts were derived from bone marrow, indicating that circulating fibrocytes contributed to reparative process of the hearts after MI.[sup][21] Similar results were obtained from other studies.[sup][14],[20],[32],[68],[69] In addition to acute cardiomyocyte loss, daily, brief coronary occlusion, which does not cause death of cardiomyocytes, leads to increase of circulating fibrocytes in myocardium. It was shown that ischemia/reperfusion cardiomyopathy cause induction of monocyte chemotactic protein-1 (MCP-1, also known as chemokine [C-C motif] ligand-2) in cardiomyocytes, thus contributing to the recruitment of monocytes and circulating fibrocytes and cardiac fibrosis.[sup][18],[70] Although animal models of cardiac ischemia have shown that coronary occlusion leads to infiltration of circulating fibrocytes into myocardium, it is reported that patients with AMI had less circulating fibrocytes in peripheral blood.[sup][71] As it was shown that circulating fibrocytes were present in fibrous caps,[sup][72] the decrease of circulating fibrocytes may contribute to instability of atherosclerotic plaques. This result indicated that elevated circulating fibrocytes may not always be unfavorable.

Circulating fibrocytes in atrial fibrillation

AF is the most common sustained cardiac arrhythmia, and its morbidity and mortality are now increasing.[sup][73] Atrial fibrosis is an important contributor to the pathogenesis of AF.[sup][74] It was reported that the number of circulating fibrocytes in peripheral blood was also increased in patients with AF compared to patients with sinus rhythm.[sup][17] Examination of left atrial tissue from the two groups also revealed that cardiac fibrosis was enhanced in tissue from patients with AF, coinciding with 3-fold more fibrocytes presenting in the atrial tissue.[sup][17] In addition, it was shown in the same study that circulating fibrocytes from patients with AF had enhanced ability to produce collagen when cultured in complete medium,[sup][17] further unveiling important role of circulating fibrocytes in the development of atrial fibrosis.

Circulating fibrocytes in aging hearts

Age is a risk factor for many cardiovascular diseases, including heart failure, hypertension, and cardiac arrhythmia. Aging hearts are characterized by loss of cardiomyocytes and progressive fibrosis. Many mechanisms are involved in age-related cardiac fibrosis, including TGF-[sz] unresponsiveness and fibrocyte infiltration.[sup][75] It was found that compared with younger individuals, aging mice had more circulating fibrocytes in the hearts.[sup][23],[28] This increase of fibrocytes is correlated with up-regulation of MCP-1, Th2 cytokines (IL-4, IL-13), thereby enhancing infiltration of monocytes and monocyte to fibrocyte differentiation.


Circulating fibrocytes, a unique cell population, are of hematopoietic origin and circulate in peripheral blood. They are reminiscent of leukocytes and fibroblasts because of their co-expression of hematopoietic and mesenchymal markers. Accumulating evidence suggests that circulating fibrocytes are involved in the process of cardiac fibrosis, and it is shown that there are many ways to regulate biological behavior of circulating fibrocytes, such as modulating the recruitment and differentiation of circulating fibrocytes. Findings in the present study indicate that circulating fibrocytes can serve as a potential target for diminishing adverse effect of cardiac fibrosis, thereby improving prognosis of these patients. However, many aspects of circulating fibrocytes remain elusive, for instance, signaling pathway of cytokines in circulating fibrocytes is still unknown. Therefore, more studies are still needed to expand our understanding of circulating fibrocytes.

Financial support and sponsorship

This work was supported by the grant from the National Natural Science Foundation of China (No. 81000101).

Conflicts of interest

There are no conflicts of interest.


1. Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev 1999;79:215-62.

2. Burstein B, Nattel S. Atrial fibrosis: Mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol 2008;51:802-9. doi: 10.1016/j.jacc.2007.09.064.

3. McArthur L, Chilton L, Smith GL, Nicklin SA. Electrical consequences of cardiac myocyte: Fibroblast coupling. Biochem Soc Trans 2015;43:513-8. doi: 10.1042/bst20150035.

4. Hao PP, Yang JM, Zhang MX, Zhang K, Chen YG, Zhang C, et al. Angiotensin-(1-7) treatment mitigates right ventricular fibrosis as a distinctive feature of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 2015;308:H1007-19. doi: 10.1152/ajpheart.00563.2014.

5. Hao P, Yang J, Liu Y, Zhang M, Zhang K, Gao F, et al. Combination of angiotensin-(1-7) with perindopril is better than single therapy in ameliorating diabetic cardiomyopathy. Sci Rep 2015;5:8794. doi: 10.1038/srep08794.

6. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 2007;13:952-61. doi: 10.1038/nm1613.

7. Ngo MA, Muller A, Li Y, Neumann S, Tian G, Dixon IM, et al. Human mesenchymal stem cells express a myofibroblastic phenotype in vitro : Comparison to human cardiac myofibroblasts. Mol Cell Biochem 2014;392:187-204. doi: 10.1007/s11010-014-2030-6.

8. Wang CH, Huang CD, Lin HC, Lee KY, Lin SM, Liu CY, et al. Increased circulating fibrocytes in asthma with chronic airflow obstruction. Am J Respir Crit Care Med 2008;178:583-91. doi: 10.1164/rccm.200710-1557OC.

9. Baker DW, Tsai YT, Weng H, Tang L. Alternative strategies to manipulate fibrocyte involvement in the fibrotic tissue response: Pharmacokinetic inhibition and the feasibility of directed-adipogenic differentiation. Acta Biomater 2014;10:3108-16. doi: 10.1016/j.actbio.2014.03.011.

10. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1994;1:71-81.

11. Bellini A, Mattoli S. The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses. Lab Invest 2007;87:858-70. doi: 10.1038/labinvest.3700654.

12. King TE Jr., Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 2011;378:1949-61. doi: 10.1016/s0140-6736(11)60052-4.

13. Reich B, Schmidbauer K, Rodriguez Gomez M, Johannes Hermann F, Gobel N, Bruhl H, et al. Fibrocytes develop outside the kidney but contribute to renal fibrosis in a mouse model. Kidney Int 2013;84:78-89. doi: 10.1038/ki.2013.84.

14. Mollmann H, Nef HM, Kostin S, von Kalle C, Pilz I, Weber M, et al. Bone marrow-derived cells contribute to infarct remodelling. Cardiovasc Res 2006;71:661-71. doi: 10.1016/j.cardiores.2006.06.013.

15. Fang L, Beale A, Ellims AH, Moore XL, Ling LH, Taylor AJ, et al. Associations between fibrocytes and postcontrast myocardial T1 times in hypertrophic cardiomyopathy. J Am Heart Assoc 2013;2:e000270. doi: 10.1161/JAHA.113.000270.

16. Chu PY, Mariani J, Finch S, McMullen JR, Sadoshima J, Marshall T, et al. Bone marrow-derived cells contribute to fibrosis in the chronically failing heart. Am J Pathol 2010;176:1735-42. doi: 10.2353/ajpath.2010.090574.

17. Xie X, Liu Y, Gao S, Wu B, Hu X, Chen J. Possible involvement of fibrocytes in atrial fibrosis in patients with chronic atrial fibrillation. Circ J 2014;78:338-44. doi: 10.1253/circj.CJ-13-0776.

18. Haudek SB, Xia Y, Huebener P, Lee JM, Carlson S, Crawford JR, et al. Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Proc Natl Acad Sci U S A 2006;103:18284-9. doi: 10.1073/pnas.0608799103.

19. Dupuis J, Prefontaine A, Villeneuve L, Ruel N, Lefebvre F, Calderone A. Bone marrow-derived progenitor cells contribute to lung remodelling after myocardial infarction. Cardiovasc Pathol 2007;16:321-8. doi: 10.1016/j.carpath.2007.04.006.

20. Odorfer KI, Walter I, Kleiter M, Sandgren EP, Erben RG. Role of endogenous bone marrow cells in long-term repair mechanisms after myocardial infarction. J Cell Mol Med 2008;12:2867-74. doi: 10.1111/j.1582-4934.2008.00511.x.

21. van Amerongen MJ, Bou-Gharios G, Popa E, van Ark J, Petersen AH, van Dam GM, et al. Bone marrow-derived myofibroblasts contribute functionally to scar formation after myocardial infarction. J Pathol 2008;214:377-86. doi: 10.1002/path.2281.

22. Haudek SB, Cheng J, Du J, Wang Y, Hermosillo-Rodriguez J, Trial J, et al. Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy. J Mol Cell Cardiol 2010;49:499-507. doi: 10.1016/j.yjmcc.2010.05.005.

23. Cieslik KA, Taffet GE, Carlson S, Hermosillo J, Trial J, Entman ML. Immune-inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart. J Mol Cell Cardiol 2011;50:248-56. doi: 10.1016/j.yjmcc.2010.10.019.

24. Qi G, Jia L, Li Y, Bian Y, Cheng J, Li H, et al. Angiotensin II infusion-induced inflammation, monocytic fibroblast precursor infiltration, and cardiac fibrosis are pressure dependent. Cardiovasc Toxicol 2011;11:157-67. doi: 10.1007/s12012-011-9109-z.

25. Xu J, Lin SC, Chen J, Miao Y, Taffet GE, Entman ML, et al. CCR2 mediates the uptake of bone marrow-derived fibroblast precursors in angiotensin II-induced cardiac fibrosis. Am J Physiol Heart Circ Physiol 2011;301:H538-47. doi: 10.1152/ajpheart.01114.2010.

26. Keeley EC, Mehrad B, Janardhanan R, Salerno M, Hunter JR, Burdick MM, et al. Elevated circulating fibrocyte levels in patients with hypertensive heart disease. J Hypertens 2012;30:1856-61. doi: 10.1097/HJH.0b013e32835639bb.

27. Sopel M, Falkenham A, Oxner A, Ma I, Lee TD, Legare JF. Fibroblast progenitor cells are recruited into the myocardium prior to the development of myocardial fibrosis. Int J Exp Pathol 2012;93:115-24. doi: 10.1111/j.1365-2613.2011.00797.x.

28. Szardien S, Nef HM, Troidl C, Willmer M, Voss S, Liebetrau C, et al. Bone marrow-derived cells contribute to cell turnover in aging murine hearts. Int J Mol Med 2012;30:283-7. doi: 10.3892/ijmm.2012.995.

29. Duerrschmid C, Crawford JR, Reineke E, Taffet GE, Trial J, Entman ML, et al. TNF receptor 1 signaling is critically involved in mediating angiotensin-II-induced cardiac fibrosis. J Mol Cell Cardiol 2013;57:59-67. doi: 10.1016/j.yjmcc.2013.01.006.

30. Falkenham A, Sopel M, Rosin N, Lee TD, Issekutz T, Legare JF. Early fibroblast progenitor cell migration to the AngII-exposed myocardium is not CXCL12 or CCL2 dependent as previously thought. Am J Pathol 2013;183:459-69. doi: 10.1016/j.ajpath.2013.04.011.

31. Kazakov A, Hall R, Jagoda P, Bachelier K, Muller-Best P, Semenov A, et al. Inhibition of endothelial nitric oxide synthase induces and enhances myocardial fibrosis. Cardiovasc Res 2013;100:211-21. doi: 10.1093/cvr/cvt181.

32. Lei PP, Tao SM, Shuai Q, Bao YX, Wang SW, Qu YQ, et al. Extracorporeal cardiac shock wave therapy ameliorates myocardial fibrosis by decreasing the amount of fibrocytes after acute myocardial infarction in pigs. Coron Artery Dis 2013;24:509-15. doi: 10.1097/MCA.0b013e3283640ec7.

33. Rosin NL, Falkenham A, Sopel MJ, Lee TD, Legare JF. Regulation and role of connective tissue growth factor in AngII-induced myocardial fibrosis. Am J Pathol 2013;182:714-26. doi: 10.1016/j.ajpath.2012.11.014.

34. Marko L, Henke N, Park JK, Spallek B, Qadri F, Balogh A, et al. Bcl10 mediates angiotensin II-induced cardiac damage and electrical remodeling. Hypertension 2014;64:1032-9. doi: 10.1161/HYPERTENSIONAHA.114.03900.

35. Williams SM, Golden-Mason L, Ferguson BS, Schuetze KB, Cavasin MA, Demos-Davies K, et al. Class I HDACs regulate angiotensin II-dependent cardiac fibrosis via fibroblasts and circulating fibrocytes. J Mol Cell Cardiol 2014;67:112-25. doi: 10.1016/j.yjmcc.2013.12.013.

36. Duerrschmid C, Trial J, Wang Y, Entman ML, Haudek SB. Tumor necrosis factor: A mechanistic link between angiotensin-II-Induced cardiac inflammation and fibrosis. Circ Heart Fail 2015;8:352-61. doi: 10.1161/CIRCHEARTFAILURE.114.001893.

37. Mori L, Bellini A, Stacey MA, Schmidt M, Mattoli S. Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res 2005;304:81-90. doi: 10.1016/j.yexcr.2004.11.011.

38. Ebihara Y, Masuya M, Larue AC, Fleming PA, Visconti RP, Minamiguchi H, et al. Hematopoietic origins of fibroblasts: II. In vitro studies of fibroblasts, CFU-F, and fibrocytes. Exp Hematol 2006;34:219-29. doi: 10.1016/j.exphem.2005.10.008.

39. Suga H, Rennert RC, Rodrigues M, Sorkin M, Glotzbach JP, Januszyk M, et al. Tracking the elusive fibrocyte: Identification and characterization of collagen-producing hematopoietic lineage cells during murine wound healing. Stem Cells 2014;32:1347-60. doi: 10.1002/stem.1648.

40. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 2001;166:7556-62. doi: 10.4049/jimmunol.166.12.7556

41. Yano T, Miura T, Ikeda Y, Matsuda E, Saito K, Miki T, et al. Intracardiac fibroblasts, but not bone marrow derived cells, are the origin of myofibroblasts in myocardial infarct repair. Cardiovasc Pathol 2005;14:241-6. doi: 10.1016/j.carpath.2005.05.004.

42. Shao DD, Suresh R, Vakil V, Gomer RH, Pilling D. Pivotal advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J Leukoc Biol 2008;83:1323-33. doi: 10.1189/jlb.1107782.

43. Barth PJ, Westhoff CC. CD34+ fibrocytes: morphology, histogenesis and function. Curr Stem Cell Res Ther 2007;2:221-7. doi: 10.2174/157488807781696249

44. Barth PJ, Ramaswamy A, Moll R. CD34(+) fibrocytes in normal cervical stroma, cervical intraepithelial neoplasia III, and invasive squamous cell carcinoma of the cervix uteri. Virchows Arch 2002;441:564-8. doi: 10.1007/s00428-002-0713-y.

45. Metz CN. Fibrocytes: A unique cell population implicated in wound healing. Cell Mol Life Sci 2003;60:1342-50. doi: 10.1007/s00018-003-2328-0.

46. Pilling D, Fan T, Huang D, Kaul B, Gomer RH. Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts. PLoS One 2009;4:e7475. doi: 10.1371/journal.pone.0007475.

47. Chesney J, Metz C, Stavitsky AB, Bacher M, Bucala R. Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. J Immunol 1998;160:419-25.

48. Weng CM, Chen BC, Wang CH, Feng PH, Lee MJ, Huang CD, et al. The endothelin A receptor mediates fibrocyte differentiation in chronic obstructive asthma. The involvement of connective tissue growth factor. Am J Respir Crit Care Med 2013;188:298-308. doi: 10.1164/rccm.201301-0132OC.

49. Kao HK, Chen B, Murphy GF, Li Q, Orgill DP, Guo L. Peripheral blood fibrocytes: Enhancement of wound healing by cell proliferation, re-epithelialization, contraction, and angiogenesis. Ann Surg 2011;254:1066-74. doi: 10.1097/SLA.0b013e3182251559.

50. Kuwana M, Okazaki Y, Kodama H, Izumi K, Yasuoka H, Ogawa Y, et al. Human circulating CD14+ monocytes as a source of progenitors that exhibit mesenchymal cell differentiation. J Leukoc Biol 2003;74:833-45. doi: 10.1189/jlb.0403170.

51. Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 2003;171:380-9. doi: 10.4049/jimmunol.171.1.380.

52. Hong KM, Belperio JA, Keane MP, Burdick MD, Strieter RM. Differentiation of human circulating fibrocytes as mediated by transforming growth factor-beta and peroxisome proliferator-activated receptor gamma. J Biol Chem 2007;282:22910-20. doi: 10.1074/jbc.M703597200.

53. Fan X, Liang HP. Circulating fibrocytes: a potent cell population in antigen-presenting and wound healing. Chin J Traumatol 2010;13:111-6. doi: 10.3760/cma.j.issn.1008-1275.2010.02.010.

54. Li J, Tan H, Wang X, Li Y, Samuelson L, Li X, et al. Circulating fibrocytes stabilize blood vessels during angiogenesis in a paracrine manner. Am J Pathol 2014;184:556-71. doi: 10.1016/j.ajpath.2013.10.021.

55. Kleaveland KR, Moore BB, Kim KK. Paracrine functions of fibrocytes to promote lung fibrosis. Expert Rev Respir Med 2014;8:163-72. doi: 10.1586/17476348.2014.862154.

56. Mehrad B, Burdick MD, Zisman DA, Keane MP, Belperio JA, Strieter RM. Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease. Biochem Biophys Res Commun 2007;353:104-8. doi: 10.1016/j.bbrc.2006.11.149.

57. Moeller A, Gilpin SE, Ask K, Cox G, Cook D, Gauldie J, et al. Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;179:588-94. doi: 10.1164/rccm.200810-1534OC.

58. Wang CH, Punde TH, Huang CD, Chou PC, Huang TT, Wu WH, et al. Fibrocyte trafficking in patients with chronic obstructive asthma and during an acute asthma exacerbation. J Allergy Clin Immunol 2015;135:1154-62.e1-5. doi: 10.1016/j.jaci.2014.09.011.

59. Inomata M, Kamio K, Azuma A, Matsuda K, Kokuho N, Miura Y, et al. Pirfenidone inhibits fibrocyte accumulation in the lungs in bleomycin-induced murine pulmonary fibrosis. Respir Res 2014;15:16. doi: 10.1186/1465-9921-15-16.

60. Geng XC, Hu ZP, Lian GY. Erythropoietin ameliorates renal interstitial fibrosis via the inhibition of fibrocyte accumulation. Mol Med Rep 2015;11:3860-5. doi: 10.3892/mmr.2015.3157.

61. Xia Y, Entman ML, Wang Y. Critical role of CXCL16 in hypertensive kidney injury and fibrosis. Hypertension 2013;62:1129-37. doi: 10.1161/hypertensionaha.113.01837.

62. Sopel MJ, Rosin NL, Lee TD, Legare JF. Myocardial fibrosis in response to Angiotensin II is preceded by the recruitment of mesenchymal progenitor cells. Lab Invest 2011;91:565-78. doi: 10.1038/labinvest.2010.190.

63. Cox N, Pilling D, Gomer RH. NaCl potentiates human fibrocyte differentiation. PLoS One 2012;7:e45674. doi: 10.1371/journal.pone.0045674.

64. Segura AM, Frazier OH, Buja LM. Fibrosis and heart failure. Heart Fail Rev 2014;19:173-85. doi: 10.1007/s10741-012-9365-4.

65. Pranavchand R, Reddy BM. Current status of understanding of the genetic etiology of coronary heart disease. J Postgrad Med 2013;59:30-41. doi: 10.4103/0022-3859.109492.

66. Tatic V, Rafajlovski S, Kanjuh V, Gajanin R, Suscevic D, Balint B, et al . Histochemical and immunohistochemical analyses of the myocardial scar fallowing acute myocardial infarction. Vojnosanit Pregl 2012;69:581-8. doi: 10.2298/VSP110110008T.

67. Gabbiani G. The cellular derivation and the life span of the myofibroblast. Pathol Res Pract 1996;192:708-11. doi: 10.1016/s0344-0338(96)80092-6.

68. Morimoto H, Takahashi M, Izawa A, Ise H, Hongo M, Kolattukudy PE, et al. Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction. Circ Res 2006;99:891-9. doi: 10.1161/01.RES.0000246113.82111.2d.

69. Fujita J, Mori M, Kawada H, Ieda Y, Tsuma M, Matsuzaki Y, et al. Administration of granulocyte colony-stimulating factor after myocardial infarction enhances the recruitment of hematopoietic stem cell-derived myofibroblasts and contributes to cardiac repair. Stem Cells 2007;25:2750-9. doi: 10.1634/stemcells.2007-0275.

70. Haudek SB, Trial J, Xia Y, Gupta D, Pilling D, Entman ML. Fc receptor engagement mediates differentiation of cardiac fibroblast precursor cells. Proc Natl Acad Sci U S A 2008;105:10179-84. doi: 10.1073/pnas.0804910105.

71. Fang L, Moore XL, Chan W, White DA, Chin-Dusting J, Dart AM. Decreased fibrocyte number is associated with atherosclerotic plaque instability in man. Cardiovasc Res 2012;95:124-33. doi: 10.1093/cvr/cvs156.

72. Medbury HJ, Tarran SL, Guiffre AK, Williams MM, Lam TH, Vicaretti M, et al . Monocytes contribute to the atherosclerotic cap by transformation into fibrocytes. Int Angiol 2008;27:114-23. doi: 10.1016/S1567-5688(08)70207-1.

73. Lip GY, Tse HF, Lane DA. Atrial fibrillation. Lancet 2012;379:648-61. doi: 10.1016/s0140-6736(11)61514-6.

74. Nattel S. New ideas about atrial fibrillation 50 years on. Nature 2002;415:219-26. doi: 10.1038/415219a.

75. Cieslik KA, Trial J, Crawford JR, Taffet GE, Entman ML. Adverse fibrosis in the aging heart depends on signaling between myeloid and mesenchymal cells; role of inflammatory fibroblasts. J Mol Cell Cardiol 2014;70:56-63. doi: 10.1016/j.yjmcc.2013.10.017.
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Title Annotation:Review Article
Author:Lin, Rong-Jie; Su, Zi-Zhuo; Liang, Shu-Min; Chen, Yu-Yang; Shu, Xiao-Rong; Nie, Ru-Qiong; Wang, Jing
Publication:Chinese Medical Journal
Article Type:Report
Geographic Code:9CHIN
Date:Mar 1, 2016
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