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 , we observed that all the LSK and ISM1LSK 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.