Phase separation participates in the genetic regulation mechanism of hematopoietic stem cells: potential therapeutic methods

Abstract

Hematopoietic stem cells (HSCs) are the primitive cells that give rise to common precursors for all blood cell lineages. Abnormalities in their number and/or function are important factors leading to the decline of immune function and the occurrence of various systemic diseases. Phase separation refers to a physicochemical mechanism in which intracellular liquid-liquid phase separation (LLPS) forms membrane-less organelles. It participates in various physiological activities and is related to the occurrence of diseases. Studies have shown that the functional activity of HSCs is regulated by complex mechanisms, and phase separation is closely related to these complex mechanisms such as genetic regulation, epigenetic regulation, microenvironment regulation, gene expression, autophagy degradation, and cell proliferation. With the deepening of research, the importance of phase separation in the pathogenesis and treatment of diseases such as leukemia and tumors has gradually emerged, but the deep mechanism of its regulation of HSCs genetic regulation still lacks exploration, and the direction of clinical targeted therapy is not yet clear. Here, we will summarize and elaborate the genetic regulation mechanism of HSCs, discuss the relationship between phase separation and the functional regulation of HSCs, and analyze the possibility of phase separation participating in the genetic regulation of HSCs to treat diseases, in order to provide help for the clinical implementation of targeted therapy for HSCs regulation.

1. Introduction

Hematopoietic stem cells (HSCs) are a type of stem cell with long-term self-renewal ability and multi-directional differentiation ability [1]. They are at the top of the hematopoietic hierarchy and play a crucial role in development, tissue repair and regeneration. The functional activity of HSCs is regulated by multiple complex mechanisms, including genetic regulation, epigenetic regulation, and microenvironment regulation. These heterogeneous and diverse HSCs abnormalities are related to the occurrence and development of multiple diseases [2].

As a new intracellular regulatory mechanism, phase separation has received extensive attention in recent years. Studies have shown that the liquid-liquid phase separation (LLPS) of biological macromolecules can form multiple membrane-less compartments in cells. The biomolecular condensates generated by phase separation in cells can participate in various biological activities and functional processes, such as gene expression, stem cell regulation, transcriptional dysregulation, signal transduction and stress response, providing a method to regulate cell function. There are many factors that affect phase separation, including molecular concentration, temperature, ionic strength (salt concentration), pH value, crowding effect, and the impact of nucleic acid molecules on protein phase separation. These factors, acting alone or in combination, affect the fusion and infiltration of biomolecules [3]. Abnormal phase separation is closely related to various diseases such as neurodegenerative diseases and cancer, and may play a role in disease treatment [4]. Phase separation also plays a key role in the regulation of stem cells. Existing studies have found that biomolecular condensates represented by phase separation will affect the epigenetic regulation of cancer stem cells. Understanding its principles and characteristics will help accurately curb the occurrence and development of diseases and find potential therapeutic targets, bringing new possibilities for tumor treatment [5].