bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2024‒03‒03
fifteen papers selected by
William Grey, University of York
  1. Ferritin-mediated mitochondrial iron homeostasis is essential for the survival of hematopoietic stem cells and leukemic stem cells.
  2. Deregulated protein homeostasis constrains fetal hematopoietic stem cell pool expansion in Fanconi anemia.
  3. How CBX proteins regulate normal and leukemic blood cells.
  4. Metformin reduces the clonal fitness of Dnmt3aR878H hematopoietic stem and progenitor cells by reversing their aberrant metabolic and epigenetic state.
  5. circFAM193B interaction with PRMT6 regulates AML leukemia stem cells chemoresistance through altering the oxidative metabolism and lipid peroxidation.
  6. Maintenance of proteostasis by Drosophila Rer1 is essential for competitive cell survival and Myc-driven overgrowth.
  7. CD38 promotes hematopoietic stem cell dormancy.
  8. Near-infrared dye IR-780 alleviates hematopoietic system damage by promoting hematopoietic stem cells into quiescence.
  9. Bidirectional substrate shuttling between the 26S proteasome and the Cdc48 ATPase promotes protein degradation.
  10. N-MYC regulates cell survival via eIF4G1 in inv(16) acute myeloid leukemia.
  11. An iron rheostat controls hematopoietic stem cell fate.
  12. Spatial Mapping of Hematopoietic Clones in Human Bone Marrow.
  13. MarShie: a clearing protocol for 3D analysis of single cells throughout the bone marrow at subcellular resolution.
  14. Subunits of an E3 Ligase Complex as Degrons for Efficient Degradation of Cytosolic, Nuclear, and Membrane Proteins.
  15. Macrophage depletion damages hematopoiesis partially through inhibition of cell homing and expansion after hematopoietic cell transplantation.
  1. Leukemia. 2024 Feb 24.
    Ferritin-mediated mitochondrial iron homeostasis is essential for the survival of hematopoietic stem cells and leukemic stem cells.
    Weiwei Yi, Jinhua Zhang, Yingxin Huang, Qiang Zhan, Mi Zou, Xiang Cheng, Xuguang Zhang, Zhinan Yin, Si Tao, Hui Cheng, Fudi Wang, Jun Guo, Zhenyu Ju, Zhiyang Chen.
      Iron metabolism plays a crucial role in cell viability, but its relationship with adult stem cells and cancer stem cells is not fully understood. The ferritin complex, responsible for intracellular iron storage, is important in this process. We report that conditional deletion of ferritin heavy chain 1 (Fth1) in the hematopoietic system reduced the number and repopulation capacity of hematopoietic stem cells (HSCs). These effects were associated with a decrease in cellular iron level, leading to impaired mitochondrial function and the initiation of apoptosis. Iron supplementation, antioxidant, and apoptosis inhibitors reversed the reduced cell viability of Fth1-deleted hematopoietic stem and progenitor cells (HSPCs). Importantly, leukemic stem cells (LSCs) derived from MLL-AF9-induced acute myeloid leukemia (AML) mice exhibited reduced Fth1 expression, rendering them more susceptible to apoptosis induced by the iron chelation compared to normal HSPCs. Modulating FTH1 expression using mono-methyl fumarate increased LSCs resistance to iron chelator-induced apoptosis. Additionally, iron supplementation, antioxidant, and apoptosis inhibitors protected LSCs from iron chelator-induced cell death. Fth1 deletion also extended the survival of AML mice. These findings unveil a novel mechanism by which ferritin-mediated iron homeostasis regulates the survival of both HSCs and LSCs, suggesting potential therapeutic strategies for blood cancer with iron dysregulation.
    DOI:  https://doi.org/10.1038/s41375-024-02169-y
  2. Nat Commun. 2024 Feb 29. 15(1): 1852
    Deregulated protein homeostasis constrains fetal hematopoietic stem cell pool expansion in Fanconi anemia.
    Narasaiah Kovuru, Makiko Mochizuki-Kashio, Theresa Menna, Greer Jeffrey, Yuning Hong, Young Me Yoon, Zhe Zhang, Peter Kurre.
      Demand-adjusted and cell type specific rates of protein synthesis represent an important safeguard for fate and function of long-term hematopoietic stem cells. Here, we identify increased protein synthesis rates in the fetal hematopoietic stem cell pool at the onset of hematopoietic failure in Fanconi Anemia, a prototypical DNA repair disorder that manifests with bone marrow failure. Mechanistically, the accumulation of misfolded proteins in Fancd2-/- fetal liver hematopoietic stem cells converges on endoplasmic reticulum stress, which in turn constrains midgestational expansion. Restoration of protein folding by the chemical chaperone tauroursodeoxycholic acid, a hydrophilic bile salt, prevents accumulation of unfolded proteins and rescues Fancd2-/- fetal liver long-term hematopoietic stem cell numbers. We find that proteostasis deregulation itself is driven by excess sterile inflammatory activity in hematopoietic and stromal cells within the fetal liver, and dampened Type I interferon signaling similarly restores fetal Fancd2-/- long-term hematopoietic stem cells to wild type-equivalent numbers. Our study reveals the origin and pathophysiological trigger that gives rise to Fanconi anemia hematopoietic stem cell pool deficits. More broadly, we show that fetal protein homeostasis serves as a physiological rheostat for hematopoietic stem cell fate and function.
    DOI:  https://doi.org/10.1038/s41467-024-46159-1
  3. FEBS Lett. 2024 Mar 01.
    How CBX proteins regulate normal and leukemic blood cells.
    Anne P de Groot, Gerald de Haan.
      Hematopoietic stem cell (HSC) fate decisions are dictated by epigenetic landscapes. The Polycomb Repressive Complex 1 (PRC1) represses genes that induce differentiation, thereby maintaining HSC self-renewal. Depending on which chromobox (CBX) protein (CBX2, CBX4, CBX6, CBX7, or CBX8) is part of the PRC1 complex, HSC fate decisions differ. Here, we review how this occurs. We describe how CBX proteins dictate age-related changes in HSCs and stimulate oncogenic HSC fate decisions, either as canonical PRC1 members or by alternative interactions, including non-epigenetic regulation. CBX2, CBX7, and CBX8 enhance leukemia progression. To target, reprogram, and kill leukemic cells, we suggest and describe multiple therapeutic strategies to interfere with the epigenetic functions of oncogenic CBX proteins. Future studies should clarify to what extent the non-epigenetic function of cytoplasmic CBX proteins is important for normal, aged, and leukemic blood cells.
    Keywords:  CBX; HSC; PRC1; Polycomb; aging; epigenetics; hematopoiesis; leukemia; subcellular CBX localization
    DOI:  https://doi.org/10.1002/1873-3468.14839
  4. Res Sq. 2024 Feb 06. pii: rs.3.rs-3874821. [Epub ahead of print]
    Metformin reduces the clonal fitness of Dnmt3aR878H hematopoietic stem and progenitor cells by reversing their aberrant metabolic and epigenetic state.
    Steven Chan, Mohsen Hosseini, Veronique Voisin, Ali Chegini, Angelica Varesi, Severine Cathelin, Dhanoop Manikoth Ayyathan, Alex Liu, Yitong Yang, Vivian Wang, Abdula Maher, Eric Grignano, Julie Haines, Angelo D'Alessandro, Kira Young, Yiyan Wu, Martina Fiumara, Samuele Ferrari, Luigi Naldini, Federico Gaiti, Shraddha Pai, Aaron Schimmer, Gary Bader, John Dick, Stephanie Z Xie, Jennifer Trowbridge.
      Clonal hematopoiesis (CH) arises when a hematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type (WT) HSCs, resulting in its clonal expansion. Individuals with CH are at an increased risk of developing hematologic neoplasms and a range of age-related inflammatory illnesses1-3. Therapeutic interventions that suppress the expansion of mutant HSCs have the potential to prevent these CH-related illnesses; however, such interventions have not yet been identified. The most common CH driver mutations are in the DNA methyltransferase 3 alpha (DNMT3A) gene with arginine 882 (R882) being a mutation hotspot. Here we show that murine hematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, which is equivalent to human DNMT3AR882H/+, have increased mitochondrial respiration compared with WT cells and are dependent on this metabolic reprogramming for their competitive advantage. Importantly, treatment with metformin, an oral anti-diabetic drug with inhibitory activity against complex I in the electron transport chain (ETC), reduced the fitness of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we discovered that metformin acts by enhancing the methylation potential in Dnmt3aR878H/+ HSPCs and reversing their aberrant DNA CpG methylation and histone H3K27 trimethylation (H3K27me3) profiles. Metformin also reduced the fitness of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against illnesses associated with DNMT3AR882 mutation-driven CH in humans.
    DOI:  https://doi.org/10.21203/rs.3.rs-3874821/v1
  5. Leukemia. 2024 Feb 29.
    circFAM193B interaction with PRMT6 regulates AML leukemia stem cells chemoresistance through altering the oxidative metabolism and lipid peroxidation.
    Xinyu Yang, Jinting Liu, Wancheng Liu, Hanyang Wu, Yihong Wei, Xiaodong Guo, Hexiao Jia, Can Can, Dongmei Wang, Xiang Hu, Daoxin Ma.
      Most forms of chemotherapy for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), as their underlying mechanisms remain unclear. Here, we have identified circFAM193B, which regulates the redox biology of LSCs and is associated with unfavorable outcomes in AML patients. In vitro and in vivo assays suggested that circFAM193B significantly inhibits LSCs chemotherapy resistance and AML progression. Knockdown circFAM193B enhances mitochondrial OXPHOS function and inhibits the accumulation of reactive oxygen species and lipid peroxidation mediated by chemotherapy, which protects AML cells from oxidative stress-induced cell death. Mechanistically, circFAM193B physically interacts with arginine methyltransferase PRMT6 catalytic domain and enhances the transcription efficiency of key lipid peroxidation factor ALOX15 by decreasing H3R2me2a modification. In summary, we have identified circFAM193B was downregulated in LSCs to promote the survival of LSC by modulating energy metabolism and the redox balance in the postchemotherapy persistence of LSC. Our studies provide a conceptual advance and biological insights regarding the drug resistance of LSCs via circRNA mediated PRMT6-deposited methylarginine signaling.
    DOI:  https://doi.org/10.1038/s41375-024-02189-8
  6. PLoS Genet. 2024 Feb 26. 20(2): e1011171
    Maintenance of proteostasis by Drosophila Rer1 is essential for competitive cell survival and Myc-driven overgrowth.
    Pranab Kumar Paul, Shruti Umarvaish, Shivani Bajaj, Rishana Farin S, Hrudya Mohan, Wim Annaert, Varun Chaudhary.
      Defects in protein homeostasis can induce proteotoxic stress, affecting cellular fitness and, consequently, overall tissue health. In various growing tissues, cell competition based mechanisms facilitate detection and elimination of these compromised, often referred to as 'loser', cells by the healthier neighbors. The precise connection between proteotoxic stress and competitive cell survival remains largely elusive. Here, we reveal the function of an endoplasmic reticulum (ER) and Golgi localized protein Rer1 in the regulation of protein homeostasis in the developing Drosophila wing epithelium. Our results show that loss of Rer1 leads to proteotoxic stress and PERK-mediated phosphorylation of eukaryotic initiation factor 2α. Clonal analysis showed that rer1 mutant cells are identified as losers and eliminated through cell competition. Interestingly, we find that Rer1 levels are upregulated upon Myc-overexpression that causes overgrowth, albeit under high proteotoxic stress. Our results suggest that increased levels of Rer1 provide cytoprotection to Myc-overexpressing cells by alleviating the proteotoxic stress and thereby supporting Myc-driven overgrowth. In summary, these observations demonstrate that Rer1 acts as a novel regulator of proteostasis in Drosophila and reveal its role in competitive cell survival.
    DOI:  https://doi.org/10.1371/journal.pgen.1011171
  7. PLoS Biol. 2024 Feb 29. 22(2): e3002517
    CD38 promotes hematopoietic stem cell dormancy.
    Liliia Ibneeva, Sumeet Pal Singh, Anupam Sinha, Sema Elif Eski, Rebekka Wehner, Luise Rupp, Iryna Kovtun, Juan Alberto Pérez-Valencia, Alexander Gerbaulet, Susanne Reinhardt, Manja Wobus, Malte von Bonin, Jaime Sancho, Frances Lund, Andreas Dahl, Marc Schmitz, Martin Bornhäuser, Triantafyllos Chavakis, Ben Wielockx, Tatyana Grinenko.
      A subpopulation of deeply quiescent, so-called dormant hematopoietic stem cells (dHSCs) resides at the top of the hematopoietic hierarchy and serves as a reserve pool for HSCs. The state of dormancy protects the HSC pool from exhaustion throughout life; however, excessive dormancy may prevent an efficient response to hematological stresses. Despite the significance of dHSCs, the mechanisms maintaining their dormancy remain elusive. Here, we identify CD38 as a novel and broadly applicable surface marker for the enrichment of murine dHSCs. We demonstrate that cyclic adenosine diphosphate ribose (cADPR), the product of CD38 cyclase activity, regulates the expression of the transcription factor c-Fos by increasing the release of Ca2+ from the endoplasmic reticulum (ER). Subsequently, we uncover that c-Fos induces the expression of the cell cycle inhibitor p57Kip2 to drive HSC dormancy. Moreover, we found that CD38 ecto-enzymatic activity at the neighboring CD38-positive cells can promote human HSC quiescence. Together, CD38/cADPR/Ca2+/c-Fos/p57Kip2 axis maintains HSC dormancy. Pharmacological manipulations of this pathway can provide new strategies to improve the success of stem cell transplantation and blood regeneration after injury or disease.
    DOI:  https://doi.org/10.1371/journal.pbio.3002517
  8. Shock. 2024 Feb 27.
    Near-infrared dye IR-780 alleviates hematopoietic system damage by promoting hematopoietic stem cells into quiescence.
    Jie Wu, Le Ma, Qiang Gong, Yan Chen, Long Chen, Chunmeng Shi.
      ABSTRACT: Worrying about potential radiation exposure is a general concern, but no effective pre-exposure radioprotective countermeasure is generally accepted1. Here, we found a small molecular near-infrared (NIR) dye IR-780, which promoted hematopoietic stem cells (HSCs) into quiescence to resist stress. When mice were treated with IR-780 before stress, increased HSC quiescence and better hematopoietic recovery were observed in IR-780-treated mice in stress conditions. However, when given after radiation, IR-780 did not show obvious benefit. Transplantation assay and colony-forming assay were carried out to determine self-renewal ability and repopulation capacity. Furthermore, IR-780 reduced the generation of reactive oxygen species (ROS) and DNA damage in HSCs after radiation. In homeostasis, the percentage of Lineage-, Sca-1+, and c-Kit+ cells (LSKs) and long-term HSCs (LT-HSCs) were improved, and more HSCs were in G0 state after administration of IR-780. Further investigations showed that IR-780 selectively accumulated in LT-HSCs with high mitochondria membrane potential (MMP) and entered cells by organic anion transporting polypeptides 1b2(Oatp1b2). Finally, IR-780 promoted human CD34+ hematopoietic stem cell reconstruction ability in NOD-PrkdcscidIl2rgnull (NSG) mice after transplantation and improved repopulation capacity in vitro culture. Our research showed that IR-780 selectively entered MMP-high LT-HSCs and promoted them into dormancy, thus reducing hematopoietic injury and improving regeneration capacity. This novel approach might hold promise as a potential radiation countermeasure.
    DOI:  https://doi.org/10.1097/SHK.0000000000002317
  9. Mol Cell. 2024 Feb 22. pii: S1097-2765(24)00096-0. [Epub ahead of print]
    Bidirectional substrate shuttling between the 26S proteasome and the Cdc48 ATPase promotes protein degradation.
    Hao Li, Zhejian Ji, Joao A Paulo, Steven P Gygi, Tom A Rapoport.
      Most eukaryotic proteins are degraded by the 26S proteasome after modification with a polyubiquitin chain. Substrates lacking unstructured segments cannot be degraded directly and require prior unfolding by the Cdc48 ATPase (p97 or VCP in mammals) in complex with its ubiquitin-binding partner Ufd1-Npl4 (UN). Here, we use purified yeast components to reconstitute Cdc48-dependent degradation of well-folded model substrates by the proteasome. We show that a minimal system consists of the 26S proteasome, the Cdc48-UN ATPase complex, the proteasome cofactor Rad23, and the Cdc48 cofactors Ubx5 and Shp1. Rad23 and Ubx5 stimulate polyubiquitin binding to the 26S proteasome and the Cdc48-UN complex, respectively, allowing these machines to compete for substrates before and after their unfolding. Shp1 stimulates protein unfolding by the Cdc48-UN complex rather than substrate recruitment. Experiments in yeast cells confirm that many proteins undergo bidirectional substrate shuttling between the 26S proteasome and Cdc48 ATPase before being degraded.
    Keywords:  AAA ATPase; Cdc48; ERAD; p97; proteasome; protein degradation; protein unfolding; shuttling factor; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.029
  10. Sci Adv. 2024 Mar;10(9): eadh8493
    N-MYC regulates cell survival via eIF4G1 in inv(16) acute myeloid leukemia.
    Philomina Sona Peramangalam, Sridevi Surapally, Anthony J Veltri, Shikan Zheng, Robert Burns, Nan Zhu, Sridhar Rao, Carsten Muller-Tidow, John H Bushweller, John A Pulikkan.
      N-MYC (encoded by MYCN) is a critical regulator of hematopoietic stem cell function. While the role of N-MYC deregulation is well established in neuroblastoma, the importance of N-MYC deregulation in leukemogenesis remains elusive. Here, we demonstrate that N-MYC is overexpressed in acute myeloid leukemia (AML) cells with chromosome inversion inv(16) and contributes to the survival and maintenance of inv(16) leukemia. We identified a previously unknown MYCN enhancer, active in multiple AML subtypes, essential for MYCN mRNA levels and survival in inv(16) AML cells. We also identified eukaryotic translation initiation factor 4 gamma 1 (eIF4G1) as a key N-MYC target that sustains leukemic survival in inv(16) AML cells. The oncogenic role of eIF4G1 in AML has not been reported before. Our results reveal a mechanism whereby N-MYC drives a leukemic transcriptional program and provides a rationale for the therapeutic targeting of the N-MYC/eIF4G1 axis in myeloid leukemia.
    DOI:  https://doi.org/10.1126/sciadv.adh8493
  11. Cell Stem Cell. 2024 Feb 19. pii: S1934-5909(24)00041-9. [Epub ahead of print]
    An iron rheostat controls hematopoietic stem cell fate.
    Yun-Ruei Kao, Jiahao Chen, Rajni Kumari, Anita Ng, Aliona Zintiridou, Madhuri Tatiparthy, Yuhong Ma, Maria M Aivalioti, Deeposree Moulik, Sriram Sundaravel, Daqian Sun, Julie A Reisz, Juliane Grimm, Nuria Martinez-Lopez, Stephanie Stransky, Simone Sidoli, Ulrich Steidl, Rajat Singh, Angelo D'Alessandro, Britta Will.
      Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron-particularly during mitosis. To study the functional and molecular consequences of iron restriction, we developed models allowing for transient iron bioavailability limitation and combined single-molecule RNA quantification, metabolomics, and single-cell transcriptomic analyses with functional studies. Our data reveal that the activation of the limited iron response triggers coordinated metabolic and epigenetic events, establishing stemness-conferring gene regulation. Notably, we find that aging-associated cytoplasmic iron loading reversibly attenuates iron-dependent cell fate control, explicating intervention strategies for dysfunctional aged stem cells.
    Keywords:  Tip60/KAT5; aging; gene regulation; hematopoiesis; iron; metabolism; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2024.01.011
  12. Blood Cancer Discov. 2024 Feb 29.
    Spatial Mapping of Hematopoietic Clones in Human Bone Marrow.
    Andrew L Young, Hannah C Davis, Maggie J Cox, Tyler M Parsons, Samantha C Burkart, Diane E Bender, Lulu Sun, Stephen T Oh, Grant A Challen.
      Clonal hematopoiesis (CH) is the expansion of somatically mutated cells in the hematopoietic compartment of individuals without hematopoietic dysfunction. Large CH clones (i.e. >2% variant allele fraction) predispose to hematologic malignancy, but CH is detected at lower levels in nearly all middle-aged individuals. Prior work has extensively characterized CH in peripheral blood, but the spatial distribution of hematopoietic clones in human bone marrow is largely undescribed. To understand CH at this level, we developed a method for spatially aware somatic mutation profiling and characterized the bone marrow of a patient with polycythemia vera. We identified complex clonal distribution of somatic mutations in the hematopoietic compartment, restriction of somatic mutations to specific subpopulations of hematopoietic cells, and spatial constraints of these clones in the bone marrow. This proof-of-principle paves the way to answering fundamental questions regarding CH spatial organization and factors driving CH expansion and malignant transformation in the bone marrow.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0110
  13. Nat Commun. 2024 Feb 26. 15(1): 1764
    MarShie: a clearing protocol for 3D analysis of single cells throughout the bone marrow at subcellular resolution.
    Till Fabian Mertens, Alina Tabea Liebheit, Johanna Ehl, Ralf Köhler, Asylkhan Rakhymzhan, Andrew Woehler, Lukas Katthän, Gernot Ebel, Wjatscheslaw Liublin, Ana Kasapi, Antigoni Triantafyllopoulou, Tim Julius Schulz, Raluca Aura Niesner, Anja Erika Hauser.
      Analyzing immune cell interactions in the bone marrow is vital for understanding hematopoiesis and bone homeostasis. Three-dimensional analysis of the complete, intact bone marrow within the cortex of whole long bones remains a challenge, especially at subcellular resolution. We present a method that stabilizes the marrow and provides subcellular resolution of fluorescent signals throughout the murine femur, enabling identification and spatial characterization of hematopoietic and stromal cell subsets. By combining a pre-processing algorithm for stripe artifact removal with a machine-learning approach, we demonstrate reliable cell segmentation down to the deepest bone marrow regions. This reveals age-related changes in the marrow. It highlights the interaction between CX3CR1+ cells and the vascular system in homeostasis, in contrast to other myeloid cell types, and reveals their spatial characteristics after injury. The broad applicability of this method will contribute to a better understanding of bone marrow biology.
    DOI:  https://doi.org/10.1038/s41467-024-45827-6
  14. ACS Synth Biol. 2024 Feb 26.
    Subunits of an E3 Ligase Complex as Degrons for Efficient Degradation of Cytosolic, Nuclear, and Membrane Proteins.
    Anže Verbič, Tina Lebar, Arne Praznik, Roman Jerala.
      Protein degradation is a highly regulated cellular process crucial to enable the high dynamic range of the response to external and internal stimuli and to balance protein biosynthesis to maintain cell homeostasis. Within mammalian cells, hundreds of E3 ubiquitin ligases target specific protein substrates and could be repurposed for synthetic biology. Here, we present a systematic analysis of the four protein subunits of the multiprotein E3 ligase complex as scaffolds for the designed degrons. While all of them were functional, the fusion of a fragment of Skp1 with the target protein enabled the most effective degradation. Combination with heterodimerizing peptides, protease substrate sites, and chemically inducible dimerizers enabled the regulation of protein degradation. While the investigated subunits of E3 ligases showed variable degradation efficiency of the membrane and cytosolic and nuclear proteins, the bipartite SSD (SOCSbox-Skp1(ΔC111)) degron enabled fast degradation of protein targets in all tested cellular compartments, including the nucleus and plasma membrane, in different cell lines and could be chemically regulated. These subunits could be employed for research as well as for diverse applications, as demonstrated in the regulation of Cas9 and chimeric antigen receptor proteins.
    Keywords:  E3 ligase; control of protein expression; degrons; synthetic biology
    DOI:  https://doi.org/10.1021/acssynbio.3c00588
  15. Int Immunopharmacol. 2024 Feb 29. pii: S1567-5769(24)00278-9. [Epub ahead of print]130 111760
    Macrophage depletion damages hematopoiesis partially through inhibition of cell homing and expansion after hematopoietic cell transplantation.
    Qi Zhou, Can Cao, Yurong Bao, Tiantian Sun, Seyram Yao Adzraku, Xiaowen Hao, Yue Li, Shengnan Yuan, Yujin Huang, Kailin Xu, Jianlin Qiao, Wen Ju, Lingyu Zeng.
      Bone marrow macrophages (Mφ) are essential components of the bone marrow niche that regulate the function of hematopoietic stem cells. Poor graft function and inhibition of hematopoietic production can result from abnormal macrophage function; however, the underlying mechanism is unclear. Clodronate liposomes (Clo-Lip) have been used widely to deplete macrophages and study their functions. Our previous results showed that Clod-Lip-mediated clearance of macrophages plays a vital role in regulating hematopoietic reconstruction after allogeneic hematopoietic cell transplantation (HCT). In this study, using an isogenic hematopoietic stem cell transplantation model, we found that Clod-Lip-mediated clearance of macrophages suppressed hematopoietic reconstruction by inhibiting the homing process of hematopoietic cells. We also demonstrated that macrophage depletion inhibited the direct supportive effect of macrophages on hematopoietic stem and progenitor cells and erythroid differentiation but promoted the production of megakaryocytic progenitors ex vivo. We showed that macrophages increase CD49e expression on hematopoietic stem and progenitor cells (HSPCs). However, CD49e inhibitors did not support the proliferative effect of macrophages on hematopoietic cells. In contrast, macrophage E-selectin/ intercellular cell adhesion molecule-1 (ICAM-1) may be involved in directly regulating HSPCs. In conclusion, macrophage depletion with Clo-Lip partially disrupts bone marrow hematopoiesis after HCT by impeding donor cell homing and macrophage-HSPCs interactions.
    Keywords:  Clodronate Liposomes; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Homing; Macrophage
    DOI:  https://doi.org/10.1016/j.intimp.2024.111760
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