Isthmin 1 is Expressed by Progenitor-Like Cells in the Lung: Phenotypical Analysis of Isthmin 1 + Hematopoietic Stem-Like Cells in Homeostasis and during Infection.

The process by which blood cells are generated has been widely studied in homeostasis and during pathogen-triggered inflammatory response. Recently, murine lungs have been shown to be a significant source of hematopoietic progenitors in a process known as extramedullary hematopoiesis. Using multiparametric flow cytometry, we have identified mesenchymal, endothelial, and hematopoietic progenitor cells that express the secreted small protein Isthmin 1 (ISM1). Further characterization of hematopoietic progenitor cells indicated that ISM1 + Lineage - Sca-1 + c-kit + (ISM1 + LSK) cells are enriched in short-term hematopoietic stem cells (ST-HSCs). Moreover, most Sca-1 + ISM1 + cells express the residence marker CD49a, and this correlated with their localization in the extravascular region of the lung, indicating that ISM1 + cells are lung-resident cells. We also observed that ISM1 + cells express TLR4, TLR5, and TLR9, and, in a mouse model of sepsis induced by P. aeruginosa , we observed that all the LSK and ISM1 + LSK cells were affected. We conclude that ISM1 is a novel biomarker associated with progenitor-like cells. ISM1 + cells are involved in the response to a bacterial challenge, suggesting an association between ISM1-producing cells and dangerous inflammatory responses like sepsis.