bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024–02–04
seven papers selected by
William Grey, University of York
  1. Age-related changes in the hematopoietic stem cell pool revealed via quantifying the balance of symmetric and asymmetric divisions.
  2. Leukemia and mitophagy: a novel perspective for understanding oncogenesis and resistance.
  3. The glutaminase inhibitor CB-839 targets metabolic dependencies of JAK2-mutant hematopoiesis in MPN.
  4. Autophagy prevents graft failure during murine Graft versus Host Disease.
  5. Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis.
  6. Protein homeostasis and degradation in quiescent neural stem cells.
  7. A mouse model of Zhu-Tokita-Takenouchi-Kim syndrome reveals indispensable SON functions in organ development and hematopoiesis.
  1. PLoS One. 2024 ;19(1): e0292575
    Age-related changes in the hematopoietic stem cell pool revealed via quantifying the balance of symmetric and asymmetric divisions.
    Teiko Kawahigashi, Shoya Iwanami, Munetomo Takahashi, Joydeep Bhadury, Shingo Iwami, Satoshi Yamazaki.
      Hematopoietic stem cells (HSCs) are somatic stem cells that continuously generate lifelong supply of blood cells through a balance of symmetric and asymmetric divisions. It is well established that the HSC pool increases with age. However, not much is known about the underlying cause for these observed changes. Here, using a novel method combining single-cell ex vivo HSC expansion with mathematical modeling, we quantify HSC division types (stem cell-stem cell (S-S) division, stem cell-progenitor cell (S-P) division, and progenitor cell-progenitor cell (P-P) division) as a function of the aging process. Our time-series experiments reveal how changes in these three modes of division can explain the increase in HSC numbers with age. Contrary to the popular notion that HSCs divide predominantly through S-P divisions, we show that S-S divisions are predominant throughout the lifespan of the animal, thereby expanding the HSC pool. We, therefore, provide a novel mathematical model-based experimental validation for reflecting HSC dynamics in vivo.
    DOI:  https://doi.org/10.1371/journal.pone.0292575
  2. Ann Hematol. 2024 Jan 29.
    Leukemia and mitophagy: a novel perspective for understanding oncogenesis and resistance.
    Yueyao Liu, Zhigui Ma.
      Mitophagy, the selective autophagic process that specifically degrades mitochondria, serves as a vital regulatory mechanism for eliminating damaged mitochondria and maintaining cellular balance. Emerging research underscores the central role of mitophagy in the initiation, advancement, and treatment of cancer. Mitophagy is widely acknowledged to govern mitochondrial homeostasis in hematopoietic stem cells (HSCs), influencing their metabolic dynamics. In this article, we integrate recent data to elucidate the regulatory mechanisms governing mitophagy and its intricate significance in the context of leukemia. An in-depth molecular elucidation of the processes governing mitophagy may serve as a basis for the development of pioneering approaches in targeted therapeutic interventions.
    Keywords:  Autophagy; HSCs; Leukemia; Mitophagy; Resistance; Therapy
    DOI:  https://doi.org/10.1007/s00277-024-05635-w
  3. Blood Adv. 2024 Jan 31. pii: bloodadvances.2023010950. [Epub ahead of print]
    The glutaminase inhibitor CB-839 targets metabolic dependencies of JAK2-mutant hematopoiesis in MPN.
    Marc Usart, Nils Hansen, Jan Stetka, Tiago Almeida Fonseca, Alexandre Guy, Quentin Kimmerlin, Shivam Rai, Hui Hao-Shen, Julien Roux, Stefan Dirnhofer, Radek C Skoda.
      Hyperproliferation of myeloid and erythroid cells in myeloproliferative neoplasms driven by the JAK2-V617F mutation is associated with altered metabolism. Given the central role of glutamine in anabolic and catabolic pathways, we examined the effects of pharmacologically inhibiting glutaminolysis, i.e. the conversion of glutamine (Gln) to glutamate (Glu), using CB-839, a small molecular inhibitor of the enzyme glutaminase (GLS). We show that CB-839 strongly reduced the mitochondrial respiration rate of bone marrow cells from JAK2-V617F mutant (VF) mice, demonstrating a marked dependence of these cells on Gln-derived ATP production. Consistently, in vivo treatment with CB-839 normalized blood glucose levels, reduced splenomegaly and decreased erythrocytosis in VF mice. These effects were more pronounced when CB-839 was combined with the JAK1/2 inhibitor ruxolitinib or the glycolysis inhibitor 3PO, indicating possible synergies when co-targeting different metabolic and oncogenic pathways. Furthermore, we show that the inhibition of glutaminolysis with CB-839 preferentially lowered the proportion of JAK2-mutant hematopoietic stem cells (HSCs). The total number of HSCs was decreased by CB-839, primarily by reducing HSCs in the G1 phase of the cell cycle. CB-839 in combination with ruxolitinib also strongly reduced myelofibrosis at later stages of MPN. In line with the effects shown in mice, proliferation of CD34+ hematopoietic stem and progenitor cells from PV patients was inhibited by CB-839 at nanomolar concentrations. These data suggest that inhibiting glutaminase alone or in combination with inhibitors of glycolysis or JAK2 inhibitors represents an attractive new therapeutic approach to MPN.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010950
  4. Blood Adv. 2024 Jan 31. pii: bloodadvances.2023010972. [Epub ahead of print]
    Autophagy prevents graft failure during murine Graft versus Host Disease.
    Katie E Lineburg, Lucie Leveque-El Mouttie, Christopher R Hunter, Laeitia Le Texier, Crystal McGirr, Bianca Teal, Bruce R Blazar, Steven W Lane, Geoffrey R Hill, Jean-Pierre Levesque, Kelli P A MacDonald.
      Autophagy is an intracellular survival process that has established roles in the long-term survival and function of hematopoietic stem cells (HSC). We investigated the contribution of autophagy to HSC fitness during allogeneic transplantation and GVHD. We demonstrate in vitro that both TNF and IL-1β, major components of GVHD cytokine storm, synergistically promote autophagy in both HSC and their more mature hematopoietic progenitor cells (HPC). In vivo we demonstrate that autophagy is increased in donor HSC and HPC during GVHD. Competitive transplant experiments demonstrated that autophagy deficient cells display reduced capacity to reconstitute the hematopoietic system compared to wild-type counterparts. In an MHC mismatched model of GVHD and associated cytokine dysregulation, we demonstrate that autophagy-deficient HSC and progenitors fail to establish durable hematopoiesis, leading to primary graft failure and universal transplant related mortality. Using several different models, we confirm that autophagy activity is increased in early progenitor and HSC populations in the presence of T cell-derived inflammatory cytokines and that these HSC populations require autophagy to survive. Thus autophagy serves as a key survival mechanism in HSC and progenitor populations after allogeneic SCT and may represent a therapeutic target to prevent graft failure during GVHD.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010972
  5. Sci Adv. 2024 Feb 02. 10(5): eadj9479
    Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis.
    Adam G Maynard, Nancy K Pohl, Annabel P Mueller, Boryana Petrova, Alan Y L Wong, Peng Wang, Andrew J Culhane, Jeannette R Brook, Leah M Hirsch, Ngoc Hoang, Orville Kirkland, Tatum Braun, Sarah Ducamp, Mark D Fleming, Hojun Li, Naama Kanarek.
      Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: megaloblastic anemia. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines and primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis and accumulation of the purine synthesis intermediate and signaling molecule, 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR), followed by enhanced heme metabolism, hemoglobin synthesis, and erythroid differentiation. This is phenocopied by inhibition of folate metabolism using the inhibitor SHIN1, and by AICAR supplementation. Mechanistically, the metabolically driven differentiation is independent of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine 5'-monophosphate-activated protein kinase (AMPK) and is instead mediated by protein kinase C. Our findings suggest that folate deprivation-induced premature differentiation of erythroid progenitor cells is a molecular etiology to folate deficiency-induced anemia.
    DOI:  https://doi.org/10.1126/sciadv.adj9479
  6. J Biochem. 2024 Jan 31. pii: mvae006. [Epub ahead of print]
    Protein homeostasis and degradation in quiescent neural stem cells.
    Taeko Kobayashi.
      Tissue stem cells are maintained in the adult body throughout life and are crucial for tissue homeostasis as they supply newly functional cells. Quiescence is a reversible arrest in the G0/G1 phase of the cell cycle and a strategy to maintain the quality of tissue stem cells. Quiescence maintains stem cells in a self-renewable and differentiable state for a prolonged period by suppressing energy consumption and cell damage and depletion. Most adult neural stem cells in the brain maintain the quiescent state and produce neurons and glial cells through differentiation after activating from the quiescent state to the proliferating state. In this process, proteostasis, including proteolysis, is essential to transition between the quiescent and proliferating states associated with proteome remodeling. Recent reports have demonstrated that quiescent and proliferating neural stem cells have different expression patterns and roles as proteostatic molecules and are affected by age, indicating differing processes for protein homeostasis in these two states in the brain. This review discusses the multiple regulatory stages from protein synthesis (protein birth) to proteolysis (protein death) in quiescent neural stem cells.
    Keywords:  Adult mouse brain; Lysosomes; Neural stem cells; Proteostasis; Quiescence
    DOI:  https://doi.org/10.1093/jb/mvae006
  7. JCI Insight. 2024 Jan 30. pii: e175053. [Epub ahead of print]
    A mouse model of Zhu-Tokita-Takenouchi-Kim syndrome reveals indispensable SON functions in organ development and hematopoiesis.
    Lana Vukadin, Bohye Park, Mostafa Mohamed, Huashi Li, Amr Elkholy, Alex Torrelli-Diljohn, Jung-Hyun Kim, Kyuho Jeong, James M Murphy, Caitlin A Harvey, Sophia Dunlap, Leah Gehrs, Hanna Lee, Hyung-Gyoon Kim, Jay Prakash Sah, Seth N Lee, Denise Stanford, Robert A Barrington, Jeremy B Foote, Anna G Sorace, Robert S Welner, Blake E Hildreth Iii, Ssang-Taek Steve Lim, Eun-Young Erin Ahn.
      Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss-of-function of SON. While ZTTK syndrome patients suffer from numerous symptoms, the lack of model organisms hampers our understanding of SON and this complex syndrome. Here, we developed Son haploinsufficiency (Son+/-) mice as a model of ZTTK syndrome and identified the indispensable roles of Son in organ development and hematopoiesis. Son+/- mice recapitulated clinical symptoms of ZTTK syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis. Furthermore, we identified hematopoietic abnormalities in Son+/- mice, including leukopenia and immunoglobulin deficiency, similar to those observed in human patients. Surface marker analyses and single-cell transcriptome profiling of hematopoietic stem and progenitor cells revealed that Son haploinsufficiency shifts cell fate more toward the myeloid lineage but compromises lymphoid lineage development by reducing genes required for lymphoid and B-cell lineage specification. Additionally, Son haploinsufficiency causes inappropriate activation of erythroid genes and impaired erythropoiesis. These findings highlight the importance of the full gene expression of Son in multiple organs. Our model serves as an invaluable research tool for this rare disease and related disorders associated with SON dysfunction.
    Keywords:  Development; Genetic diseases; Genetics; Molecular genetics; Mouse models
    DOI:  https://doi.org/10.1172/jci.insight.175053
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