Study uncovers important mechanism of haematopoietic stem cell regulation

Preface /

How have human long-term haematopoietic stem cells sensed signals for a long time? How are they subsequently transformed into active haematopoietic stem cells? Recent studies have identified lysosomes as complex nutrient sensing and signalling centres, regulated by the transcription factor EB (TFEB), that balance the catabolic and anabolic processes required to activate long-term human haematopoietic stem cells and regulate their cell lineage stereotyping.

Human long-term haematopoietic stem cells (LT-HSC) are located at the apical end of the haematopoietic system and are used to meet the enormous daily haematopoietic demand (~1011 cells per day) while maintaining the lifelong activity of the stem cell pool, and it is now widely accepted that this hierarchical structure maintains the homeostatic and undifferentiated state of LT-HSC.LT-HSC are activated only by microenvironmental signals and give rise to highly proliferative, but short-lived, cells, including short-term haematopoietic stem cells and progenitor cells. including short-lived haematopoietic stem and progenitor cells. When LT-HSC cells receive signals to exit their dormant state, they respond and adjust their metabolism and nutrient uptake to meet the bioenergetic demands of cell growth and differentiation in vivo.

Figure 1: The two TFEB-MYC sites regulate lysosomal activity, thereby affecting haematopoietic stem cell metabolism and synthesis

Signalling and nutrient uptake depend on proteins embedded in the plasma membrane, including mTORC1, AMPK, GSK3 and some inflammatory vesicles. These proteins can be degraded by endocytosis in lysosomes, which are not only sites of degradation but also signalling centres for the assembly of signalling complexes. These signals integrate and facilitate interactions between different signals, culminating in responses such as autophagy, cell growth, membrane repair and microbial killing. The role of these lysosomes has been studied to a large extent in cell line models and tissues, but their study in stem cells requires further discovery.

Image (video source: ref.) Proliferation of short-term haematopoietic stem cells compared to long-term haematopoietic stem cells

TFEB can sense and respond to, including nutrient starvation or mitochondrial damage, through endocytosis, autophagy and transcriptional activation of lysosomal genes [2]. Due to a high degree of binding sequence homology, TFEB and MYC appear to compete for binding to the same chromatin regions, while MYC can regulate multifaceted metabolic levels and play a role in mouse HSC by balancing rates of self-renewal and differentiation. The researchers found that MYC-TFEB-mediated lysosomal activity regulates and balances the processes of anabolic and catabolic metabolism, ultimately regulating human LT-HSC.

This study identifies an organelle-based model of stem cell differentiation in which TFEB and MYC can balance lysosomal activity to regulate the self-renewal and differentiation properties of human LT-HSC. In a homeostatic environment, TFEB induces lysosomal flow in LT-HSC to maintain homeostasis, preserve self-renewal, and control depletion. These effects correlate with lysosomal degradation within the membrane receptor, suggesting that TFEB is coordinating how LT-HSC sense environmental changes, initiate differentiation and cell lineage stereotyping.

Figure 2: TFEB-mediated colocalisation analysis of TFEB, MYC and LAMP1 by endolysosomes

This study also identified a novel mechanism by which TFEB-induced lysosomal degradation of lysosomes by endocytotic transport via external sensing mechanisms, including signalling and nutrient uptake receptors, maintains LT-HSC in an inactive state. In LT-HSC, inhibition of TfR1 degradation by TFEB and its downstream lysosomes is required for red lineage cell stereotyping. Transcriptomic analyses showed that lysosomal degradation of other membrane receptors, such as IGF1R (insulin receptor) upstream of the mTOR pathway, also occurs in LT-HSC, a finding that is consistent with the observed degradation of EGFR in neural stem cells.

In addition, TFEB-MYC-mediated lysosomal binary regulation is likely to be associated with other tissue-specific adult stem cells, such as neural and muscle stem cells, which are chronically underactive. This study reveals the transcriptional control of lysosomes and their critical role in the regulation of haematopoietic stem cells, opening new avenues of exploration for regenerative medicine

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