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

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 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE196551 | GEO | 2022/10/19

REPOSITORIES: GEO

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Project description:The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during the stressful events surrounding early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.

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

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