bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024‒03‒31
sixteen papers selected by
William Grey, University of York
  1. Making Human Hematopoietic Stem Cells Without Transgenes.
  2. Fetal liver macrophages contribute to the hematopoietic stem cell niche by controlling granulopoiesis.
  3. Yin Yang 1 regulates cohesin complex protein SMC3 in mouse hematopoietic stem cells.
  4. Generating human bone marrow organoids for disease modeling and drug discovery.
  5. Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity.
  6. Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress.
  7. Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species.
  8. Spatially Segregated Macrophage Populations Predict Distinct Outcomes In Colon Cancer.
  9. Recent Advances in Signaling Pathways and Kinase Inhibitors for Leukemia Chemotherapy.
  10. Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair.
  11. Myeloperoxidase inhibition protects bone marrow mononuclear cells from DNA damage induced by the TOP2 poison anti-cancer drug etoposide.
  12. The GTPase activating protein Gyp7 regulates Rab7/Ypt7 activity on late endosomes.
  13. OMA1 protease eliminates arrested protein import intermediates upon mitochondrial depolarization.
  14. Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.
  15. S-nitrosylation-triggered unfolded protein response maintains hematopoietic progenitors in Drosophila.
  16. Macrophage migration inhibitory factor blockade reprograms macrophages and disrupts prosurvival signaling in acute myeloid leukemia.
  1. Cell Reprogram. 2024 Mar 26.
    Making Human Hematopoietic Stem Cells Without Transgenes.
    Luis G Palma, Anna Bigas.
      Creating hematopoietic stem cells (HSCs) capable of multilineage engraft while possessing the ability to self-renew stands as a pivotal achievement within the field of regenerative medicine. However, achieving the generation of these cells without transgene expression or teratoma formation has not been fully accomplished. In a recent publication featured in Cell Stem Cell, Piau et al. document the production of functional HSCs derived from human-induced pluripotent stem cells (hiPSCs). They achieved this through a one-step differentiation protocol that notably does not require any transgene expression. hiPSCs-derived HSCs can engraft and self-renew upon serial transplantation and they are able to reconstitute lymphoid, myeloid, and erythroid compartments. This study presents a promising system to further study human HSC ontogeny, and it might represent a crucial step to obtain HSCs.
    Keywords:  directed differentiation; hematopoietic stem cells; iPSCs
    DOI:  https://doi.org/10.1089/cell.2024.0020
  2. Elife. 2024 Mar 25. pii: e86493. [Epub ahead of print]13
    Fetal liver macrophages contribute to the hematopoietic stem cell niche by controlling granulopoiesis.
    Amir Hossein Kayvanjoo, Iva Splichalova, David Alejandro Bejarano, Hao Huang, Katharina Mauel, Nikola Makdissi, David Heider, Hui Ming Tew, Nora Reka Balzer, Eric Greto, Collins Osei-Sarpong, Kevin Baßler, Joachim L Schultze, Stefan Uderhardt, Eva Kiermaier, Marc Beyer, Andreas Schlitzer, Elvira Mass.
      During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.
    Keywords:  developmental biology; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.86493
  3. Blood Adv. 2024 Mar 26. pii: bloodadvances.2023011411. [Epub ahead of print]
    Yin Yang 1 regulates cohesin complex protein SMC3 in mouse hematopoietic stem cells.
    Zhanping Lu, Yinghua Wang, Anna L F V Assumpção, Peng Liu, Audrey Kopp, Sahitya Saka, Sean J Mcilwain, Aaron D Viny, Marjorie Brand, Xuan Pan.
      Yin Yang 1 (YY1) and Structural Maintenance of Chromosomes 3 (SMC3) are two critical chromatin structural factors that mediate long-distance enhancer-promoter interactions and promote developmentally regulated changes in chromatin architecture in hematopoietic stem/progenitor cells (HSPCs). While YY1 plays critical functions in promoting hematopoietic stem cell (HSC) self-renewal and maintaining HSC quiescence, SMC3 is required for proper myeloid lineage differentiation. However, many questions remain unanswered regarding how YY1 and SMC3 interact with each other and impact hematopoiesis. We found that YY1 physically interacts with SMC3 and co-occupies with SMC3 at a large cohort of promoters genome-wide, and YY1 deficiency deregulates the genetic network governing cell metabolism. YY1 occupies the Smc3 promoter and represses SMC3 expression in HSPCs. While deletion of one Smc3 allele partially restores HSC numbers and quiescence in YY1 knockout mice, Yy1-/- Smc3+/- HSCs fail to reconstitute blood after bone marrow transplant. YY1 regulates HSC metabolic pathways and maintains proper intracellular reactive oxygen species levels in HSCs, and this regulation is independent of YY1- SMC3 axis. Our results establish a distinct YY1-SMC3 axis and its impact on HSC quiescence and metabolism.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011411
  4. Nat Protoc. 2024 Mar 26.
    Generating human bone marrow organoids for disease modeling and drug discovery.
    Aude-Anais Olijnik, Antonio Rodriguez-Romera, Zoë C Wong, Yuqi Shen, Jasmeet S Reyat, Natalie J Jooss, Julie Rayes, Bethan Psaila, Abdullah O Khan.
      The bone marrow supports and regulates hematopoiesis, responding to physiological requirements for blood cell production over ontogeny and during pathological challenges. Interactions between hematopoietic cells and niche components are challenging to study mechanistically in the human context, but are important to delineate in order to explore the pathobiology of blood and bone marrow disorders. Organoids are proving transformative in many research settings, but an accurate human bone marrow model incorporating multiple hematopoietic and stromal elements has been lacking. This protocol describes a method to generate three-dimensional, multilineage bone marrow organoids from human induced pluripotent stem cells (hiPSCs), detailing the steps for the directed differentiation of hiPSCs using a series of cytokine cocktails and hydrogel embedding. Over 18 days of differentiation, hiPSCs yield the key lineages that are present in central myelopoietic bone marrow, organized in a well-vascularized architecture that resembles native hematopoietic tissues. This presents a robust, in vitro system that can model healthy and perturbed hematopoiesis in a scalable three-dimensional microenvironment. Bone marrow organoids also support the growth of immortalized cell lines and primary cells from healthy donors and patients with myeloid and lymphoid cancers, including cell types that are poorly viable in standard culture systems. Moreover, we discuss assays for the characterization of organoids, including interrogation of pathogenic remodeling using recombinant TGF-ß treatment, and methods for organoid engraftment with exogenous cells. This protocol can be readily adapted to specific experimental requirements, can be easily implemented by users with tissue culture experience and does not require access to specialist equipment.
    DOI:  https://doi.org/10.1038/s41596-024-00971-7
  5. Nature. 2024 Mar 27.
    Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity.
    Jason B Ross, Lara M Myers, Joseph J Noh, Madison M Collins, Aaron B Carmody, Ronald J Messer, Erica Dhuey, Kim J Hasenkrug, Irving L Weissman.
      Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies1,2. Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena3. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune responses, while limiting the production of myeloid cells, which can be pro-inflammatory4. Ageing is associated with increased proportions of my-HSCs, resulting in decreased lymphopoiesis and increased myelopoiesis3,5,6. Transfer of bal-HSCs results in abundant lymphoid and myeloid cells, a stable phenotype that is retained after secondary transfer; my-HSCs also retain their patterns of production after secondary transfer5. The origin and potential interconversion of these two subsets is still unclear. If they are separate subsets postnatally, it might be possible to reverse the ageing phenotype by eliminating my-HSCs in aged mice. Here we demonstrate that antibody-mediated depletion of my-HSCs in aged mice restores characteristic features of a more youthful immune system, including increasing common lymphocyte progenitors, naive T cells and B cells, while decreasing age-related markers of immune decline. Depletion of my-HSCs in aged mice improves primary and secondary adaptive immune responses to viral infection. These findings may have relevance to the understanding and intervention of diseases exacerbated or caused by dominance of the haematopoietic system by my-HSCs.
    DOI:  https://doi.org/10.1038/s41586-024-07238-x
  6. Cell Rep. 2024 Mar 28. pii: S2211-1247(24)00346-2. [Epub ahead of print]43(4): 114018
    Distinct types of intramitochondrial protein aggregates protect mitochondria against proteotoxic stress.
    Lea Bertgen, Jan-Eric Bökenkamp, Tim Schneckmann, Christian Koch, Markus Räschle, Zuzana Storchová, Johannes M Herrmann.
      Mitochondria consist of hundreds of proteins, most of which are inaccessible to the proteasomal quality control system of the cytosol. How cells stabilize the mitochondrial proteome during challenging conditions remains poorly understood. Here, we show that mitochondria form spatially defined protein aggregates as a stress-protecting mechanism. Two different types of intramitochondrial protein aggregates can be distinguished. The mitoribosomal protein Var1 (uS3m) undergoes a stress-induced transition from a soluble, chaperone-stabilized protein that is prevalent under benign conditions to an insoluble, aggregated form upon acute stress. The formation of Var1 bodies stabilizes mitochondrial proteostasis, presumably by sequestration of aggregation-prone proteins. The AAA chaperone Hsp78 is part of a second type of intramitochondrial aggregate that transiently sequesters proteins and promotes their folding or Pim1-mediated degradation. Thus, mitochondrial proteins actively control the formation of distinct types of intramitochondrial protein aggregates, which cooperate to stabilize the mitochondrial proteome during proteotoxic stress conditions.
    Keywords:  CP: Cell biology; CP: Molecular biology; Hsp78; MitoStores; Pim1 protease; Var1 bodies; aggregates; chaperones; mitochondria; mitoribosome; protein folding; protein import
    DOI:  https://doi.org/10.1016/j.celrep.2024.114018
  7. Cell Death Differ. 2024 Mar 22.
    Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species.
    Shun-Ichi Yamashita, Yuki Sugiura, Yuta Matsuoka, Rae Maeda, Keiichi Inoue, Kentaro Furukawa, Tomoyuki Fukuda, David C Chan, Tomotake Kanki.
      Mitophagy plays an important role in the maintenance of mitochondrial homeostasis and can be categorized into two types: ubiquitin-mediated and receptor-mediated pathways. During receptor-mediated mitophagy, mitophagy receptors facilitate mitophagy by tethering the isolation membrane to mitochondria. Although at least five outer mitochondrial membrane proteins have been identified as mitophagy receptors, their individual contribution and interrelationship remain unclear. Here, we show that HeLa cells lacking BNIP3 and NIX, two of the five receptors, exhibit a complete loss of mitophagy in various conditions. Conversely, cells deficient in the other three receptors show normal mitophagy. Using BNIP3/NIX double knockout (DKO) cells as a model, we reveal that mitophagy deficiency elevates mitochondrial reactive oxygen species (mtROS), which leads to activation of the Nrf2 antioxidant pathway. Notably, BNIP3/NIX DKO cells are highly sensitive to ferroptosis when Nrf2-driven antioxidant enzymes are compromised. Moreover, the sensitivity of BNIP3/NIX DKO cells is fully rescued upon the introduction of wild-type BNIP3 and NIX, but not the mutant forms incapable of facilitating mitophagy. Consequently, our results demonstrate that BNIP3 and NIX-mediated mitophagy plays a role in regulating mtROS levels and protects cells from ferroptosis.
    DOI:  https://doi.org/10.1038/s41418-024-01280-y
  8. Cancer Discov. 2024 Mar 28.
    Spatially Segregated Macrophage Populations Predict Distinct Outcomes In Colon Cancer.
    Magdalena Matusiak, John W Hickey, David G P van IJzendoorn, Guolan Lu, Lukasz Kidzinski, Shirley Zhu, Deana R C Colburg, Bogdan Luca, Darci J Phillips, Sky W Brubaker, Gregory W Charville, Jeanne Shen, Kyle M Loh, Derick K Okwan-Duodu, Garry P Nolan, Aaron M Newman, Robert B West, Matt van de Rijn.
      Tumor-associated macrophages are transcriptionally heterogeneous, but the spatial distribution and cell interactions that shape macrophage tissue roles remain poorly characterized. Here, we spatially resolve five distinct human macrophage populations in normal and malignant human breast and colon tissue and reveal their cellular associations. This spatial map reveals that distinct macrophage populations reside in spatially segregated micro-environmental niches with conserved cellular compositions that are repeated across healthy and diseased tissue. We show that IL4I1+ macrophages phagocytose dying cells in areas with high cell turnover and predict good outcome in colon cancer. In contrast, SPP1+ macrophages are enriched in hypoxic and necrotic tumor regions and portend worse outcome in colon cancer. A subset of FOLR2+ macrophages is embedded in plasma cell niches. NLRP3+ macrophages co-localize with neutrophils and activate an inflammasome in tumors. Our findings indicate that a limited number of unique human macrophage niches function as fundamental building blocks in tissue.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1300
  9. Curr Med Chem. 2024 Feb 16.
    Recent Advances in Signaling Pathways and Kinase Inhibitors for Leukemia Chemotherapy.
    Yuying Liu, Zeyu Yang, Qingqing Zhang, Ping Hai, Yongbiao Zheng, Jie Zhang, Xiaoyan Pan.
      Leukemia is a malignant clonal disease of hematopoietic stem cells, which accounts for about 3% of the total incidence of tumors and is particularly prevalent among children and adolescents. It mainly includes four types of leukemia, namely ALL, AML, CLL, and CML, which are often aggressive and challenging diseases to treat. Several signaling pathways are dysregulated in almost all types of leukemia, such as JAK, PI3K, and MAPK, and others are dysregulated in specific types of leukemia, like Wnt/β-catenin, Hedgehog, FLT3, Bcr-Abl, and so on. Many efforts have been devoted to developing small molecule inhibitors targeting protein kinases involved in leukemia-related signaling pathways. In this review, we focus on the study of signaling pathways and protein kinases that developed as targets of anti-leukemia drug therapy and report the research progress of relevant small molecule kinase inhibitors over the last five years.
    Keywords:  inhibitors; leukemia; protein kinase; signal pathway
    DOI:  https://doi.org/10.2174/0109298673267738231129104216
  10. Nat Commun. 2024 Mar 23. 15(1): 2625
    Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair.
    Juan A Perez-Bermejo, Oghene Efagene, William M Matern, Jeffrey K Holden, Shaheen Kabir, Glen M Chew, Gaia Andreoletti, Eniola Catton, Craig L Ennis, Angelica Garcia, Trevor L Gerstenberg, Kaisle A Hill, Aayami Jain, Kristina Krassovsky, Cassandra D Lalisan, Daniel Lord, B Joy Quejarro, Jade Sales-Lee, Meet Shah, Brian J Silva, Jason Skowronski, Yuri G Strukov, Joshua Thomas, Michael Veraz, Twaritha Vijay, Kirby A Wallace, Yue Yuan, Jane L Grogan, Beeke Wienert, Premanjali Lahiri, Sebastian Treusch, Daniel P Dever, Vanessa B Soros, James R Partridge, Kristen L Seim.
      Homology Directed Repair (HDR) enables precise genome editing, but the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes, such as Non-Homologous End Joining (NHEJ). In this study, we develop a functional, pooled screening platform to identify protein-based reagents that improve HDR in human hematopoietic stem and progenitor cells (HSPCs). We leverage this screening platform to explore sequence diversity at the binding interface of the NHEJ inhibitor i53 and its target, 53BP1, identifying optimized variants that enable new intermolecular bonds and robustly increase HDR. We show that these variants specifically reduce insertion-deletion outcomes without increasing off-target editing, synergize with a DNAPK inhibitor molecule, and can be applied at manufacturing scale to increase the fraction of cells bearing repaired alleles. This screening platform can enable the discovery of future gene editing reagents that improve HDR outcomes.
    DOI:  https://doi.org/10.1038/s41467-024-46816-5
  11. FEBS Open Bio. 2024 Mar 26.
    Myeloperoxidase inhibition protects bone marrow mononuclear cells from DNA damage induced by the TOP2 poison anti-cancer drug etoposide.
    Ian G Cowell, Caroline A Austin.
      Myeloperoxidase (MPO) is found almost exclusively in granulocytes and immature myeloid cells. It plays a key role in the innate immune system, catalysing the formation of reactive oxygen species that are important in anti-microbial action, but MPO also oxidatively transforms the topoisomerase II (TOP2) poison etoposide to chemical forms that have elevated DNA damaging properties. TOP2 poisons such as etoposide are widely used anti-cancer drugs, but they are linked to cases of secondary acute myeloid leukaemias through a mechanism that involves DNA damage and presumably erroneous repair leading to leukaemogenic chromosome translocations. This leads to the possibility that myeloperoxidase inhibitors could reduce the rate of therapy-related leukaemia by protecting haematopoietic cells from TOP2 poison-mediated genotoxic damage while preserving the anti-cancer efficacy of the treatment. We show here that myeloperoxidase inhibition reduces etoposide-induced TOP2B-DNA covalent complexes and resulting DNA double-strand break formation in primary ex vivo expanded CD34+ progenitor cells and unfractionated bone marrow mononuclear cells. Since MPO inhibitors are currently being developed as anti-inflammatory agents this raises the possibility that repurposing of these potential new drugs could provide a means of suppressing secondary acute myeloid leukaemias associated with therapies containing TOP2 poisons.
    Keywords:  DNA damage; TOP2; etoposide; myeloperoxidase; myelotoxicity; topoisomerase
    DOI:  https://doi.org/10.1002/2211-5463.13799
  12. J Cell Biol. 2024 Jun 03. pii: e202305038. [Epub ahead of print]223(6):
    The GTPase activating protein Gyp7 regulates Rab7/Ypt7 activity on late endosomes.
    Nadia Füllbrunn, Raffaele Nicastro, Muriel Mari, Janice Griffith, Eric Herrmann, René Rasche, Ann-Christin Borchers, Kathrin Auffarth, Daniel Kümmel, Fulvio Reggiori, Claudio De Virgilio, Lars Langemeyer, Christian Ungermann.
      Organelles of the endomembrane system contain Rab GTPases as identity markers. Their localization is determined by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). It remains largely unclear how these regulators are specifically targeted to organelles and how their activity is regulated. Here, we focus on the GAP Gyp7, which acts on the Rab7-like Ypt7 protein in yeast, and surprisingly observe the protein exclusively in puncta proximal to the vacuole. Mistargeting of Gyp7 to the vacuole strongly affects vacuole morphology, suggesting that endosomal localization is needed for function. In agreement, efficient endolysosomal transport requires Gyp7. In vitro assays reveal that Gyp7 requires a distinct lipid environment for membrane binding and activity. Overexpression of Gyp7 concentrates Ypt7 in late endosomes and results in resistance to rapamycin, an inhibitor of the target of rapamycin complex 1 (TORC1), suggesting that these late endosomes are signaling endosomes. We postulate that Gyp7 is part of regulatory machinery involved in late endosome function.
    DOI:  https://doi.org/10.1083/jcb.202305038
  13. J Cell Biol. 2024 May 06. pii: e202306051. [Epub ahead of print]223(5):
    OMA1 protease eliminates arrested protein import intermediates upon mitochondrial depolarization.
    Magda Krakowczyk, Anna M Lenkiewicz, Tomasz Sitarz, Dominika Malinska, Mayra Borrero, Ben Hur Marins Mussulini, Vanessa Linke, Andrzej A Szczepankiewicz, Joanna M Biazik, Agata Wydrych, Hanna Nieznanska, Remigiusz A Serwa, Agnieszka Chacinska, Piotr Bragoszewski.
      Most mitochondrial proteins originate from the cytosol and require transport into the organelle. Such precursor proteins must be unfolded to pass through translocation channels in mitochondrial membranes. Misfolding of transported proteins can result in their arrest and translocation failure. Arrested proteins block further import, disturbing mitochondrial functions and cellular proteostasis. Cellular responses to translocation failure have been defined in yeast. We developed the cell line-based translocase clogging model to discover molecular mechanisms that resolve failed import events in humans. The mechanism we uncover differs significantly from these described in fungi, where ATPase-driven extraction of blocked protein is directly coupled with proteasomal processing. We found human cells to rely primarily on mitochondrial factors to clear translocation channel blockage. The mitochondrial membrane depolarization triggered proteolytic cleavage of the stalled protein, which involved mitochondrial protease OMA1. The cleavage allowed releasing the protein fragment that blocked the translocase. The released fragment was further cleared in the cytosol by VCP/p97 and the proteasome.
    DOI:  https://doi.org/10.1083/jcb.202306051
  14. Mol Biol Cell. 2024 Mar 27. mbcE24010041
    Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.
    Nicole Madrazo, Zinia Khattar, Evan T Powers, Jessica D Rosarda, R Luke Wiseman.
      Imbalances in mitochondrial proteostasis are associated with pathologic mitochondrial dysfunction implicated in etiologically-diverse diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria in response to mitochondrial stress. Numerous stress-responsive signaling pathways have been suggested to regulate mitochondria in response to proteotoxic stress. These include the integrated stress response (ISR), the heat shock response (HSR), and the oxidative stress response (OSR). Here, we define the stress signaling pathways activated in response to chronic mitochondrial proteostasis perturbations by monitoring the expression of sets of genes regulated downstream of each of these signaling pathways in published Perturb-seq datasets from K562 cells CRISPRi-depleted of mitochondrial proteostasis factors. Interestingly, we find that the ISR is preferentially activated in response to chronic, genetically-induced mitochondrial proteostasis stress, with no other pathway showing significant activation. Further, we demonstrate that CRISPRi depletion of other mitochondria-localized proteins similarly shows preferential activation of the ISR relative to other stress-responsive signaling pathways. These results both establish our gene set profiling approach as a viable strategy to probe stress responsive signaling pathways induced by perturbations to specific organelles and identify the ISR as the predominant stress-responsive signaling pathway activated in response to chronically disrupted of mitochondrial proteostasis.
    DOI:  https://doi.org/10.1091/mbc.E24-01-0041
  15. Dev Cell. 2024 Mar 19. pii: S1534-5807(24)00145-X. [Epub ahead of print]
    S-nitrosylation-triggered unfolded protein response maintains hematopoietic progenitors in Drosophila.
    Bumsik Cho, Mingyu Shin, Eunji Chang, Seogho Son, Incheol Shin, Jiwon Shim.
      The Drosophila lymph gland houses blood progenitors that give rise to myeloid-like blood cells. Initially, blood progenitors proliferate, but later, they become quiescent to maintain multipotency before differentiation. Despite the identification of various factors involved in multipotency maintenance, the cellular mechanism controlling blood progenitor quiescence remains elusive. Here, we identify the expression of nitric oxide synthase in blood progenitors, generating nitric oxide for post-translational S-nitrosylation of protein cysteine residues. S-nitrosylation activates the Ire1-Xbp1-mediated unfolded protein response, leading to G2 cell-cycle arrest. Specifically, we identify the epidermal growth factor receptor as a target of S-nitrosylation, resulting in its retention within the endoplasmic reticulum and blockade of its receptor function. Overall, our findings highlight developmentally programmed S-nitrosylation as a critical mechanism that induces protein quality control in blood progenitors, maintaining their undifferentiated state by inhibiting cell-cycle progression and rendering them unresponsive to paracrine factors.
    Keywords:  Drosophila; EGFR; Ire1/Xbp1; S-nitrosylation; blood progenitor; hematopoiesis; hemocyte; lymph gland; nitric oxide; unfolded protein response
    DOI:  https://doi.org/10.1016/j.devcel.2024.02.013
  16. Cell Death Discov. 2024 Mar 28. 10(1): 157
    Macrophage migration inhibitory factor blockade reprograms macrophages and disrupts prosurvival signaling in acute myeloid leukemia.
    Caroline Spertini, Alexandre P Bénéchet, Flora Birch, Axel Bellotti, Mónica Román-Trufero, Caroline Arber, Holger W Auner, Robert A Mitchell, Olivier Spertini, Tatiana Smirnova.
      The malignant microenvironment plays a major role in the development of resistance to therapies and the occurrence of relapses in acute myeloid leukemia (AML). We previously showed that interactions of AML blasts with bone marrow macrophages (MΦ) shift their polarization towards a protumoral (M2-like) phenotype, promoting drug resistance; we demonstrated that inhibiting the colony-stimulating factor-1 receptor (CSF1R) repolarizes MΦ towards an antitumoral (M1-like) phenotype and that other factors may be involved. We investigated here macrophage migration inhibitory factor (MIF) as a target in AML blast survival and protumoral interactions with MΦ. We show that pharmacologically inhibiting MIF secreted by AML blasts results in their apoptosis. However, this effect is abrogated when blasts are co-cultured in close contact with M2-like MΦ. We next demonstrate that pharmacological inhibition of MIF secreted by MΦ, in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF), efficiently reprograms MΦ to an M1-like phenotype that triggers apoptosis of interacting blasts. Furthermore, contact with reprogrammed MΦ relieves blast resistance to venetoclax and midostaurin acquired in contact with CD163+ protumoral MΦ. Using intravital imaging in mice, we also show that treatment with MIF inhibitor 4-IPP and GM-CSF profoundly affects the tumor microenvironment in vivo: it strikingly inhibits tumor vasculature, reduces protumoral MΦ, and slows down leukemia progression. Thus, our data demonstrate that MIF plays a crucial role in AML MΦ M2-like protumoral phenotype that can be reversed by inhibiting its activity and suggest the therapeutic targeting of MIF as an avenue towards improved AML treatment outcomes.
    DOI:  https://doi.org/10.1038/s41420-024-01924-5
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