Abstract
BackgroundMesenchymal stem/progenitor cells (MSC) have shown beneficial effects in many models of disease in part by modulating excessive inflammatory and immune responses. Frequently the beneficial effects of MSC persist long after their disappearance from host tissues, suggesting that MSC interact with intermediate cells in the host that relay or amplify their effects. The cells have usually been injected intravenously, but beneficial effects have also been reported with intraperitoneal (IP) injection of MSC. However the fate of IP injection of MSC has not been examined.MethodsThe fate of the human MSC injected IP into immune-competent mice was studied. In vivo imaging was used to track green fluorescent protein-labeled MSC in the peritoneal cavity. In addition, their retention in peritoneal tissues was measured by real-time polymerase chain reaction for human GAPDH mRNA. To describe the effects of human MSC on the immune system of the peritoneum, the peritoneal lavage, omentum, lymph nodes and mesenteric tissues were collected. Flow cytometry was used to evaluate the immune cell populations, while cytokine/chemokine production was measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Challenge with lipopolysaccharide at 3 days after the administration of MSC was used to evaluate the preconditioning of the immune system.ResultsWithin 20 min, single MSC were no longer detected in peritoneal lavage fluid. Instead they were recovered as aggregates of varying size that contained mouse macrophages and a few B220+ lymphocytes. After 1 day, most of the aggregates containing live MSC were attached to sites throughout the peritoneal cavity including the omentum and mesentery. Less than 0.05 % of the live injected cells were detected in the spleen and jejunal lymph nodes. In all locations, MSC colocalized with mouse macrophages and B220+ lymphocytes. Attachment to the omentum and mesentery was accompanied by the recruitment of immune cells and changes in the production of a series of mouse cytokines. A similar increase in mouse cytokines in the peritoneum was seen after IP injections of human fibroblasts.ConclusionsIP injected human MSC rapidly formed aggregates with mouse macrophages and B220+ lymphocytes and attached to the walls of the peritoneal cavity. The formation of the aggregates probably limits access of the cells to the systemic circulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0284-5) contains supplementary material, which is available to authorized users.
Highlights
Mesenchymal stem/progenitor cells (MSC) have shown beneficial effects in many models of disease in part by modulating excessive inflammatory and immune responses
IP administration of different human MSC preparations and fibroblasts Different preparations of MSC from human bone marrow vary in their properties and biological activities, a feature loosely referred to as donor variation [35, 36]
Because MSC designated as Donor 7075 had the most consistent effects, we employed the Donor 7075 in further experiments
Summary
Mesenchymal stem/progenitor cells (MSC) have shown beneficial effects in many models of disease in part by modulating excessive inflammatory and immune responses. The cells have usually been injected intravenously, but beneficial effects have been reported with intraperitoneal (IP) injection of MSC. In direct comparisons with IV administrations, IP injected MSC were shown to have comparable or even more profound effects in experimental autoimmune encephalitis [8], twitcher mice with globoid cell leukodystrophy [9], mice with cisplatin-induced renal injury [10], mice with experimental intestinal colitis [11], mice with sterile inflammation of the cornea [12], and mice with zymosan-induced peritonitis [13]. The beneficial effects of MSC in these and other disease models have been linked to the ability of the cells to modify both the innate and acquired immune systems [14, 15]
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