Crucial Regulator MYCT1 Controls Environmental Sensing and Stemness in Human Hematopoietic Stem Cells

Core Concepts

MYCT1 is a crucial regulator that moderates endocytosis and environmental sensing in human hematopoietic stem cells, governing their stemness properties and expansion potential.

Abstract

The content discusses the role of MYCT1 (MYC target 1) in regulating human hematopoietic stem cell (HSC) self-renewal and engraftment. Key insights: MYCT1 is selectively expressed in undifferentiated human hematopoietic stem and progenitor cells (HSPCs) and endothelial cells, but becomes downregulated during HSC culture. Knockdown of MYCT1 prevents expansion and engraftment of human fetal liver and cord blood HSPCs, while restoring MYCT1 expression improves the expansion and engraftment of cultured cord blood HSPCs. Single-cell RNA sequencing reveals that MYCT1 governs key regulatory programs and cellular properties essential for HSC stemness, such as ETS factor expression and low mitochondrial activity. MYCT1 is localized in the endosomal membrane and interacts with vesicle trafficking regulators and signaling machinery in HSPCs. Loss of MYCT1 leads to excessive endocytosis and hyperactive signaling responses in HSPCs, while restoring MYCT1 expression balances culture-induced endocytosis and dysregulated signaling. Sorting cultured cord blood HSPCs with the lowest endocytosis rate identifies cells with preserved MYCT1 expression and MYCT1-regulated HSC stemness programs. The data suggests that silencing of MYCT1 is a cell-culture-induced vulnerability that compromises human HSC expansion.

Stats

MYCT1 is selectively expressed in undifferentiated human hematopoietic stem and progenitor cells and endothelial cells. Knockdown of MYCT1 prevents expansion and engraftment of human fetal liver and cord blood HSPCs. Restoring MYCT1 expression improves the expansion and engraftment of cultured cord blood HSPCs.

Quotes

"MYCT1 governs important regulatory programmes and cellular properties essential for HSC stemness, such as ETS factor expression and low mitochondrial activity." "MYCT1 loss in HSPCs led to excessive endocytosis and hyperactive signalling responses, whereas restoring MYCT1 expression balanced culture-induced endocytosis and dysregulated signalling."

Key Insights Distilled From

MYCT1 controls environmental sensing in human haematopoietic stem cells - Nature

by Júli... at www.nature.com 06-05-2024

https://www.nature.com/articles/s41586-024-07478-x

Deeper Inquiries

How might the MYCT1-mediated regulation of endocytosis and environmental sensing in HSCs be leveraged to improve ex vivo expansion and engraftment of HSCs for clinical applications?

The MYCT1-mediated regulation of endocytosis and environmental sensing in HSCs presents a promising avenue for enhancing ex vivo expansion and engraftment of HSCs in clinical settings. By understanding how MYCT1 influences crucial regulatory programs and cellular properties essential for HSC stemness, such as ETS factor expression and low mitochondrial activity, researchers can develop targeted strategies to manipulate MYCT1 levels to optimize HSC culture conditions. For instance, modulating MYCT1 expression levels could help maintain the balance between endocytosis and signaling responses, thereby preserving HSC stemness during ex vivo expansion. Additionally, sorting HSPCs based on their endocytosis rate, which correlates with MYCT1 expression and regulated stemness programs, could enable the identification and enrichment of HSC populations with superior engraftment potential. Overall, leveraging MYCT1-mediated mechanisms offers a promising approach to enhance the efficiency and functionality of ex vivo expanded HSCs for clinical applications.

What other key regulators or signaling pathways interact with MYCT1 to maintain HSC stemness, and how could targeting these interactions further enhance HSC expansion and function?

In addition to MYCT1, several other key regulators and signaling pathways interact to maintain HSC stemness and could be targeted to further enhance HSC expansion and function. For example, MYCT1 interacts with vesicle trafficking regulators and signaling machinery in the endosomal membrane of HSPCs, suggesting a complex network of regulatory interactions. One such regulator is the ETS family of transcription factors, which are essential for HSC self-renewal and differentiation. Targeting the interaction between MYCT1 and ETS factors could provide a means to modulate HSC stemness properties and improve expansion efficiency. Moreover, signaling pathways such as the Wnt/β-catenin pathway, known to regulate HSC self-renewal, could potentially crosstalk with MYCT1-mediated mechanisms to influence HSC function. By elucidating these interactions and developing targeted interventions, researchers can enhance HSC expansion and function by fine-tuning the regulatory networks that govern HSC stemness.

Given the role of MYCT1 in endothelial cells, what implications might this have for the vascular niche and its influence on HSC biology?

The role of MYCT1 in endothelial cells has significant implications for the vascular niche and its influence on HSC biology. Endothelial cells play a crucial role in the maintenance of the HSC niche, providing essential signals and support for HSC self-renewal and differentiation. As MYCT1 is selectively expressed in endothelial cells, its involvement in moderating endocytosis and environmental sensing suggests a direct impact on the vascular niche. By regulating these processes, MYCT1 may influence the interactions between HSCs and endothelial cells within the niche, thereby affecting HSC behavior and function. Furthermore, the dysregulation of MYCT1 in endothelial cells could disrupt the balance of signals and cues necessary for proper HSC maintenance, potentially compromising HSC biology and function. Understanding the implications of MYCT1 in the vascular niche can provide insights into how endothelial-HSC interactions are orchestrated and how targeting MYCT1 in endothelial cells could be a novel strategy to modulate the HSC niche and enhance HSC biology.