Abstract
To understand the cellular mechanism underlying the therapeutic effects exerted by hematopoietic stem cell transplantation in the repair of tissue damage, we investigated the in vivo dynamics of bone marrow (BM) lineage-negative (Lin−) cells transplanted into mice with hyper sensitivity dermatitis. Longitudinal in vivo imaging and flow cytometry analyses revealed that Lin− cells home directly to inflamed skin within 6 h, where they undergo extensive expansion with the peak on day 14 post-transplantation, and preferential differentiation into CD11b+Ly6GintLy6C+ cells by day 7. Cells with phenotypic profiles of neutrophils, macrophages, and DCs appeared in inflamed skin on day 14. Progenies of transplanted Lin− cells showed similar kinetics of expansion and myeloid differentiation in BM. However, differentiation into CD11b+Ly6GintLy6C+ cells in the inflamed skin on day 7 was more skewed toward CD115+ cells (≥60%) with immune suppressive function and higher expression levels of iNOS, arginase, and IL-10, compared with those in the BM. Transplantation of Lin− cells reduced the levels of Cd3 transcript and CD4+/CD8+ cells in inflamed skin. These results demonstrate differentiation of transplanted Lin− cells into myeloid-derived suppressor cells in inflamed skin to be the basis of the alleviation of skin inflammation after Lin− cell transplantation.
Highlights
Tissue recruitment[3,4,5]
We exploited the advantage of the enhanced luciferase sensitivity displayed in a recently developed luciferase transgenic mouse, which was successfully used for tracing immune cells in vivo[18,19], and evaluated CD45.1 congenic marker expression in hematopoietic cells from CD45.1+ mice using these mice as stem cell donors in Bioluminescence imaging (BLI) and flow cytometric analyses, respectively
Providing detailed information regarding the in vivo fate of exogenously administered hematopoietic stem cells (HSCs), we demonstrate that expansion and concurrent differentiation into myeloid-derived suppressor cells (MDSCs) in situ at the site of local inflammation are correlated with the therapeutic effect of HSC transplantation
Summary
Chemokine receptors, such as CXCR4 and CCR2, along with adhesion molecules expressed on HSCs mediate their homing to the BM, and are considered important regulators of tissue recruitment[6,7,8,9] Other than these molecular studies, the detailed cellular dynamics of exogenous HSCs, including distribution/migration behavior in the recipients, have not been investigated extensively due to the lack of tools to properly analyze the rare infused cells in the recipients. We performed longitudinal BLI and flow cytometric analyses of exogenously administered HSCs, using lineage-negative (Lin−) cells in BM, which do not express lymphoid or myeloid lineage markers These approaches revealed that the therapeutic effects generated by transplanted Lin− cells depend on their targeted migration to sites of inflammation and subsequent expansion. Providing detailed information regarding the in vivo fate of exogenously administered HSCs, we demonstrate that expansion and concurrent differentiation into MDSCs in situ at the site of local inflammation are correlated with the therapeutic effect of HSC transplantation
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