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

MYCT1 作为人类 HSC 与其生态位之间信号传导的调节剂

基本信息

批准号：
10593103
负责人：
Hanna Katri Annikki Mikkola
金额：
$ 31.2万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593103
关键词：
Address Affect Biological Assay Blood Blood Cells Cell Cycle Progression Cell Line Cell division Cell physiology Cells Clinical Cues Data Endocytosis Endosomes Endothelial Cells Engraftment Environment Equilibrium Functional disorder Gene Expression Genes Hematologic Neoplasms Hematological Disease Hematopoiesis Hematopoietic Cell Production Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Inherited Kinetics Life Link MLLT3 gene Mediating Modeling Molecular Mus Natural regeneration Patients Proteins Receptor Signaling Regulation Signal Pathway Signal Transduction TGFBR1 gene TGFBR2 gene Therapeutic Transforming Growth Factor beta Transplantation Vesicle Work clinical application ethnic bias ethnic minority expression vector extracellular functional improvement gain of function hematopoietic stem cell expansion hematopoietic stem cell niche improved insight knock-down loss of function mutant novel novel strategies overexpression prevent process improvement programs response self-renewal stem cell division stem cell function stem-like cell stemness transplantation therapy

项目摘要

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.

概括造血干细胞（HSC）需要整合微环境线索来改变它们的命运静止、自我更新和分化，从而维持整个生命的造血作用。然而，控制 HSC 干性的分子程序在培养过程中变得严重失调，阻碍了我们的能力扩大用于治疗血液疾病的功能性造血干细胞。我们的数据发现 MYCT1（Myc 目标 1）为人类 HSC 调节因子，对其扩张和植入至关重要，但在复制过程中受到抑制差异化和文化。我们发现 MYCT1 定位于内体中，与囊泡成分相互作用并在 HSC 中具有关键功能的信号传导受体（例如 TGFBR1 和 2），并控制内吞速率，它调节细胞信号传导，必须严格调节以维持 HSC 干性。许多基因 MYCT1 敲低 (KD) 后的失调与 HSC 分裂和自我更新有关。我们假设 MYCT1 通过微调多个信号来控制 HSC 干性及其在命运选择之间平衡的能力通过内吞作用的控制来提示。我们创建了 MYCT1 敲低和过表达工具箱载体，包括各种 MYCT1 缺失突变体，可用于原代人类 HSPC 以及 HSC- 样和内皮细胞系模型来研究 MYCT1 的作用机制。我们将研究 MYCT1- 内吞作用介导的控制影响 HSC 中的信号传导，以及这如何影响 HSC 细胞的命运决定包括静止和不对称与对称分裂。然后我们将评估拯救 MYCT1 是否受到监管过程改善了培养的人类 HSC 的功能，包括使用 MLLT3 扩展的那些过度表达。我们的工作可能会开辟新的策略来维持体外造血干细胞的可移植性扩展并最终帮助扩大 HSC 临床应用。