title: Monocytes infiltrate the pancreas via the MCP-1/CCR2 pathway and differentiate into stellate cells.
abstract: 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 α-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.
authors.affiliation: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Ino
authors.affiliation: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Masuya
authors.affiliation: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Tawara
authors.affiliation: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Miyata
authors.affiliation: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Oda
authors.affiliation: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nakamori
authors.affiliation: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Kohshi
authors.initials: K
authors.lastname: Ohishi
authors.affiliation: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Katayama
mesh_terms: D019264:Adoptive Transfer; D000808:Angiotensinogen / Q000096:biosynthesis; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002251:Carbon Tetrachloride / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D000077405:Irbesartan; D017493:Leukocyte Common Antigens / Q000172:deficiency; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010179:Pancreas / Q000166:cytology*; D058954:Pancreatic Stellate Cells / Q000166:cytology* / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D001713:Biphenyl Compounds; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D044140:Receptor, Angiotensin, Type 1; D054390:Receptors, CCR2; D013777:Tetrazoles; C485184:enhanced green fluorescent protein; D000808:Angiotensinogen; D049452:Green Fluorescent Proteins; D002251:Carbon Tetrachloride; D017493:Leukocyte Common Antigens; D000077405:Irbesartan