Publications by authors named "Nakamura-Ishizu A"
Article Synopsis
- Lifelong maintenance of blood cell production relies on the proper functioning of hematopoietic stem cells, which are regulated by thrombopoietin, a key cytokine.
- Thrombopoietin not only helps maintain these stem cells but also plays a crucial role in the development of megakaryocytes, the cells responsible for producing platelets.
- Research using thrombopoietin gene-deficient mice has revealed how thrombopoietin receptor agonists aid in sustaining stem cell populations and their differentiation, highlighting their importance in treating bone marrow failure disorders like aplastic anemia.
We have reported that an environmental pollutant, cadmium, promotes cell death in the human renal tubular cells (RTCs) through hyperactivation of a serine/threonine kinase Akt. However, the molecular mechanisms downstream of Akt in this process have not been elucidated. Cadmium has a potential to accumulate misfolded proteins, and proteotoxicity is involved in cadmium toxicity.
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- Aging affects stem cells, leading to decreased function and impacting tissue health, but hematopoietic stem cells (HSCs) develop a resilience that helps them survive.* -
- Old HSCs shift their metabolism by activating the pentose phosphate pathway, allowing them to resist oxidative stress and operate independently of glycolysis.* -
- The study reveals that old HSCs enhance energy production through mitochondrial changes, aided by increased levels of a specific factor (SDHAF1), improving their survival during stress and addressing age-related blood cell formation issues.*
Article Synopsis
- Metabolic pathways adapt quickly to stress, impacting cell behavior, especially in rare hematopoietic stem cells (HSCs).
- Researchers focused on how key enzymes affect glycolytic metabolism in HSCs under different conditions.
- They identified that the enzyme phosphofructokinase (PFK) plays a crucial role in increasing glycolysis during stress, with its regulation influenced by specific modifications, ultimately affecting HSC proliferation and differentiation.
Article Synopsis
- Erythropoiesis, the process of producing red blood cells, in adult bone marrow relies on mitochondrial transporters, particularly the ABC transporter 10 (Abcb10), which is crucial for maintaining hematopoietic stem cells (HSCs) and supporting their differentiation into erythroid cells.
- When Abcb10 was deleted in adult mice, there was a notable increase in erythroid progenitor cells but a decrease in HSCs, indicating that Abcb10 plays a key role in balancing stem cell maintenance and differentiation toward red blood cell lineage.
- The loss of Abcb10 resulted in excess iron and oxidative stress within HSCs, although basic mitochondrial energy function remained unchanged, and
MBTD1 preserves adult hematopoietic stem cell pool size and function.
Proc Natl Acad Sci U S A
August 2023
Article Synopsis
- - The study investigates the role of MBTD1, a protein important in hematopoietic stem cells (HSCs), showing it is vital for maintaining HSC quantity and functionality, particularly in fetal development.
- - Researchers created conditional knockout mice to explore MBTD1's influence on adult HSCs, finding that its absence led to increased HSC numbers but caused defects in stress response and cell cycle regulation.
- - The findings suggest that MBTD1 helps maintain the quiescence of HSCs by interacting with the FOXO3a protein; restoring FOXO3a in deficient HSCs corrected the observed abnormalities, establishing MBTD1 as key in regulating HSC pool size and health.
Article Synopsis
- Most adult hematopoietic stem cells (HSCs) stay in a quiescent state, and while glycolysis has a payoff phase crucial for HSC function, the role of its preparatory phase is not well understood.
- This study explores the necessity of both glycolytic phases using key genes Gpi1 and Gapdh; findings reveal that while quiescent HSCs can maintain function despite defects, proliferative HSCs struggle significantly without the payoff phase.
- The research indicates that quiescent HSCs compensate for glycolytic deficiencies through oxidative phosphorylation (OXPHOS), while proliferative HSCs use the nonoxidative pentose phosphate pathway (PPP) to offset issues in the prepar
Fanconi Anemia (FA) is an inherited bone marrow (BM) failure disorder commonly diagnosed during school age. However, in murine models, disrupted function of FA genes leads to a much earlier decline in fetal liver hematopoietic stem cell (FL HSC) number that is associated with increased replication stress (RS). Recent reports have shown mitochondrial metabolism and clearance are essential for long-term BM HSC function.
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- The study introduces a new platform to investigate hematopoietic stem cell (HSC) quiescence using a combination of special culture conditions and a CRISPR-Cas9 genome editing system tailored for HSCs.
- It was found that pre-culturing HSCs boosts editing efficiency by aiding the transport of essential components into the cell nucleus.
- The research indicates that HSCs maintain their traits and remain quiescent better in low-cytokine, low-oxygen environments than in proliferative conditions, even after being edited genetically.
Article Synopsis
- Quiescence in hematopoietic stem cells (HSCs) is essential for maintaining a reserve of cells that can quickly expand when needed, particularly in response to stress.
- Thrombopoietin (THPO) is known to support quiescent HSCs while also stimulating their metabolism and differentiation, though how it manages the balance between promoting cell proliferation and maintaining quiescence is still unclear.
- The study suggests the existence of a THPO-independent HSC subpopulation with low mitochondrial activity that can revert to a quiescent state and regain stem cell functionality when exposed to certain stimuli.
Adult erythropoiesis entails a series of well-coordinated events that produce mature red blood cells. One of such events is the mitochondria clearance that occurs cell-autonomously via autophagy-dependent mechanisms. Interestingly, recent studies have shown mitochondria transfer activities between various cell types.
View Article and Find Full Text PDFHematopoietic stem cells (HSCs) reside in a hypoxic microenvironment that enables glycolysis-fueled metabolism and reduces oxidative stress. Nonetheless, metabolic regulation in organelles such as the mitochondria and lysosomes as well as autophagic processes have been implicated as essential for the determination of HSC cell fate. This review encompasses the current understanding of anaerobic metabolism in HSCs as well as the emerging roles of mitochondrial metabolism and lysosomal regulation for hematopoietic homeostasis.
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- Hematopoietic stem cells (HSCs) are critical for lifelong blood production and can either self-renew or differentiate; their quiescent state is linked to low mitochondrial activity.
- Recent research suggests that autophagy helps maintain HSC quiescence by reducing mitochondrial metabolism, but its role in neonatal HSCs— which actively divide— is not well understood.
- This study found that while autophagy-related gene 7 (Atg7) deficiency in neonatal HSCs leads to increased divisions and mitochondrial activity, it does not significantly impact their blood-forming ability or metabolic state, indicating that autophagy is not essential for HSC function during the neonatal stage.
Article Synopsis
- Hematopoietic stem cells (HSCs) usually remain inactive and only divide during stress, but the cytokine thrombopoietin (Thpo) has contradictory effects by both inducing quiescence and promoting self-renewal in these cells.
- Research comparing Thpo-deficient models revealed that Thpo-/- HSCs lose their quiescence, struggle with cell cycle progression, and undergo increased cell death, along with reduced mitochondrial function.
- Interestingly, these negative effects can be reversed through HSC transplantation or by using a Thpo receptor stimulant, although prolonged stress from competitive transplantation can lead to stem cell exhaustion.
Article Synopsis
- Thrombopoietin (Thpo) is a key cytokine that regulates the production of blood cells and supports hematopoietic stem cells (HSCs) in the bone marrow.
- Thpo not only stimulates the growth of HSCs but also keeps some in a resting state to ensure a reserve population in case of need.
- Mpl agonists, which activate the Thpo receptor without triggering adverse immune responses, are being explored for treating conditions like immune thrombocytopenia and aplastic anemia, highlighting the need for more research on their effects.
Bone Marrow Transplantation Dynamics: When Progenitor Expansion Prevails.
Trends Cell Biol
November 2020
The transplantation of healthy hematopoietic stem cells (HSCs) contained in the bone marrow is a frontline treatment option for hematopoietic diseases. Detailed analysis of post-transplant HSC kinetics is crucial as the initial engraftment of HSCs influences prognosis. Dong et al.
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- Hematopoietic stem cells (HSCs) have unique metabolic needs that change as they move through different developmental stages and tissues.
- Understanding how HSCs adapt their metabolism is critical, especially since these changes support their role in blood cell formation (hematopoiesis).
- This review focuses on the importance of mitochondrial metabolism in determining HSC fate and explores the relationships between mitochondria, endoplasmic reticulum, and lysosomes in their metabolic processes.
RUNX1 is among the most frequently mutated genes in human leukemia, and the loss or dominant-negative suppression of RUNX1 function is found in myelodysplastic syndrome and acute myeloid leukemia (AML). How posttranslational modifications (PTMs) of RUNX1 affect its in vivo function, however, and whether PTM dysregulation of RUNX1 can cause leukemia are largely unknown. We performed targeted deep sequencing on a family with 3 occurrences of AML and identified a novel RUNX1 mutation, R237K.
View Article and Find Full Text PDFThrombopoietin (THPO) has long been known to influence megakaryopoiesis and hematopoietic stem and progenitor cells (HSPCs), though the exact mechanisms through which it acts are unknown. Here we show that MPL expression correlates with megakaryopoietic potential of HSPCs and identify a population of quiescent progenitor cells that show limited dependence on THPO signalling. We show that THPO is primarily responsible for maintenance of hematopoietic cells with megakaryocytic (Mk) differentiation potential and their subsequent Mk differentiation and maturation.
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- The tumor suppressor folliculin (FLCN) regulates the movement of TFE3, a key transcription factor for lysosome production, by controlling Rag GTPases related to amino acid sensing.
- In mice with a specific deletion of Flcn in blood cell lineage, researchers observed an increase in unhealthy phagocytes that resembled symptoms of lysosomal storage disorders (LSD).
- The study suggests that FLCN and TFE3 work in a feedback loop to manage lysosomal function, where FLCN loss increases TFE3 activity, leading to enhanced glycogenesis and abnormal phagocyte behavior; deleting TFE3 in Flcn-deficient mice can reduce these negative effects.
Article Synopsis
- HSCs (hematopoietic stem cells) can be categorized by the amount of mitochondria they contain, which is referred to as mitochondrial mass.
- Cells with a higher mitochondrial mass are typically in a quiescent state, meaning they are not actively dividing or differentiating.
- Additionally, these high mitochondrial mass HSCs demonstrate a greater ability to reconstitute or restore the blood system when needed.
Multifaceted roles of thrombopoietin in hematopoietic stem cell regulation.
Ann N Y Acad Sci
April 2020
Article Synopsis
- * Thpo signaling helps in the self-renewal of hematopoietic stem cells (HSCs), which has led to the creation of Thpo mimetic drugs aimed at treating diseases like aplastic anemia where HSC function is impaired.
- * This review focuses on the details of how Thpo-Mpl signaling influences the regulation and function of HSCs in the body.
Article Synopsis
- Baryawno et al. created a detailed atlas of mouse bone marrow stroma using single-cell RNA-sequencing data.
- Their study identified 17 different cell types within the bone marrow, each with unique functions.
- This research underscores the complexity of the bone marrow environment and sets the stage for future in vivo studies.