**6. Opportunities for research and therapeutic targets**

The study of fibrocytes and their participation in the pathogenesis of chronic inflammation and fibroproliferative diseases presents both important challenges and opportunities for researchers. To advance this eld, detailed molecular characterization of these cells and establishment of dened experimental strategies in animals and humans will be necessary to catalyze progress in this area of investigation. Recent studies and emerging concepts have significantly improved our understanding of the participation of fibrocytes in health and disease and so have opened the door to new hypotheses and approaches aimed at therapeutic targets and strategies.

One of the main therapeutic targets, suggested since the initial works on fibrocyte biology research, was the serum amyloid P (SAP), a member of the pentraxin family of proteins. In this context, it was first demonstrated that SAP could inhibit the differentiation of monocytes into fibrocytes (Pilling et al., 2003). SAP binds to Fcγ receptors through which apparently mediates its anti-fibrotic activities affecting peripheral blood monocyte differentiation and activation states (Lu et al., 2008). In a rat model of bleomycin-induced lung injury it was shown that purified rat SAP could suppress development of lung fibrosis which correlated with reduced fibrocyte numbers within the lung tissue (Pilling et al., 2007). More recently, SAP ability to reduce fibrosis was tested in models of renal and lung fibrosis where this therapeutic potential was confirmed. In both models, the mechanisms through which SAP exerts its antifibrotic effect seemed to be independent of monocyte to fibrocyte differentiation (Casraño et al., 2009; Murray 2010). Further analysis of this molecule and its potential as antifibrogenic therapy is needed to identify all the mechanisms involved in its effect as well as the feasibility of its use in human disease.

Several chemokines are abundantly expressed in experimental models of fibrosis and in the human disease (Agostini & Gurrieri 2006). Regarding fibrocytes, several studies have focused on the role of chemokines in recruiting these cells to the injured lung. In human IPF, the

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CXCL12/CXCR4 axis may be of particular significance (Andersson-Sjoland et al., 2008). As mentioned human circulating fibrocytes express CXCR4 and α-SMA, and can traffic toward the unique CXCR4 ligand, CXCL12 (Mehrad et al., 2007; Andersson-Sjoland et al., 2008). Supporting a major role of this axis in the lung disease, it was demonstrated that the administration of neutralizing anti-CXCL12 antibodies to bleomycin-treated mice resulted in a signicant reduction of brocyte lung homing and collagen deposition, but interestingly without affecting the numbers of other leukocyte populations in the lungs (Phillips et al., 2004). These data suggest that blocking or interfering with chemokine/chemokine receptor networks may help to diminish or stop fibrocyte recruitment in fibrotic lung disorders. Recently, two groups have explored this hypothesis. Xu et al., 2007 used an antagonist of the receptor CXCR4 (TN14003) in a model of bleomycin-induced pulmonary fibrosis. Intraperitoneal treatment of mice with TN14003 attenuated the development of lung fibrosis and blocked in vitro migration of bone marrow derived stem cells towards CXCL12 or lung homogenates of bleomycin treated mice. Likewise, Song and coworkers showed that intraperitoneal treatment of mice with AMD3100 (Plerixafor, which is a small synthetic specific inhibitor of CXCR4), resulted in decreased levels of CXCL12 in the bronchoalveolar fluid and decreased numbers of fibrocytes in the lungs of mice treated with bleomycin (Song et al 2010). Collagen deposition and pulmonary fibrosis were also attenuated by treatment with AMD3100 (Song et al., 2010). Though the initial results seem to be optimistic, this is still an area of active research, and further studies are needed to elucidate whether pharmacologic inhibition of the CXCR4/CXCL12 axis could modify the lung fibrotic process in human disease.

The potential use of circulating fibrocytes as biomarkers in fibrosing diseases is a window of opportunity that has to be explored; diverse groups have reported differences in the percentages of circulating fibrocytes between healthy controls and patients (Mehard et al., 2007; Moeller et al., 2008; Chun-Hua et al., 2008). An increase in the percentages of circulating brocytes was demonstrated in a cohort of 51 patients with stable IPF, compared to healthy controls, but more important, a huge increase was observed during an acute exacerbation, a highly lethal process in IPF. Moreover, the number of fibrocytes returned to the values of stable IPF in the few patients that recovered. In general, fibrocyte numbers were an independent predictor of early mortality (Moeller et al., 2008).

However, higher number of patients should be evaluated and larger longitudinal studies should be done in order to establish if differences in percentages of circulating fibrocytes as well as changes in the percentages of circulating fibrocytes in a given patient with a given disease may predict outcome. The possibility of using differences in the percentages of circulating fibrocytes as biomarkers for disease diagnostic, outcome, or therapeutic response is an important biomedical area of research that needs attention.

Fibrocytes are progenitor cells capable to differentiate not only into myobroblasts but also in other mesenchymal cells (Hong et al., 2005 and 2007; Choi et al., 2010). The ability of fibrocytes to undergo differentiation to osteoblasts and chondrocytes like cells when treated with specic cytokines and dened media raises the opportunity of their use for regenerative therapy related to bone or articular cartilage repair. Hypothetically, circulating brocytes could be isolated from the patient's own blood, processed for differentiation into osteoblasts or chondrocytes, followed by transplantation into the damaged tissue. Tissue engineering is a growing field in the biomedical sciences, and the role of brocytes in regenerative therapy has to be assessed with future studies in the area.

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However, higher number of patients should be evaluated and larger longitudinal studies should be done in order to establish if differences in percentages of circulating fibrocytes as well as changes in the percentages of circulating fibrocytes in a given patient with a given disease may predict outcome. The possibility of using differences in the percentages of circulating fibrocytes as biomarkers for disease diagnostic, outcome, or therapeutic response

Fibrocytes are progenitor cells capable to differentiate not only into myobroblasts but also in other mesenchymal cells (Hong et al., 2005 and 2007; Choi et al., 2010). The ability of fibrocytes to undergo differentiation to osteoblasts and chondrocytes like cells when treated with specic cytokines and dened media raises the opportunity of their use for regenerative therapy related to bone or articular cartilage repair. Hypothetically, circulating brocytes could be isolated from the patient's own blood, processed for differentiation into osteoblasts or chondrocytes, followed by transplantation into the damaged tissue. Tissue engineering is a growing field in the biomedical sciences, and the role of brocytes in


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**Part 4** 

**Hematopoietic Stem Cell Therapy** 

