PMID- 24416305 OWN - NLM STAT- MEDLINE DCOM- 20140910 LR - 20211021 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 1 DP - 2014 TI - Monocytes infiltrate the pancreas via the MCP-1/CCR2 pathway and differentiate into stellate cells. PG - e84889 LID - 10.1371/journal.pone.0084889 [doi] LID - e84889 AB - Recent studies have shown that monocytes possess pluripotent plasticity. We previously reported that monocytes could differentiate into hepatic stellate cells. Although stellate cells are also present in the pancreas, their origin remains unclear. An accumulation of enhanced green fluorescent protein (EGFP)(+)CD45(-) cells was observed in the pancreases and livers of chimeric mice, which were transplanted with a single hematopoietic stem cell isolated from EGFP-transgenic mice and treated with carbon tetrachloride (CCl4). Because the vast majority of EGFP(+)CD45(-) cells in the pancreas expressed stellate cell-associated antigens such as vimentin, desmin, glial fibrillary acidic protein, procollagen-I, and alpha-smooth muscle actin, they were characterized as pancreatic stellate cells (PaSCs). EGFP(+) PaSCs were also observed in CCl4-treated mice adoptively transferred with monocytes but not with other cell lineages isolated from EGFP-transgenic mice. The expression of monocyte chemoattractant protein-1 (MCP-1) and angiotensin II (Ang II) increased in the pancreas of CCl4-treated mice and their respective receptors, C-C chemokine receptor 2 (CCR2) and Ang II type 1 receptor (AT1R), were expressed on Ly6C(high) monocytes isolated from EGFP-transgenic mice. We examined the effect of an AT1R antagonist, irbesartan, which is also a CCR2 antagonist, on the migration of monocytes into the pancreas. Monocytes migrated toward MCP-1 but not Ang II in vitro. Irbesartan inhibited not only their in vitro chemotaxis but also in vivo migration of adoptively transferred monocytes from peripheral blood into the pancreas. Irbesartan treatment significantly reduced the numbers of EGFP(+)F4/80(+)CCR2(+) monocytic cells and EGFP(+) PaSCs in the pancreas of CCl4-treated chimeric mice receiving EGFP(+) bone marrow cells. A specific CCR2 antagonist RS504393 inhibited the occurrence of EGFP(+) PaSCs in injured mice. We propose that CCR2(+) monocytes migrate into the pancreas possibly via the MCP-1/CCR2 pathway and give rise to PaSCs. FAU - Ino, Kazuko AU - Ino K AD - Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan. FAU - Masuya, Masahiro AU - Masuya M AD - Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan. FAU - Tawara, Isao AU - Tawara I AD - Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan. FAU - Miyata, Eri AU - Miyata E AD - Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan. FAU - Oda, Keiko AU - Oda K AD - Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan. FAU - Nakamori, Yoshiki AU - Nakamori Y AD - Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan. FAU - Suzuki, Kei AU - Suzuki K AD - Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan. FAU - Ohishi, Kohshi AU - Ohishi K AD - Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan. FAU - Katayama, Naoyuki AU - Katayama N AD - Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140108 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Biphenyl Compounds) RN - 0 (Ccl2 protein, mouse) RN - 0 (Ccr2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (Receptor, Angiotensin, Type 1) RN - 0 (Receptors, CCR2) RN - 0 (Tetrazoles) RN - 0 (enhanced green fluorescent protein) RN - 11002-13-4 (Angiotensinogen) RN - 147336-22-9 (Green Fluorescent Proteins) RN - CL2T97X0V0 (Carbon Tetrachloride) RN - EC 3.1.3.48 (Leukocyte Common Antigens) RN - J0E2756Z7N (Irbesartan) SB - IM MH - Adoptive Transfer MH - Angiotensinogen/biosynthesis MH - Animals MH - Biphenyl Compounds/pharmacology MH - Carbon Tetrachloride/pharmacology MH - *Cell Differentiation/drug effects MH - Chemokine CCL2/*metabolism MH - *Chemotaxis/drug effects MH - Gene Expression Regulation/drug effects MH - Green Fluorescent Proteins/metabolism MH - Hematopoietic Stem Cells/cytology/drug effects MH - Irbesartan MH - Leukocyte Common Antigens/deficiency MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Monocytes/*cytology/drug effects/immunology/metabolism MH - Pancreas/*cytology MH - Pancreatic Stellate Cells/*cytology/drug effects MH - Receptor, Angiotensin, Type 1/metabolism MH - Receptors, CCR2/*metabolism MH - Signal Transduction/drug effects MH - Tetrazoles/pharmacology PMC - PMC3885670 COIS- Competing Interests: M.M. has received research funding from Dainippon-Sumitomo Pharmaceutical within the past two years. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. The other authors declare no potential conflicts of interest. EDAT- 2014/01/15 06:00 MHDA- 2014/09/11 06:00 PMCR- 2014/01/08 CRDT- 2014/01/14 06:00 PHST- 2013/02/04 00:00 [received] PHST- 2013/11/24 00:00 [accepted] PHST- 2014/01/14 06:00 [entrez] PHST- 2014/01/15 06:00 [pubmed] PHST- 2014/09/11 06:00 [medline] PHST- 2014/01/08 00:00 [pmc-release] AID - PONE-D-13-05236 [pii] AID - 10.1371/journal.pone.0084889 [doi] PST - epublish SO - PLoS One. 2014 Jan 8;9(1):e84889. doi: 10.1371/journal.pone.0084889. eCollection 2014.