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

Abstract

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 nascent blood stem cells in zebrafish embryos. Macrophage interactions frequently led to either removal of cytoplasmic material and stem cell division or complete engulfment and stem cell death. Stressed stem cells were marked by surface Calreticulin, which stimulated macrophage interactions. Using cellular barcoding, we found that Calreticulin knock-down or embryonic macrophage depletion reduced the number of stem cell clones that established adult hematopoiesis. Our work supports a model in which embryonic macrophages determine hematopoietic clonality by monitoring stem cell quality.

M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism

“…The authors identified HSCs that expressed Calr/3a/3b which interacted with Lrp1ab on macrophages. As a result, some of the HSCs were completely engulfed, while in other HSCs, cell cycle progression was induced ( 50 ) very similar to our observations with macrophage-leukemic blast interactions. We find that one of the consequences of direct interactions of leukemic blasts with macrophages is the transfer of mitochondria, thereby driving OXPHOS metabolism in AML cells, which was also reported for interactions with MSCs ( 51 ).…”

“…Recently, Wattrus et al. ( 50 ) showed that the depletion of macrophages significantly decreased the number of HSC clones using the brainbow zebrafish model. The authors identified HSCs that expressed Calr/3a/3b which interacted with Lrp1ab on macrophages.…”

Fetal liver macrophages contribute to the hematopoietic stem cell niche by controlling granulopoiesis

“…A study in zebrafish supports the notion of macrophage-HSC crosstalk requirement during development, uncovering a ‘grooming’ mechanism of embryonic macrophages that had a long-lasting impact on adult stem cells: HSPCs in the CHT often completed a cell division shortly after macrophage interactions and lack of CHT macrophages led to a decreased HSPC clonality in the adult marrow (Wattrus et al, 2022). Interestingly, their data suggests that HSPC proliferation in the CHT is mediated through ERK/MAPK activity, which is controlled by macrophage-derived Il1b (Wattrus et al, 2022). Indeed, the scRNA-seq macrophage cluster 2 is specifically expressing Il1b and could have a similar effect on a subset of LT-HSCs in the mouse fetal liver.…”

Copper overload impairs hematopoietic stem and progenitor cell proliferation via prompting HSF1/SP1 aggregation and the subsequently downregulating FOXM1-Cytoskeleton axis

“…The collected runx1 promoter driving GFP + cells ( runx1 GFP + cells) showed abundant expression of HSPC genes runx1 , cmyb , and gata2b , while little expression of neural genes ( olig2 , mbp ), liver gene ( fabp2 ), and muscle gene ( myod ), suggesting the HSPC identity of the runx1 GFP + cells ( Figures 1 E and S1 B) as reported recently. 27 After FACS analysis of runx1 GFP + cells (HSPCs) labeled by Cu ion probe, the proportion of PE + GFP + cells labeled with Cu probe ( Figure 1 A) and the Cu content in individual runx1 GFP + cells (HSPCs) ( Figure 1 B) were found to be significantly increased (p < 0.05) in the Cu-stressed embryos. Additionally, red fluorescence was observed in some cells but not in the runx1 GFP + cells of the whole embryos labeled with Cu ion probe in low magnification ( Figure S1 C).…”