MYCT1 as a moderator for signaling between human HSC and their niche

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SUMMARY Hematopoietic stem cells (HSC) need to integrate microenvironmental cues to switch their fate between quiescence, self-renewal, and differentiation, thereby sustaining hematopoiesis through life. However, the molecular programs governing HSC stemness become grossly dysregulated during culture, hindering our ability to expand functional HSCs for treating hematological diseases. Our data uncovered MYCT1 (Myc target 1) as human HSC regulatory factor that is critical for their expansion and engraftment, but becomes suppressed during differentiation and culture. We found that MYCT1 localizes in endosomes, interacts with vesicle components and signaling receptors with critical functions in HSCs (e.g. TGFBR1 and 2), and controls the rate of endocytosis, which modulates cell signaling and must be tightly regulated to maintain HSC stemness. Many genes dysregulated upon MYCT1 knockdown (KD) are linked to HSC division and self-renewal. We hypothesize that MYCT1 governs HSC stemness and their ability to balance between fate options by fine-tuning multiple signaling cues through the control of endocytosis. We have created a toolbox of MYCT1 knockdown and overexpression vectors, including various MYCT1 deletion mutants, that can be used in primary human HSPCs as well as HSC- like and endothelial cell line models to investigate MYCT1 mechanism of action. We will investigate how MYCT1- mediated control of endocytosis affects signaling in HSCs, and how this influences HSC cell-fate decisions including quiescence and asymmetric vs symmetric division. We will then assess if rescuing MYCT1 regulated processes improves the function of cultured human HSC, including those expanded using MLLT3 overexpression. Our work may open up new strategies to maintain HSC transplantability during ex vivo expansion and ultimately help broaden HSC clinical applications.