EUROPEAN  TISSUE  REPAIR  SOCIETY

Given that fibrocytes rapidly enter sites of tissue injury, it is not surprising that these cells have been found to produce a variety of cytokines that can serve to co-ordinate the successive inflammatory and reparative responses. Analysis of mRNA expression patterns of fibrocytes purified from wound chambers by fluorescence-activated cell sorting has shown that these cells are an especially abundant source of growth factors, cytokines, and matrix components. Fibrocytes express high levels of the fibrogenic growth factors, PDGF-A and TGF-ß1, the hematopoietic growth factor M-CSF, and the chemokines MIP-1a and MIP-214. Fibrocytes also express detectable mRNAs for the pro-inflammatory cytokines, IL-1ß, but relatively little message for the mediators MIF or TNFa.¹⁴

Recent studies suggest that fibrocyte collagen production is tightly regulated in the context of the inflammation and wound healing responses. For instance, addition of the critical wound healing mediator IL-1b to fibrocytes in culture suppresses Type I collagen production.¹⁴ Conversely, IL-1ß induces fibrocyte secretion of the inflammatory chemokines MIP-1a, MIP-1ß, MCP-1, IL-8, and GROa, the hematopoietic growth factors IL-6 and M-CSF, and the fibrogenic cytokines TGF-ß1 and TNFa. Interestingly, when compared to monocytes/macrophages, the chemokine expression profile of fibrocytes more closely resembles that of activated fibroblasts rather than monocytes/macrophages. Given the various cytokines produced by these cells, one can conclude that fibrocytes are likely to play an important role in the recruitment and activation of both inflammatory and connective tissue cells during the tissue repair response. We have found that IL-1ß is a particularly important regulator of fibrocyte function.  IL-1ß increases fibrocyte proliferation, and spreading, while decreasing fibrocyte collagen production. This cytokine, which is present in high quantities in wounds and arises from a number of cell sources, may function to maintain peripheral blood fibrocytes in a pro-inflammatory state early in tissue repair, resulting in the increased production of molecules that recruit and expand the inflammatory cell population within the wound environment.

Physiological Role of Fibrocytes

Based on the identification of fibrocytes by co-labelling studies in wound chambers, various scars, and areas of fibrosis, we have proposed that peripheral blood fibrocytes may play a critical role in wound healing in precisely those circumstances when subjacent, connective tissue fibroblasts cannot contribute significantly to the wound repair response. We remain impressed by our initial observations that in wound chambers, which create an exudative reaction of peripheral blood cells and where the early entry of subdermal cells is strongly disfavored, virtually all the connective tissue cells that comprise fibrotic areas are CD34 positive.⁹ In dermal scars, on the other hand, the percentage of CD34 cells is significantly lower and decreases over time with the age and the overall cellularity of the scar. We believe that fibrocytes are particularly important in those circumstances of wound repair or tissue injury where there is poor availability of adjacent fibroblast or other connective tissue types. Accordingly, in the injury of organs such as the brain where a gliosis response takes weeks to occur, peripheral blood fibrocytes may play a particularly important role in the overall repair process.

Therapeutic Applications of Fibrocytes

The ease with which fibrocytes can be isolated and expanded in vitro has presented interesting possibilities for their application to clinical medicine. Fibrocytes may be considered to be a readily expandable source of autologous connective tissue cells for use in situations of compromised wound repair. Recent studies have established that fibrocytes are readily transfectable with foreign genes by standard methodologies, including lipofectamine, DEAE-dextran, and gene gun.¹⁵ This property, together with their ability to traffick to sites of injury may make them attractive vehicles for the therapeutic delivery of particular gene products to wound sites.

References

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9. 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.
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12. Grab DJ, Lanners H, Martin LN, et al: Interaction of Borrelia burgdorferi with peripheral blood fibrocytes, antigen-presenting cells with the potential for connective tissue targeting. Mol. Med. 1999; 5: 46–54.
13. Golde DW, Hocking WG, Quan SG, Sparkes RS, Gale RP: Origin of human bone marrow fibroblasts. Brit. J. Hematol. 1980; 44; 183–187.
14. 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: 419–425.
15. Zhu Y, Koo K, Bradshaw J, et al: Macaque blood-derived antigen-presenting cells elicit siv-specific immune responses. J. Med. Primatology 2000 (submitted).

Professor Richard Bucala
Scientific Director
The Picower Institute for Medical Research
350 Community Drive, Manhasset, NY 11030, USA
Tel: 516–562–9406
Fax: 516–869–6097
http:// www.picower.edu