Quality assurance of hematopoietic stem cells by macrophages determines stem cell clonality [macrophages]

Tissue-specific stem cells persist for a lifetime and can differentiate to maintain homeostasis or transform to initiate cancer. Despite their importance, there are no described quality assurance mechanisms for newly formed stem cells. We observed intimate and specific interactions between macrophages and blood stem cells in zebrafish embryos. Stressed stem cells were marked by surface Calreticulin, which stimulates macrophage interaction as an “eat me” signal. Macrophage-stem cell interactions either lead to removal of cytoplasmic material and stem cell proliferation or resulted in complete stem cell engulfment. Using cellular barcoding, we found that calreticulin knock-down or embryonic macrophage depletion substantially reduced the number of stem cell clones into adulthood. Our work supports a model in which embryonic macrophages determine hematopoietic clonality by monitoring stem cell quality. Single-cell RNA-seq of FACS purified embryonic mpeg1:EGFP macrophages on the basis of uptake of fluorescence from runx1+23:mCherry HSPCs.