Circulating fibrocytes--biology and mechanisms in wound healing and scar formation.

Fibrocytes were first described in 1994 as fibroblast-like, peripheral blood cells. These bone marrow-derived mesenchymal progenitor cells migrate into regions of tissue injury. They are unique in their expression of hematopoietic and monocyte lineage markers and extracellular matrix proteins. Several studies have focused on the specific role of fibrocytes in the process of wound repair and tissue regeneration. We discuss herein the biology and mechanistic action of fibrocytes in wound healing, scar formation, and maintenance of tissue integrity. Fibrocytes synthesize and secrete different cytokines, chemokines, and growth factors, providing a wound milieu that supports tissue repair. They further promote angiogenesis and contribute to wound closure via pathways involving specific cytokines, leukocyte-specific protein-1, serum amyloid P, and adenosine A(2A) receptors. Fibrocytes are involved in inflammatory fibrotic processes in such diseases as systemic fibrosis, atherosclerosis, asthma, hypertrophic scarring, and keloid formation. Accumulating literature has emphasized the important role of fibrocytes in wound healing and fibrosis. Detailed mechanisms nevertheless remain to be investigated to elucidate the full therapeutic potential of fibrocytes in the treatment of fibrosing disorders and the enhancement of tissue repair.

[1]  F. Unglaub,et al.  Effect of Chronic Wound Exudates and MMP-2/-9 Inhibitor on Angiogenesis In Vitro , 2005, Plastic and reconstructive surgery.

[2]  D. Greenhalgh,et al.  The role of apoptosis in wound healing. , 1998, The international journal of biochemistry & cell biology.

[3]  A. Barbul,et al.  Nutrition and Wound Healing , 2006, The Surgical clinics of North America.

[4]  Stephen M Bauer,et al.  Angiogenesis, Vasculogenesis, and Induction of Healing in Chronic Wounds , 2005, Vascular and endovascular surgery.

[5]  R. Diegelmann,et al.  Wound healing: an overview of acute, fibrotic and delayed healing. , 2004, Frontiers in bioscience : a journal and virtual library.

[6]  R. Bucala,et al.  Culture and analysis of circulating fibrocytes. , 2007, Methods in molecular medicine.

[7]  B. Cronstein,et al.  Wound Healing Is Accelerated by Agonists of Adenosine A2 (Gα s-linked) Receptors , 1997, The Journal of experimental medicine.

[8]  B. Cronstein,et al.  Adenosine A2A Receptor Blockade or Deletion Diminishes Fibrocyte Accumulation in the Skin in a Murine Model of Scleroderma, Bleomycin-induced Fibrosis , 2008, Inflammation.

[9]  E. Ayello,et al.  Conquer chronic wounds with wound bed preparation. , 2004, The Nurse practitioner.

[10]  P. Rieu,et al.  Neutrophils: Molecules, Functions and Pathophysiological Aspects , 2000, Laboratory Investigation.

[11]  K. Harding,et al.  Advances in Wound Care and Healing Technology , 2000, American journal of clinical dermatology.

[12]  P. Janmey,et al.  The lymphocyte-specific protein LSP1 binds to F-actin and to the cytoskeleton through its COOH-terminal basic domain , 1992, The Journal of cell biology.

[13]  Vishal Kapoor,et al.  Contribution of Bone Marrow–Derived Cells to Skin: Collagen Deposition and Wound Repair , 2004, Stem cells.

[14]  M. Burdick,et al.  Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. , 2004, The Journal of clinical investigation.

[15]  R. Gomer,et al.  Aggregated IgG inhibits the differentiation of human fibrocytes , 2006, Journal of leukocyte biology.

[16]  A. Ghahary,et al.  Immunohistochemical localization of the proteoglycans decorin, biglycan and versican and transforming growth factor‐β in human post‐burn hypertrophic and mature scars , 1995, Histopathology.

[17]  G. Gurtner,et al.  Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. , 2005, Blood.

[18]  B. Cronstein,et al.  Adenosine A2A receptors play an active role in mouse bone marrow‐derived mesenchymal stem cell development , 2009, Journal of leukocyte biology.

[19]  P. Scott,et al.  Fibrocytes from burn patients regulate the activities of fibroblasts , 2007, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[20]  Chandan K Sen,et al.  Revisiting the essential role of oxygen in wound healing. , 2003, American journal of surgery.

[21]  D. Brigstock,et al.  Connective tissue growth factor: what's in a name? , 2000, Molecular genetics and metabolism.

[22]  A. Ghahary,et al.  Identification of fibrocytes in postburn hypertrophic scar , 2005, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[23]  R. Gomer,et al.  Pivotal Advance: Th‐1 cytokines inhibit, and Th‐2 cytokines promote fibrocyte differentiation , 2008, Journal of leukocyte biology.

[24]  E. Tredget Pathophysiology and Treatment of Fibroproliferative Disorders following Thermal Injury , 1999, Annals of the New York Academy of Sciences.

[25]  A. Ghahary,et al.  Chemical characterization and quantification of proteoglycans in human post-burn hypertrophic and mature scars. , 1996, Clinical science.

[26]  Stuart Enoch,et al.  Recent advances and emerging treatments , 2006, BMJ : British Medical Journal.

[27]  E. A. Nelson,et al.  Compression for venous leg ulcers. , 2012, The Cochrane database of systematic reviews.

[28]  R. Gomer,et al.  Inhibition of Fibrocyte Differentiation by Serum Amyloid P 1 , 2003, The Journal of Immunology.

[29]  Geoffrey C Gurtner,et al.  Cellular dysfunction in the diabetic fibroblast: impairment in migration, vascular endothelial growth factor production, and response to hypoxia. , 2003, The American journal of pathology.

[30]  A. Joyner,et al.  LSP1 modulates leukocyte populations in resting and inflamed peritoneum. , 2000, Blood.

[31]  J. Giuffre,et al.  Peripheral Blood Fibrocytes from Burn Patients: Identification and Quantification of Fibrocytes in Adherent Cells Cultured from Peripheral Blood Mononuclear Cells , 2002, Laboratory Investigation.

[32]  M. Burdick,et al.  Characterization of human fibrocytes as circulating adipocyte progenitors and the formation of human adipose tissue in SCID mice , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  R. Bucala,et al.  Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. , 1998, Journal of immunology.

[34]  M. Stacey,et al.  Identification of Circulating Fibrocytes as Precursors of Bronchial Myofibroblasts in Asthma1 , 2003, The Journal of Immunology.

[35]  M. Walport,et al.  Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages. , 1989, The Journal of clinical investigation.

[36]  M. Hristov,et al.  Hypoxia-induced endothelial secretion of macrophage migration inhibitory factor and role in endothelial progenitor cell recruitment , 2010, Journal of cellular and molecular medicine.

[37]  H. Tagami,et al.  Inverse correlation between CD34 expression and proline‐4‐hydroxyase immunoreactivity on spindle cells noted in hypertrophic scars and keloids , 1997 .

[38]  R. Bucala,et al.  Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) , 2006, Current opinion in rheumatology.

[39]  R. Bucala,et al.  Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[40]  C. Linge,et al.  Hypertrophic scar cells fail to undergo a form of apoptosis specific to contractile collagen-the role of tissue transglutaminase. , 2005, The Journal of investigative dermatology.

[41]  C. Haslett,et al.  In vivo fate of the inflammatory macrophage during the resolution of inflammation: inflammatory macrophages do not die locally, but emigrate to the draining lymph nodes. , 1996, Journal of immunology.

[42]  A. Desmoulière,et al.  Perspective Article: Tissue repair, contraction, and the myofibroblast , 2005, Wound Repair and Regeneration.

[43]  A. Ghahary,et al.  Hypertrophic scars, keloids, and contractures. The cellular and molecular basis for therapy. , 1997, The Surgical clinics of North America.

[44]  Paul Martin,et al.  Wound Healing--Aiming for Perfect Skin Regeneration , 1997, Science.

[45]  J. Albina,et al.  Macrophage phagocytosis of wound neutrophils , 1999, Journal of leukocyte biology.

[46]  V. Moulin,et al.  Normal skin wound and hypertrophic scar myofibroblasts have differential responses to apoptotic inductors , 2004, Journal of cellular physiology.

[47]  J. Jongstra,et al.  LSP1 regulates anti-IgM induced apoptosis in WEHI-231 cells and normal immature B-cells. , 1999, Molecular immunology.

[48]  O. Velazquez,et al.  Angiogenesis and vasculogenesis: inducing the growth of new blood vessels and wound healing by stimulation of bone marrow-derived progenitor cell mobilization and homing. , 2007, Journal of vascular surgery.

[49]  A. Desmoulière,et al.  Apoptosis during wound healing, fibrocontractive diseases and vascular wall injury. , 1997, The international journal of biochemistry & cell biology.

[50]  A. Bellini,et al.  The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses , 2007, Laboratory Investigation.

[51]  Gary R. Grotendorst,et al.  Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor. , 1996, The Journal of investigative dermatology.

[52]  R. Bucala,et al.  Peripheral blood fibrocytes: novel fibroblast-like cells that present antigen and mediate tissue repair. , 1997, Biochemical Society transactions.

[53]  N. Pallua,et al.  Tissue Substitutes with Improved Angiogenic Capabilities: An in vitro Investigation with Endothelial Cells and Endothelial Progenitor Cells , 2009, Cells Tissues Organs.

[54]  R. Donoff,et al.  The histochemistry of glycosaminoglycans within hypertrophic scars. , 1980, The Journal of surgical research.

[55]  R. Gomer,et al.  Identification of Markers that Distinguish Monocyte-Derived Fibrocytes from Monocytes, Macrophages, and Fibroblasts , 2009, PloS one.

[56]  E. Deitch,et al.  Hypertrophic burn scars: analysis of variables. , 1983, The Journal of trauma.

[57]  Y. Cao,et al.  TGF-beta: a fibrotic factor in wound scarring and a potential target for anti-scarring gene therapy. , 2004, Current gene therapy.

[58]  A. Ghahary,et al.  Control of wound contraction. Basic and clinical features. , 2000, Hand clinics.

[59]  Jian Fei Wang,et al.  Molecular and Cell Biology of Skin Wound Healing in a Pig Model , 2000, Connective tissue research.

[60]  J. Molnar Overview of Nutrition and Wound Healing , 2006 .

[61]  Gary R. Grotendorst Connective tissue growth factor: a mediator of TGF-β action on fibroblasts , 1997 .

[62]  A. Ghahary,et al.  Molecular and cellular aspects of fibrosis following thermal injury. , 2000, Hand clinics.

[63]  D. Brigstock The CCN family: a new stimulus package. , 2003, The Journal of endocrinology.

[64]  Shawn Cowper,et al.  Circulating fibrocytes: collagen-secreting cells of the peripheral blood. , 2004, The international journal of biochemistry & cell biology.

[65]  M. Longaker,et al.  Hypertrophic Scar Fibroblasts Have Increased Connective Tissue Growth Factor Expression after Transforming Growth Factor-β Stimulation , 2005, Plastic and reconstructive surgery.

[66]  R. Bucala,et al.  Circulating Fibrocytes Define a New Leukocyte Subpopulation That Mediates Tissue Repair , 1994, Molecular medicine.

[67]  D. Hart,et al.  The pig as a model for excisional skin wound healing: characterization of the molecular and cellular biology, and bacteriology of the healing process. , 2001, Comparative medicine.

[68]  R. Bucala,et al.  The Role of Fibrocytes in Wound Healing , 2010 .

[69]  R. Gomer,et al.  Serum amyloid P inhibits dermal wound healing , 2008, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[70]  A. A. Thompson,et al.  Aberrant expression and localization of the cytoskeleton-binding pp52 (LSP1) protein in hairy cell leukemia. , 2001, Leukemia research.

[71]  M. Stacey,et al.  Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. , 2005, Experimental cell research.

[72]  R. Bucala,et al.  The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[73]  A. Ghahary,et al.  Effect of interferon‐α2b on guinea pig wound closure and the expression of cytoskeletal proteins in vivo , 1998, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[74]  S. O'Kane,et al.  Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. , 2004, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[75]  R. Bucala Fibrocytes: New Insights into Tissue Repair and Systemic Fibroses , 2007 .

[76]  Andrew Leask,et al.  TGF‐β signaling and the fibrotic response , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[77]  R. Bucala,et al.  Fibrocytes in health and disease. , 2010, Experimental hematology.

[78]  J. Bernhagen,et al.  Macrophage migration inhibitory factor is a potential inducer of endothelial progenitor cell mobilization after flap operation. , 2012, Surgery.

[79]  P. Scott,et al.  Increased severity of bleomycin-induced skin fibrosis in mice with leukocyte-specific protein 1 deficiency. , 2008, The Journal of investigative dermatology.

[80]  C. Kischer,et al.  The histiotypic organization of the hypertrophic scar in humans. , 1972, The Journal of investigative dermatology.

[81]  Geoffrey C Gurtner,et al.  Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1 , 2004, Nature Medicine.

[82]  Gary R. Grotendorst,et al.  Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. , 1996, The Journal of investigative dermatology.