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 Ly6Chigh 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.
Highlights
Monocytes are bone marrow (BM)-derived circulating leukocytes and precursors for tissue macrophages and dendritic cells [1]
We investigated the roles of the monocyte chemoattractant protein-1 (MCP-1)/chemokine receptor 2 (CCR2) pathway and angiotensin II (Ang II)/ Ang II type 1 receptor (AT1R) pathway in the recruitment of hematopoietic stem cellderived cells from the circulation into the pancreas using an AT1R antagonist, irbesartan, which acts as an antagonist of CCR2 because of its molecular structure [28]
We reported that hematopoietic stem cell-derived cells could differentiate into hepatic stellate cells (HpSCs) during CCl4 injury in chimeric mice transplanted with clonal populations of cells derived from a single enhanced green fluorescent protein (EGFP)+CD34–KSL cell [5]
Summary
Monocytes are bone marrow (BM)-derived circulating leukocytes and precursors for tissue macrophages and dendritic cells [1]. We previously reported that monocytes could become hepatic stellate cells (HpSCs) during carbon tetrachloride (CCl4)-induced injury [4]. In the course of a study using chimeric mice transplanted with a single hematopoietic stem cell isolated from enhanced green fluorescent protein (EGFP)transgenic mice [5], we detected EGFP+ hematopoietic stem cellderived cells in the pancreas. We examined the cell fate of these transplanted EGFP+ cells in the pancreas of chimeric mice, and found that hematopoietic stem cell-derived cells may partially contribute to the generation of pancreatic stellate cells (PaSCs). EGFP+ PaSCs were detected in CCl4-treated mice adoptively transferred with monocytes isolated from EGFPtransgenic mice
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