Lysosomes in Regulating Metabolism of Hematopoietic Stem Cells: History
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Contributor:
Tasleem Arif

Hematopoietic stem cells (HSCs) have the capacity to renew blood cells at all stages of life and are largely quiescent at a steady state. It is essential to understand the processes that govern quiescence in HSCs to enhance bone marrow transplantation. It is hypothesized that in their quiescent state, HSCs primarily use glycolysis for energy production rather than mitochondrial oxidative phosphorylation (OXPHOS). In addition, the HSC switch from quiescence to activation occurs along a continuous developmental path that is driven by metabolism. Specifying the metabolic regulation pathway of HSC quiescence will provide insights into HSC homeostasis for therapeutic application. Therefore, understanding the metabolic demands of HSCs at a steady state is key to developing innovative hematological therapeutics. Lysosomes are the major degradative organelle in eukaryotic cells. Catabolic, anabolic, and lysosomal function abnormalities are connected to an expanding list of diseases.

  • lysosomes
  • mitochondria
  • HSCs
  • glycolysis

1. Introduction

It is thought that the quiescent state of hematopoietic stem cells (HSCs), like that of most adult stem cells, protects them from the replicative and metabolic stress that would otherwise shorten their lifespan. So, HSC potency, which is the functional capacity of HSCs to promote multilineage engraftment for a protracted duration in lethally irradiated recipient mice, is inexplicably linked to quiescence. HSCs play a pivotal role in the development of all sorts of blood cells [1]. The blood system relies on these multipotent cells, which can differentiate into many types of adult hematopoietic lineages, whether the body is resting or under stress [2]. Most HSCs maintain a dormant state to avoid depletion caused by replication stress [3]. HSCs divide frequently to maintain their stem cell potential, producing progenitors and quiescent daughter HSCs [4]. The metabolic requirements of HSCs are crucial for the understanding of HSC biology both when they are quiescent as well as in an active state. Quiescent/dormant HSCs showed low metabolic activity, limited protein synthesis, and reduced mitochondrial activity [5][6][7][8][9]. High levels of hypoxia-inducible factor (Hif-1) expression and the predominant use of glycolysis for energy supply are characteristic of HSCs [10]. The oxidation of fatty acids is also essential for HSC homeostasis [11][12]. The release of HSCs from quiescence is accompanied by increased mitochondrial activity, reactive oxygen species (ROS) production, and protein synthesis [8][13][14][15]. A metabolic switch between HSC quiescence and the active state requires glycolysis or OXPHOS for HSC metabolism [16].
Lysosomal research acquired substantial attention after the discovery of autophagy, where lysosomes are involved in a degradative cellular process essential for recycling waste materials and preserving cellular homeostasis. However, during autophagy, lysosomes were only seen as a place for cellular waste compartments in cells [17][18]. In recent years lysosomes function as stress sensors, and controllers of cell responses to environmental stimuli such as nutrition and growth hormones have been identified in HSCs [18][19]. Lysosomes are involved in multiple functions; they attracted attention from researchers worldwide as a possible therapeutic target for cancer. More recently, lysosomal role in the maintenance of HSCs has been demonstrated [20][21][22][23].

2. Factors Regulating Glycolysis in HSCs

HSCs relied mainly on glycolysis and increased OXPHOS as they differentiated. Hif-1α acts as a primary mediator for maintaining glycolytic levels in HSCs by regulating the transcription factors of multiple downstream targets involved in glycolysis. The HSCs appear to express Hif-1α even under normoxic conditions, despite the fact that Hif-1α can interact with Hif-1α to create a heterodimer and is relatively stable under hypoxic conditions [24]. It has been shown that several signaling pathways are essential for maintaining Hif-1α stability. For example, the von Hippel–Lindau (VHL)-mediated deubiquitination pathway is required to maintain Hif-1α levels and stability [25][26]. 5’AMP-activated protein kinase (AMPK)- or NAD-dependent deacetylase sirtuin-1 (SIRT1)-mediated signaling is also involved in the maintenance of Hif-1α levels and stability [27]. AhR/aryl complex modulates Hif-1α protein levels which inhibits the interaction between the aryl hydrocarbon receptor nuclear translocator (ARNT) and Hif-1α. Moreover, AhR antagonists are responsible for the increased in vivo growth of HSCs [28]. AhR antagonists induce ROS stress; thus, Ahr molecules may help to maintain HSC functions.
A member of the HOX family of DNA-binding transcription factor, myeloid ecotropic viral integration site 1 (Meis1) is overexpressed in HSCs [29]. Meis1 deletion promotes embryonic lethality due to severe hematopoiesis defects. Meis1 regulates the glycolytic level and HSCs self-renewal through the Hif-2α/ROS/p16 pathway [9][24][30]. Meis1 null HSCs lose their quiescence, elevate ROS levels, and inhibit the expression of Hif-1 and Hif-2; this effect is reversible when HSCs are treated with a ROS scavenger N-acetylcysteine [31]. Human peripheral blood HSCs have been found to preferentially utilize glycolysis as an energy source through Meis1/Hif-1/Pbx1/HoxA9 pathways, suggesting that HSC cell fates are regulated by intrinsic metabolic networks [24].
HSCs glycolysis and function are regulated by Hif-1α, via multiple downstream targets, such as lactate dehydrogenase A (LDHA), pyruvate Kinase M2 (PKM2), glucose transporter 1 (GLUT1), 6-phosphofructokinase, liver type (PFKL), pyruvate dehydrogenase kinase 2 (PDK2), and teratocarcinoma-derived growth factor 1 (TDGF1). Hif-1α inhibits pyruvate from entering the tricarboxylic acid cycle (TCA), thus inhibiting OXPHOS levels [32]. Deleting the Hif-1α downstream targets such as LDHA or PKM2 decreases HSC function and repopulation capacity [32]. Quiescent HSCs display high levels of Hif-1α, which is also relatively stable as the cells migrate from the hypoxic BM niche into the circulating blood [24][33]. Hif-1α deletion in adult HSCs reduces reconstitution capacity and loses quiescence, indicating Hif-1α is needed to maintain the stem cell pool [10]. Furthermore, alterations in the vascular endothelial growth factor caused by mutations in the Hif-1α impair HSC stem cell activity and function [34]. HSCs switch from glycolysis to mitochondrial respiration when Hif-1α is conditionally deleted [31]. Nevertheless, it is also shown that deletion of Hif-1α has no effect on HSC activities [35], but these studies cannot entirely exclude the idea that Hif-1α may play a vital role in BM niche cells to support hematopoiesis.
Moreover, Hif-1α also interacts with Notch and Wnt signaling to control the cell fates of HSCs. Hif-1α interacts directly with Notch’s intracellular domain (NICD), which retains Notch stability and activates downstream targets [36]. Interaction of Hif-1α and catenin promotes the expression of genes influenced by Hif-1α, but it decreases the expression of genes influenced by Wnt signaling [37].
As shown above, Hif-1α seems to have a critical function in hematopoiesis at various stages of development. Deletion of Hif-1α in mice is embryonically fatal due to many abnormalities in vascular development, blood cell development, and nerve cell development [38]. Mice lacking Hif-1α have a much smaller yolk sac and fewer hematopoietic cells compared to wild-type mice [39]. Several lines of evidence demonstrate the role of glycolysis in HSCs, although the underlying regulatory networks or mechanisms still need more investigation. However, the idea of quiescent HSCs using glycolysis as their energy source has been recently challenged [22].

3. Lysosomal Metabolism

In eukaryotic cells, lysosomes are membrane-bound organelles with an acidic lumen that were first identified in 1955 by Christian de Duve [40][41], and act as degradative organelles, and cellular metabolism regulators. Lysosomes degrade damaged mitochondria, pathogens, lipids, proteins, carbohydrates, and DNA/RNA molecules which are transported to lysosomes by several pathways and converted into a wide variety of molecules and nutrients that are reused by the cells [42]. Autophagosomes transport intracellular substrates, while phagosomes and endosomes transport extracellular material to lysosomes [43]. In addition, chaperone-mediated autophagy (CMA) an independent process, helps transport proteins across the lysosomal membrane. More than sixty lysosomal hydrolases degrade lysosomal cargo before being shuttled to the cytosol for further catabolic/anabolic processing. Lysosomes have been studied for their degradative function since their discovery [41], recent research is shifting the focus away from them as “unregulated cellular waste bags” toward their role as highly dynamic organelles at the hub of cellular metabolism [42]. Lysosomes were found to play a critical role in metabolic signaling, gene regulation, plasma membrane repair, antigen presentation, cell adhesion, apoptosis, pro-inflammatory response, and exocytosis [44][45][46][47][48][49], and more recently, lysosomes were found to regulate the maintenance of HSCs [22].
Lysosomes interact with other cellular organelles by multiple ways (Fusion and non-fusion interaction). Lysosomal membranes are repaired, and antigen presentation is performed by fusion during autophagosomes formation [50][51][52]. Lysosomes are known to interact with the endoplasmic reticulum (ER), peroxisomes, and mitochondria, and transport cholesterol [53]. Regulation of mTOR complex 1 (mTORC1) activity and localization of lysosomes around the nucleus requires interaction with the Golgi bodies [54]. Multiple studies have shown that interactions with mitochondria influenced lysosomal acidity and played a role in the regulation of mitochondrial fission [55][56].
The activity of critical players, such as mTORC1, 5-AMP-activated protein kinase (AMPK), or glycogen synthase kinase-3 (GSK3b) in cellular metabolism is modulated by lysosomes [57][58][59], and activated when translocase to the lysosomal surface [60].
Lysosomal regulation influences development, differentiation, and a feedback loop that relates lysosomal biogenesis to nutrient availability [48]. Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, is phosphorylated by mTORC1 in response to a lysosomal amino acid (AA), translocating to the nucleus and enhancing transcriptional activity of lysosomal, and autophagy genes [60]. Lysosomal genes are regulated by several transcription factors in the MiTF family, including melanocyte inducing transcription factor (MITF), transcription factor E3 (TFE3), and transcription factor EC (TFEC) [18][61]. Other transcription factors, such as zinc finger with KRAB and SCAN domains 3 (ZKSCAN3), and bromodomain-containing protein 4 (BRD4), as well as the Foxo family, modulate the expression of lysosomal proteins and biogenesis [62][63][64][65].
Thus, lysosomes are responsible for regulating a variety of cellular functions, and changes or modulations to lysosomes can impact key physiological pathways.

Lysosomal Disorders

During lysosomal dysfunction, the significance of lysosomes in cellular metabolism is very important. Lysosomal storage disorders (LSDs) are a collection of seventy rare and severe genetic diseases caused by mutations in lysosomal hydrolases that interfere with their enzymatic activity and stability [23]. The buildup of substrates in lysosomes is a hallmark pathogenic feature of LSDs, which frequently leads to inhibition of other hydrolases and accumulation and limiting lysosomal functions. A lysosomes failure to degrade cargo leads to disruption in autophagy or mitophagy, vesicle trafficking, fusion with other organelles, mitochondrial function, and signaling cascades. LSDs usually cause people to become disabled and die early age [23][66].
Lysosome-associated proteins or genes in neurodegenerative disorders, including Alzheimer’s, Huntington’s, and Parkinson’s, are altered, and mutations in lysosomal proteins constitute the most important known risk factor [43][67]. Further, defects in lysosomal signaling have been linked to cancer and aging [68].
Most cancer cells have altered metabolism [69][70][71]. Cancer patients often have mutations in several metabolic pathway components, allowing these pathways a potential therapeutic target. Targeting lysosomes may help to combat cancer, eliminate leukemia stem cells (LSCs), and chemoresistance [21][72]. Targeting lysosomes in LSCs may improve comprehensive response, recurrence, and duration when coupled with chemotherapy or HSC transplantation. Schofield (1978) introduced the idea of a physiological niche of stem cells in the BM [73]. Recent findings have broadened the knowledge of the metabolic and lysosomal components essential for the functional maintenance of HSCs [22].
Leukemia is caused when HSCs undergo mutations or epigenetic alterations [74]. LSCs originate as disease progress, chronicity or acuteness of leukemia, and myeloid or lymphoid immunophenotype. HSCs sustain lifelong self-renewal capacity; thus, HSCs have a higher frequency of mutations than less primitive cells [75]. Leukemic cells develop from progenitors with mutations that enable self-renewal, and genetic and epigenetic changes in HSCs reduce cell death and enhance self-renewal [76].
Very few lysosome-targeted therapies are currently in the clinical use [77]. Therefore, identifying individuals with genetic history most likely to react to a drug could be a major advance in the field. Epigenetic variables that can distinguish lysosome-directed therapy responders and inherent lysosomal malfunctions are not known. Further research is needed to acquire more degree of understanding, which depends on disease nature, variability, and prevalence.
Recent research demonstrates that higher lysosomes and inhibited lysosomal activity/degradation capacity are critical for the regulation of quiescent HSCs [21]. Thus, lysosomes may regulate HSC maintenance and serve as a therapeutic target in hematological diseases.

4. Role of Lysosomes in Maintaining HSCs Quiescence

Nearly all eukaryotic cells rely on lysosomes as their primary degradative organelle. They help maintain cellular balance, and defects in lysosomal function have been linked to several diseases [21]. Major regulators of cellular signaling have been shown to be activated at the lysosomal surface [21], and in recent years, lysosomes have become the control hubs of cellular metabolism. Recent research demonstrates that quiescent HSCs have an overabundance of large lysosomes, which is commensurate with the mRNA expression of genes encoding lysosomes and protein degradation pathways [22]. Lysosomes are known to be involved in endocytosis, phagocytosis, and autophagy. However, lysosomes do more than just degrade cargo; they also serve as storage sites for metabolites and nutrients such as amino acids (AA). The byproducts secreted from the lysosome are reused for energy regulation [78]. Quiescent MMP-low HSCs have a greater number of lysosomes and a lower pH than activated MMP-high HSCs. Autolysosomes are present in greater numbers in the MMP-low HSCs, and mitochondria are sequestered into lysosomes, suggesting that they may initiate mitophagy, a process of mitochondrial clearance. In addition, MMP-low HSCs had higher expression of the TFEB and inhibited lysosomal degradative activity [22]. However, suppression of lysosomal activation enhanced quiescence and improved the competitive repopulation capacity of MMP-low and -high HSCs up to 9- and 90-folds, respectively [22].
In the past, lysosomes have been linked to cellular dormancy. Even though autophagy flux decreased during prolonged quiescence in rat embryonic fibroblasts or neural stem cells, lysosomal gene expression was shown to be elevated [79][80]. The deeper the cells went into quiescence in response to a decrease in lysosomal function, the more activated they became in response to an increase in function [79][80]. From these results, it can be inferred that lysosomal cargo sequestration is critical for maintaining cellular quiescence, while cargo breakdown and release of nutrients are critical for triggering HSC activation. Human HSCs (huHSCs) have also been shown to illustrate the role of lysosomes in HSC activities. Increased expression of TFEB and the autophagy-lysosomal pathway was observed in quiescent huHSC [81]. HSC repopulation activity was maintained while TFEB overexpression induced quiescence. Lysosomes in human HSCs actively break down receptors, such as the transferrin receptor CD71, to inhibit cell activity and entry into the cell cycle [81]. Interestingly, huHSC and muHSC have different lysosomal activity requirements.
Notably, quiescent neural stem cells (NSCs) were found to have more and bigger lysosomes than active NSCs [80]. Insoluble protein concentrations in large lysosomes impeded stem cell activation in aged quiescent NSCs, while increasing their lysosomal activity, thus, reinstating a younger state [80]. It is unknown how lysosomes influence quiescence in other adult stem cell types. Nutrients such as AAs released during lysosomal degradation may be essential for activating HSCs by unknown mechanisms. Lysosomes may be able to manage the level of quiescence and the rate of activation of HSCs. Carefully monitoring the degradation rate, and the transport of metabolites and AAs to the cell will increase the knowledge of maintaining HSCs activity and function. Therefore, controlling lysosomal degradation might be used to convert active HSCs back into quiescent HSCs, which may be useful for clinical purposes, such as for BM transplantations or targeting hematological disorders.

4.1. Glycolysis and Mitochondrial Biogenesis

Multiple studies have reported increased MMP and metabolic activity in HSC, pushing them into the cell cycle [12][13][14][15][22]. A fused mitochondrial network and expanded crista activate mitochondria to support increased surface area for electron transport enzymes [22]. Interestingly, the expression of genes encoding both glycolysis and mitochondrial activity increases in the hematopoietic stem and progenitor cells (HSPCs) and activated HSCs [12][13][14][15][22]. Furthermore, activated HSCs rely on glycolysis [22]. Glucose uptake also increases when the TCA cycle is triggered by dimethyl α-ketoglutarate in MMP-low HSC [22]. Notably, it is known that the activity of the mitochondrial electron transport chain is necessary to keep HSCs in a quiescence state [82][83].
Progenitors or highly differentiated HSCs showed a high glucose uptake, while HSCs in the BM have a reduced glucose uptake [84]. Liang, Arif, et al. showed that pharmacological suppression of lysosomal function by Concanamycin A (ConA) inhibits lysosomal degradation, enhances quiescence in HSCs, and decreases glucose uptake. Suppressing lysosomes enhances the HSCs competitive repopulating capacity and improves their ex vivo maintenance of functional HSCs [22]. Thus, active HSCs require a higher glucose intake to sustain entry into the cell cycle, while quiescent HSCs maintain their overall low metabolic activity. Hence, low metabolic activity protects MMP-low HSCs from premature exhaustion and ensures their survival, thus maintaining HSCs quiescence [22].
These results suggest that non-glycolytic metabolic pathways play a critical role in maintaining HSCs. These data imply that HSC activation is related to glycolysis and mitochondrial biogenesis to enhance ATP production in HSCs.

4.2. How HSCs Switch from Catabolic to Anabolic Activity?

HSCs are subjected to a particular metabolic requirement from a low to a high proliferative state during the shift from catabolic to anabolic activity. Genes encoding in both human and murine that enable transcription, and translation have been found to be upregulated in active HSCs [13][14][22][85]. TFEB and cMYC expressions are altered in huHSCs as they exit quiescence. In active HSCs, TFEB is overexpressed, whereas cMYC expression downregulates. Furthermore, inducing stress in HSCs enhances ribosomal and mitochondrial biogenesis [81]. cMYC levels are elevated in huHSC, while lysosomal catabolism is suppressed [81]. Hence, HSC activation is connected with reprogramming from a catabolic to an anabolic state. Lysosomal inheritance was followed using advanced in the aging of HSCs isolated from murine or humans and tracking of single HSCs over time to correlate HSC fate [86][87]. Using a fluorescent reporter of NUMB endocytic adaptor protein (NUMB) is found to be decreased and shows that NUMB inheritance is enhanced in a cell expressing differentiation markers such as B-lymphocyte activation marker (CD48), endoglin (CD105), and transferring receptor-1 (CD71), but not platelet glycoprotein IIb (αIIb; CD41) and stem cells antigen-1 (Sca-1) [88]. CD71 expression was found to be highly correlated with other markers of HSC activation, including mitochondrial activity, ROS generation, and cMYC overexpression. In another study using a lysosomal marker lysosomal-associated membrane protein 1 (LAMP1)- Venus reporter, a pH-sensitive fluorescent lysosome showed a low number of lysosomes in the cells [87].
It is still unclear how the release of nutrients from lysosomes activates HSCs [22]; this may be due to HSCs requiring high lysosomal catabolic activity to exist quiescence. Lysosomal degradation releases several nutrients and intermediate metabolites, which are used in the mTORC1 pathway to activate HSCs. It is well known that lysosomes have been linked to a wide variety of autophagy pathways. HSCs in adult mice are maintained by CMA, a selective form of the lysosomal degradation pathway [89]. In differentiated HSCs, CMA is overexpressed, and it plays an important role in maintaining HSCs, proteins involved in the synthesis of linoleic acid metabolism, fatty acid (FAs) biosynthesis, and oxidation. Moreover, CMA is not required for mitochondrial quality control. Fatty acid desaturase 2 (FADS2) inhibitors affect HSC functions, whereas linolenic acid, a direct product of FADS2, has been shown to rescue CMA-deficient HSC functions in vitro and in vivo [89].
Several studies reveal that HSCs retain mitochondria in a quiescent state, while mitochondrial structure and functions are altered during HSC activation or oxidative stress [13][22][83][90]. HSCs metabolic switch from catabolic to anabolic state is an intriguing phenomenon, but how it occurs remains an open question. It is still unclear how HSCs lysosomal degradation, and release of cargo activate HSCs. It is unknown how altering lysosomal activity plays a role in maintaining HSC quiescence.

4.3. Role of Anabolic Regulators in HSCs

A decrease in protein synthesis is an important and unique characteristic of quiescent HSCs [8][91]. Hence suppressing anabolic activity using pharmacological molecules may promote HSCs function and activity. mTORC1 is one of two protein complexes containing the essential kinase mTOR [68] and plays an important role in regulating protein synthesis in cells, including HSCs and inhibiting phosphorylation of S6 and 4EBP1 [92] altered protein synthesis in HSCs [93]. HSCs depend heavily on the control of mTORC1 activity. Depletion of S6 and 4EBP in HSCs coincides with cell cycle progression, and mitochondrial activation after mTORC1 is hyperactivated by knocking out tuberous sclerosis complex 1 (TSC1) or overexpressing Ras homolog enriched in brain (Rheb) [94]. Phosphatase and tensin homolog (Pten), a negative regulator of the PI3K-AKT pathway, is essential for inhibiting mTORC1 signaling in quiescent HSCs. Deleting Pten altered HSC numbers due to activation of mTORC1, whereas overexpression of p16Ink4A and p53 induces abnormal cell cycle progression in HSCs [95]. Rapamycin, an mTOR inhibitor, enhances HSC function, activity, and reconstitution capacity, and further increased mTORC1 activity induces HSC failure in vivo. Similarly, the reconstitution capability of HSCs is diminished when Raptor is knocked down in HSCs, which activates mTORC1 [96].
Liang, Arif, and colleagues show that MMP-high HSCs contain lower lysosomal content, which is linked to mTOR expression, recruitment, and activation [22]. It is well known that gene translation and cell proliferation require mTOR activation [97]. Therefore, activating mTOR signaling enhanced downstream phosphorylation of mTORC1 target 4EBP1 and upstream targets (Rheb1 and RAGA/B). MMP-low HSCs express higher TFEB levels, a regulator of lysosomal biogenesis that inhibits mTORC1. Interestingly, mTOR expression and activity were significantly reduced in MMP-low HSCs and may be promoting HSCs quiescence [22]. Lysosomal suppression by using ConA lowered mTOR protein levels, its upstream targets (Rheb1 and RAGA/B), as well as its downstream target (4EBP1) in MMP-high HSCs [22]. Therefore, lysosomal suppression by ConA increases quiescence in HSCs by reducing the expression levels of Ki67, a marker of cell proliferation, and CDK6, which predicts HSC exit from G0, both of which are associated with active MMP-high HSCs [22].
In sum, mTORC1 is essential for maintaining HSCs function and activity, whereas high levels of mTORC1 activity induce significant abnormalities in HSCs function and activity. Raptor, Rheb1 also activates mTORC1, and knocking down Rheb1 inhibits mTORC1 activity [98]. Raptor-/- vs. Rheb1-/- HSCs showed a distinct difference in competitive reconstitution assay in vivo [98], while deleting Raptor or Rheb1 increases the total number of HSCs, inhibits function, and reduces HSC competitiveness in vivo, deleting Raptor, but not Rheb1, expands HSCs, and decreases stem cell capacity while expanding HSCs without Rheb1 retain their stemness. These results indicate that maintaining HSC self-renewal activity in vivo moderate’s levels of mTORC1 activation [99][100]. Nutrient-sensing may play a critical role in the maintenance of HSCs in culture, whereas HSCs treated with rapamycin and GSK-3 inhibitor enhance HSCs number and function both in vitro and in vivo [101]. Rapamycin-treated HSCs ameliorates aged HSCs [102]. Hence maintaining or increasing healthy HSC populations in vitro and in vivo requires strict control of mTORC1 activity.
Therefore, this entry highlights metabolic regulatory factors that are important to HSC biology.
In contrast to most other cell types, HSCs do not express the aspartate transporter. Aspartate is synthesized in the cells from glutamate and oxaloacetate with the help of the mitochondrial enzyme glutamic-oxaloacetic transaminase 1 (GOT1) and glutamic-oxaloacetic transaminase 2 (GOT2) in the cytosol and converts aspartate to catabolize AAs, proteins, lipids, and nucleotides. It is well-documented that aspartate can activate the TCA cycle [103]. Aspartate and its catabolized byproducts, such as purine and pyrimidine nucleotides, play a critical role in cell proliferation [104]. Activation of HSCs may be caused by an increase in aspartate metabolism [104]. According to the research above, aspartate metabolites play an essential role in maintaining HSCs function and activity.

This entry is adapted from the peer-reviewed paper 10.3390/biology11101410

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