scholarly journals Autophagy is dispensable for the maintenance of hematopoietic stem cells in neonates

2021 ◽  
Vol 5 (6) ◽  
pp. 1594-1604
Author(s):  
Michihiro Hashimoto ◽  
Terumasa Umemoto ◽  
Ayako Nakamura-Ishizu ◽  
Takayoshi Matsumura ◽  
Tomomasa Yokomizo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Function ◽  
Bone Marrow Failure ◽  
Mitochondrial Metabolism ◽  
Conditional Knockout ◽  
Mitochondrial Activity ◽  
Hematopoietic Stem ◽  
Neonatal Stage

Abstract Hematopoietic stem cells (HSCs) undergo self-renewal or differentiation to sustain lifelong hematopoiesis. HSCs are preserved in quiescence with low mitochondrial activity. Recent studies indicate that autophagy contributes to HSC quiescence through suppressing mitochondrial metabolism. However, it remains unclear whether autophagy is involved in the regulation of neonatal HSCs, which proliferate actively. In this study, we clarified the role of autophagy in neonatal HSCs using 2 types of autophagy-related gene 7 (Atg7)-conditional knockout mice: Mx1-Cre inducible system and Vav-Cre system. Atg7-deficient HSCs exhibited excess cell divisions with enhanced mitochondrial metabolism, leading to bone marrow failure at adult stage. However, Atg7 deficiency minimally affected hematopoiesis and metabolic state in HSCs at neonatal stage. In addition, Atg7-deficient neonatal HSCs exhibited long-term reconstructing activity, equivalent to wild-type neonatal HSCs. Taken together, autophagy is dispensable for stem cell function and hematopoietic homeostasis in neonates and provide a novel aspect into the role of autophagy in the HSC regulation.

scholarly journals Mitochondrial Role in Stemness and Differentiation of Hematopoietic Stem Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Luena Papa ◽  
Mansour Djedaini ◽  
Ronald Hoffman
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Energy Production ◽  
Ex Vivo ◽  
Mitochondrial Activity ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Hypoxic Environment

Quiescent and self-renewing hematopoietic stem cells (HSCs) rely on glycolysis rather than on mitochondrial oxidative phosphorylation (OxPHOS) for energy production. HSC reliance on glycolysis is considered an adaptation to the hypoxic environment of the bone marrow (BM) and reflects the low energetic demands of HSCs. Metabolic rewiring from glycolysis to mitochondrial-based energy generation accompanies HSC differentiation and lineage commitment. Recent evidence, however, highlights that alterations in mitochondrial metabolism and activity are not simply passive consequences but active drivers of HSC fate decisions. Modulation of mitochondrial activity and metabolism is therefore critical for maintaining the self-renewal potential of primitive HSCs and might be beneficial for ex vivo expansion of transplantable HSCs. In this review, we emphasize recent advances in the emerging role of mitochondria in hematopoiesis, cellular reprograming, and HSC fate decisions.

Id2 Is Required for the Self-Renewal and Proliferation of Hematopoietic Stem Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1173-1173 ◽  
Author(s):  
Lei Sun
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Cell Biology ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Conditional Knockout ◽  
The Self ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract The production of mammalian blood cells is sustained throughout life by the self-renewal and differentiation of hematopoietic stem cells (HSCs). Dysregulation in this system leads to different pathologies including anemia, bone marrow failure and hematopoietic malignancies. The Helix-Loop-Helix transcriptional regulator Id2 plays essential roles in regulating proliferation and cell fate of hematopoietic progenitors; however, its role in regulating HSC development remains largely unknown. To assess the function of Id2 in HSCs, we developed two mouse models, including an Id2 conditional knockout model and an Id2-EYFP model, in which EYFP expression is driven by endogenous Id2 promoter. When we examined HSC function by serial transplantation, we found that mice transplanted with Id2F/F Mx1-Cre+ conditionally deleted bone marrow cells became moribund more rapidly after primary and secondary transplantation, compared to those transplanted with Id2+/F Mx1-Cre+ bone marrow, suggesting that HSC self-renewal is impaired when Id2 is deleted. To further determine if self-renewal and maintenance of HSCs depends on the expression level of Id2, we purified HSCs with different levels of Id2 expression using Id2-EYFP mice to specifically address the role of Id2 in HSCs. First, we confirmed Id2 is highly expressed in HSCs in this model. Second, when HSCs with either low or high levels of Id2-EYFP were transplanted into irradiated mice, cells with high levels of Id2 reconstituted transplanted recipients faster than those with low levels of Id2 at 3 weeks and longer, suggesting that Id2 expression is associated with repopulation advantage. Furthermore, Ki-67 staining showed that HSCs with high levels of Id2 have 15-fold more cells in G2/M phase, and fewer cells in G0. BrdU staining also suggested that there are 5-fold more BrdU+ cells in HSCs with high levels of Id2, indicating that Id2 expression correlates with cell cycle progression in HSCs. In addition, p57 has been reported to be required for quiescence of HSCs. Our preliminary data showed that p57 is downregulated in HSCs with high levels of Id2, and p57 is correspondingly upregulated in Id2-null HSCs. Altogether, our data demonstrate that Id2 is required for the self-renewal and proliferation of HSCs, and suggest a link between Id2 and the transcriptional regulatory networks that regulate the functional hematopoietic system. Since Id2 is also expressed in other adult stem cells including muscle and neuronal stem cells, as well as cancer cells, we believe our results can improve our understanding of stem cell biology and cancer development, and contribute to the identification of novel molecules that may be targeted to eliminate cancer stem cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Loss of tRNA-modifying enzyme Elp3 activates a p53-dependent antitumor checkpoint in hematopoiesis

2021 ◽  
Vol 218 (3) ◽  
Author(s):  
Adeline Rosu ◽  
Najla El Hachem ◽  
Francesca Rapino ◽  
Kevin Rouault-Pierre ◽  
Joseph Jorssen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Failure ◽  
Amino Acid Deprivation ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Transfer Rnas ◽  
Translational Machinery ◽  
Highly Sensitive

The hematopoietic system is highly sensitive to perturbations in the translational machinery, of which an emerging level of regulation lies in the epitranscriptomic modification of transfer RNAs (tRNAs). Here, we interrogate the role of tRNA anticodon modifications in hematopoiesis by using mouse models of conditional inactivation of Elp3, the catalytic subunit of Elongator that modifies wobble uridine in specific tRNAs. Loss of Elp3 causes bone marrow failure by inducing death in committing progenitors and compromises the grafting activity of hematopoietic stem cells. Mechanistically, Elp3 deficiency activates a p53-dependent checkpoint in what resembles a misguided amino acid deprivation response that is accompanied by Atf4 overactivation and increased protein synthesis. While deletion of p53 rescues hematopoiesis, loss of Elp3 prompts the development of p53-mutated leukemia/lymphoma, and inactivation of p53 and Elongator cooperatively promotes tumorigenesis. Specific tRNA-modifying enzymes thus condition differentiation and antitumor fate decisions in hematopoietic stem cells and progenitors.

The role of children's bone marrow mesenchymal stromal cells in the ex vivo expansion of autologous and allogeneic hematopoietic stem cells

2015 ◽  
Vol 39 (10) ◽  
pp. 1099-1110 ◽  
Author(s):  
Iordanis Pelagiadis ◽  
Eftichia Stiakaki ◽  
Christianna Choulaki ◽  
Maria Kalmanti ◽  
Helen Dimitriou
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Hematopoietic Stem

scholarly journals Haploinsufficiency of Dnmt1 Impairs Leukemia Stem Cell Function Through Derepression of Bivalent Chromatin Domains,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3459-3459
Author(s):  
Jennifer J. Trowbridge ◽  
Amit U. Sinha ◽  
Scott A. Armstrong ◽  
Stuart H. Orkin
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Dna Methyltransferase ◽  
Cell Function ◽  
Gene Signature ◽  
Conditional Knockout ◽  
Specific Gene ◽  
Epigenetic Mechanisms ◽  
Chromatin Domains ◽  
Hematopoietic Stem

Abstract Abstract 3459 Leukemia stem cells (LSCs) are an attractive target in treatment of many types of blood cancers. There remains an incomplete understanding of the epigenetic mechanisms driving LSC formation and maintenance, and how this compares to the epigenetic regulation of normal hematopoietic stem cells (HSCs). One of the major epigenetic modifications, DNA methylation, is catalyzed by the DNA methyltransferase enzymes Dnmt1, Dnmt3a and Dnmt3b. We observed decreased expression of Dnmt3a and Dnmt3b in LSCs isolated from a model of MLL-AF9-induced acute myeloid leukemia (AML) compared to normal HSCs. In contrast, expression of Dnmt1 was maintained in LSCs compared to HSCs, suggesting that Dnmt1 may have a critical function in the formation and maintenance of LSCs. Supporting this hypothesis, we found that conditional knockout of Dnmt1 fully ablates the development of AML. Furthermore, haploinsufficiency of Dnmt1 (Dnmt1fl/+ Mx-Cre) was sufficient to delay progression of leukemogenesis and impair LSC self-renewal. Strikingly, haploinsufficiency of Dnmt1 did not functionally alter normal hematopoiesis or HSCs, suggesting an enhanced dependence of LSCs on DNA methylation. Mechanistically, we observed that haploinsufficiency of Dnmt1 in LSCs resulted in derepression of genes that had been silenced by MLL-AF9-mediated transformation and marked by bivalent H3K27me3/H3K4me3 chromatin domains. These results suggest that the formation and maintenance of LSCs depends not only upon activation of a leukemogenic program, but also upon silencing of a specific gene signature that is active in HSCs through crosstalk between two epigenetic mechanisms, polycomb-mediated repression and DNA methylation-mediated repression. This silenced gene signature includes known and candidate tumor suppressor genes as well as genes involved in lineage restriction. These studies present evidence that distinct epigenetic regulatory mechanisms are dominant in LSCs compared to HSCs and provide novel gene candidates for targeted reactivation in AML therapy. Disclosures: Armstrong: Epizyme: Consultancy.

scholarly journals The Dynamic Interface Between the Bone Marrow Vascular Niche and Hematopoietic Stem Cells in Myeloid Malignancy

2021 ◽  
Vol 9 ◽  
Author(s):  
Laura Mosteo ◽  
Joanna Storer ◽  
Kiran Batta ◽  
Emma J. Searle ◽  
Delfim Duarte ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Vascular Niche ◽  
Dynamic Interface ◽  
Bone Marrow Vascular Niche ◽  
Bidirectional Interactions ◽  
Vascular Compartment

Hematopoietic stem cells interact with bone marrow niches, including highly specialized blood vessels. Recent studies have revealed the phenotypic and functional heterogeneity of bone marrow endothelial cells. This has facilitated the analysis of the vascular microenvironment in steady state and malignant hematopoiesis. In this review, we provide an overview of the bone marrow microenvironment, focusing on refined analyses of the marrow vascular compartment performed in mouse studies. We also discuss the emerging role of the vascular niche in “inflamm-aging” and clonal hematopoiesis, and how the endothelial microenvironment influences, supports and interacts with hematopoietic cells in acute myeloid leukemia and myelodysplastic syndromes, as exemplar states of malignant myelopoiesis. Finally, we provide an overview of strategies for modulating these bidirectional interactions to therapeutic effect in myeloid malignancies.

scholarly journals Accessibility Over Transposable Elements Reveals Genetic Determinants of Stemness Properties in Normal and Leukemic Hematopoiesis

2021 ◽  
Author(s):  
Bettina Nadorp ◽  
Giacomo Grillo ◽  
Aditi Qamra ◽  
Amanda Mitchell ◽  
Christopher Arlidge ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Chromatin Accessibility ◽  
Genetic Determinants ◽  
Hematopoietic Stem ◽  
Transcription Regulators ◽  
Docking Sites ◽  
Cellular Hierarchy ◽  
Mutational Processes

AbstractDespite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two thirds of patients will relapse with fatal disease within 5 years. AML is organized as a cellular hierarchy sustained by leukemia stem cells (LSC) at the apex, with LSC properties directly linked to tumor progression, therapy failure and disease relapse 1–5. Despite the central role of LSC in poor patient outcomes, little is known of the genetic determinants of their stemness properties 6–8. Although much AML research focuses on mutational processes and their impact on gene expression programs, the genetic determinants of cell state properties including stemness expand beyond mutations, relying on the genetic architecture captured in the chromatin of each cell 9–11. As LSCs share many functional and molecular properties with normal hematopoietic stem cells (HSC), we identified genetic determinants of primitive populations enriched for LSCs and HSCs in comparison with their downstream mature progeny by investigating their chromatin accessibility. Our work reveals how distinct transposable element (TE) subfamilies are used in primitive versus mature populations, functioning as docking sites for stem cell-associated regulators of genome topology, including CTCF, or lineage-specific transcription regulators in primitive and mature populations, respectively. We further show how TE subfamilies accessible in LSCs define docking sites for several oncogenic drivers in AML, namely FLI1, LYL1 and MEIS1. Using chromatin accessibility profiles from a cohort of AML patients, we further show the clinical utility of our TE accessibility-based LSCTE121 scoring scheme to identify patients with high rates of relapse. Collectively, our work reveals how different accessible TE subfamilies serve as genetic determinants of stemness properties in normal and leukemic hematopoietic stem cells.

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