Bone marrow-derived fibrocytes, designated as CD45+ and Collagen Type I+ cells, were implicated in the pathogenesis of lung, skin, and kidney fibrosis due to their ability to differentiate into fibrogenic myofibroblasts. We have demonstrated that fibrocytes contribute to 4-6% of Col1a1-producing cells in the fibrotic liver1,2, suggesting that fibrocytes are not a significant source of ECM. Puzzled by these data, we continued investigating fibrocytes, and have now obtained strong preliminary data suggesting that genetic or pharmacological inhibition of fibrocytes attenuates development of liver fibrosis by ?50%. The goal of this proposal is to determine the role of fibrocytes in the pathogenesis of liver fibrosis and develop therapeutic strategies of their inhibition. We hypothesize that targeting fibrocytes will inhibit liver fibrosis. The central hypothesis is that fibrocytes give rise to unique populations of fibrogenic myofibroblasts and pro-inflammatory myeloid cells that synergistically facilitate liver fibrosis by secreting TGF-?1, TNF-?, IL-1?1, CCL5 and other regulatory cytokines promoting M1 (and inhibiting anti-inflammatory M2) macrophages. To test this hypothesis, four complimentary AIMs have been developed:
AIM 1. The role of fibrocytes in liver fibrosis will be determined in fibrocyte-ablated mice (versus wt mice) subjected to chronic toxic, cholestatic, and NASH liver injury. Genetic ablation of fibrocytes will be achieved by overexpression of Diphtheria toxin-? (DTA) specifically in fibrocytes, and has not been previously reported. We anticipate that liver fibrosis of different etiologies is strongly attenuated in fibrocyte-ablated mice.
AIM 2. We have developed a cell fate mapping approach to determine fibrocyte function(s), and the mechanism by which fibrocytes mediate liver fibrosis. Using a side-by- side comparison of wt and fibrocyte-ablated mice, we will determine if fibrocytes promote intrahepatic cytokine secretion, and regulate activation of M1 (vs M2) macrophages. We predict that fibrocytes play a major immunoregulatory role in liver fibrosis.
AIM 3. The role of Col1a1 in regulation of fibrocyte biology will be studied by comparing wt and Col1a15'SL-mutant fibrocytes (with the ?loss? of Col1a1 function) and Col1?1rr- mutant fibrocytes (with ?gain? of Col1a1 function). The mechanism of Col1a1 signaling in fibrocytes, leading to their proliferation/activation, will be examined in primary and immortalized fibrocytes. We anticipate that Col1a1 regulates vital functions of fibrocytes via interaction with its ligand(s), such as DDR1 and ?2?1 integrins.
AIM 4. We test if therapeutic administration of Serum Amyloid P (SAP), a natural inhibitor of fibrocytes, can effectively attenuate liver fibrosis of different etiologies in mice, e.g. via inhibition of fibrocyte proliferation, cytokine production, and differentiation into myofibroblasts. We will analyze archived patient material to determine therapeutic potential of SAP for patients with NASH (the relationship between serum SAP, hepatic fibrocytes, and stage/progression of liver fibrosis). SAP might become a treatment of choice in patients with NASH.
Hepatic fibrosis and its end stage, cirrhosis, represent an enormous health care burden worldwide. The goal of this study is to determine the role of bone marrow-derived fibrocytes, designated as Collagen Type I expressing hematopoietic cells, in the pathogenesis of liver fibrosis. Further understanding of fibrocyte biology (mechanism of migration, cellular origin, and contribution to fibrogenesis and inflammation) can make these cells an attractive target for anti-fibrotic therapy.
|Zhong, Zhenyu; Liang, Shuang; Sanchez-Lopez, Elsa et al. (2018) New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 560:198-203|
|Moore-Morris, Thomas; Cattaneo, Paola; Guimarães-Camboa, Nuno et al. (2018) Infarct Fibroblasts Do Not Derive From Bone Marrow Lineages. Circ Res 122:583-590|
|Kisseleva, Tatiana (2017) The origin of fibrogenic myofibroblasts in fibrotic liver. Hepatology 65:1039-1043|
|Koyama, Yukinori; Wang, Ping; Liang, Shuang et al. (2017) Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis. J Clin Invest 127:1254-1270|
|Xu, Jun; Ma, Hsiao-Yen; Liang, Shuang et al. (2017) The role of human cytochrome P450 2E1 in liver inflammation and fibrosis. Hepatol Commun 1:1043-1057|