bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–05–04
eighteen papers selected by
William Grey, University of York



  1. Cancers (Basel). 2025 Apr 18. pii: 1355. [Epub ahead of print]17(8):
      Acute Myeloid Leukemia (AML) is characterized by aggressive proliferation and metabolic reprogramming that support its survival and resistance to therapy. This review explores the metabolic distinctions between AML cells and normal hematopoietic stem cells (HSCs), emphasizing the role of altered mitochondrial function, oxidative phosphorylation (OXPHOS), and biosynthetic pathways in leukemic progression. AML cells exhibit distinct metabolic vulnerabilities, including increased mitochondrial biogenesis, reliance on glycolysis and amino acid metabolism, and unique signaling interactions that sustain leukemic stem cells (LSCs). These dependencies provide potential therapeutic targets, as metabolic inhibitors have demonstrated efficacy in disrupting AML cell survival while sparing normal hematopoietic cells. We examine current and emerging metabolic therapies, such as inhibitors targeting glycolysis, amino acid metabolism, and lipid biosynthesis, highlighting their potential in overcoming drug resistance. However, challenges remain in translating these strategies into clinical practice due to AML's heterogeneity and adaptability. Further research into AML's metabolic plasticity and precision medicine approaches is crucial for improving treatment outcomes. Understanding and exploiting AML's metabolic vulnerabilities could pave the way for novel, more effective therapeutic strategies.
    Keywords:  acute myeloid leukemia; atovoquone; azactidine; glycolysis; hematopoietic stem cells; leukemic stem cells; metabolism; oxidative phosphorylation; venetoclax
    DOI:  https://doi.org/10.3390/cancers17081355
  2. Exp Hematol. 2025 Apr 29. pii: S0301-472X(25)00079-7. [Epub ahead of print] 104788
      Identification of phenotypes of human hematopoietic cells that display long-term mature cell outputs in vitro and repopulating capability in immunodeficient mice has been important to anticipating the therapeutic potential of fresh harvests of bone marrow or cord blood before or after their physical or genetic manipulation. However, characterizing their key properties and strategies for their isolation from multiple sources at increasing cell purities and elucidating the mechanisms that regulate their ability to sustain mature blood cell production continues to be of major interest. Previous studies have shown that fetal and adult human cells with long-term blood cell output potential are highly enriched in their respective GPI80+ and CD49f+ subsets of a developmentally preserved CD45+CD34+CD38-CD45RA-CD90+ population. The so-called "GPI80" hematopoietic cells found in first trimester human fetal liver are of particular interest because of their very high regenerative capability compared to their adult or even neonatal (cord blood) "CD49f" counterparts. Here it was hypothesized that high regenerative activity of the GPI80+ cells could be further enriched within a CD49f+ subset. We now demonstrate that co-expression of CD49f within the GPI80+ population identifies a subset with reduced short-term myeloid colony-forming activity in semi-solid medium, and greater progeny outputs in both 12-week growth factor-supplemented stromal co-cultures, and in transplanted immunodeficient mice. These findings demonstrate CD49f is a pervasive marker of human HSCs throughout ontogeny and aging.
    DOI:  https://doi.org/10.1016/j.exphem.2025.104788
  3. NPJ Aging. 2025 May 02. 11(1): 31
      Aging of hematopoietic and immune system (HIS) leads to cellular senescence and immune dysregulation, contributing to age-related diseases. Here, we show that Procyanidin C1 (PCC1), a compound with both senolytic and senomorphic properties, can counteract aging-related changes in HIS. Using single-cell RNA sequencing and validation experiments, we found that aging induced cellular senescence, inflammation, and immune dysregulation in the bone marrow and spleen tissues of mice. Long-term PCC1 treatment improved key physiological parameters especially the grip strength of aged mice. Further single-cell analysis revealed PCC1's broad geroprotective effects on HIS, including an increase in the proportion of B cells (BCs) and hematopoietic stem cells (HSCs), suppression of senescence-associated markers, and restoration of normal immune processes. Specifically, PCC1 mitigated inflammation and restored immune homeostasis in BCs by suppressing Cebpb expression and age-associated BCs. Moreover, PCC1 reversed aging-induced alterations in HSCs through upregulating Nedd4 and CD62L-Ca2+ axis expression. Finally, we identified senescent cells (SnCs) using machine learning and gene set enrichment analysis, revealing that PCC1 induced apoptosis of SnCs and regulated their metabolic processes, particularly in granulocytes and myeloid cells. The experimental validation further confirmed the senolytic and senomorphic effects of PCC1 both in vivo and in vitro. Overall, PCC1 holds potential as a therapeutic agent for alleviating immune dysfunction and promoting healthy aging via senolytic and senomorphic effects.
    DOI:  https://doi.org/10.1038/s41514-025-00222-3
  4. Cell Rep. 2025 Apr 30. pii: S2211-1247(25)00391-2. [Epub ahead of print]44(5): 115620
      Hematopoietic stem cells (HSCs) generating all blood cells are maintained by their niche cells, termed CXCL12-abundant reticular (CAR) cells, which strongly overlap with leptin-receptor-expressing (LepR+) cells in the bone marrow. A meta-analysis of single-cell RNA sequencing datasets across tissues hypothesized that universal fibroblasts present in all organs give rise to distinct tissue-specific fibroblast subsets designated as specialized fibroblasts, including CAR/LepR+ cells. However, there is no direct evidence that universal fibroblasts can differentiate into specialized fibroblasts at a distant location. Here, we demonstrated that CD248+ universal fibroblasts from the lung and colon outside the skeletal system, as well as from muscle, generated CAR/LepR+ cells characterized by HSC niche functions and expression of cytokines and transcription factors essential for HSC maintenance during ectopic bone formation or after intra-bone marrow transplantation. These results demonstrate that universal fibroblasts with the potential to differentiate into bone marrow-specific HSC niche cells are scattered throughout the entire body.
    Keywords:  CD248; CP: Stem cell research; CXCL12; bone marrow; fibroblasts; hematopoietic stem cells; microenvironment; niche; stem cell niche; universal fibroblasts
    DOI:  https://doi.org/10.1016/j.celrep.2025.115620
  5. Oncogene. 2025 Apr 30.
      Wnt/β-catenin signalling is important for normal hematopoietic stem/progenitor cell (HSPC) biology and heavily implicated in acute and chronic myeloid leukaemia (AML and CML). The central mediator β-catenin is an attractive therapeutic target in myeloid neoplasms however its targeting has been hampered by a poor characterisation of its molecular interactions in haematopoietic cells, which will differ from its network in solid tissues. Our previous β-catenin interactome study identified the significant enrichment of RNA-binding proteins (RBP) implying post-transcriptional roles for β-catenin in myeloid cells. To identify β-catenin interacting mRNAs we performed β-catenin RNA-immunoprecipitation coupled to RNA-sequencing (RIP-seq) and identified significantly enriched Wnt signalling pathway transcripts. Using β-catenin cross-linking immunoprecipitation (CLIP) we demonstrated a limited capacity for β-catenin to bind RNA directly, implying dependence on other RBPs. β-Catenin was found to interact with Musashi-2 (MSI2) in both myeloid cell lines and primary AML patient samples, where expression was significantly correlated. MSI2 knockdown reduced Wnt signalling output (TCF/LEF activity), through suppression of LEF-1 expression and nuclear localisation. Through both RIP and CLIP we demonstrate MSI2 binds LEF1 mRNA in a partly β-catenin dependent fashion, and may impact the post-transcriptional control of LEF-1 expression. Finally, we show that MSI2-mediated expansion of human HSPCs could be partly driven through LEF1 regulation. This is the first study to experimentally demonstrate functional crosstalk between MSI2 and Wnt signalling in human cells, and indicates potential novel post-transcriptional roles for β-catenin in a haematological context.
    DOI:  https://doi.org/10.1038/s41388-025-03415-y
  6. Blood Cancer Discov. 2025 Apr 28. OF1-OF18
       SIGNIFICANCE: We present a single-cell reference atlas of human hematopoiesis and a computational tool for rapid mapping and classification of healthy and leukemic cells. Applied to AML, this has enabled single-cell analysis at the scale of hundreds of patient samples, revealing the full breadth of derailment of differentiation in AML. See related commentary by Berger and Penter, p. XX.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-24-0342
  7. J Appl Physiol (1985). 2025 Apr 29.
      Purpose: High-fat diets (HFD) and exercise training (EX) exert differential impacts on hematopoietic stem and progenitor cell (HSPC) differentiation during stress hematopoiesis, in part, through alterations in the HSPC niche. However, how HFDs and EX alter HSPC differentiation during maintenance conditions remains unknown. Therefore, we examined HSPC and niche cell concentrations during maintenance hematopoiesis following a HFD and EX training intervention. Methods: Male CBA mice (n=40) underwent 8 weeks of HFD or control (CON) diet consumption with the latter 4 weeks involving sedentary (SED) or EX training interventions. Bone marrow cells were quantified by flow cytometry and marrow-derived HSPCs were magnetically isolated for a colony forming unit assay. Results: HFD mice had higher body weight, body fat percentage, and lean body mass compared to CON mice without any effect of exercise. EX significantly improved endurance performance in CON mice. HFD promoted HSPC and myeloid progenitor cell expansion without impacting lymphoid progenitor cells. HSPCs derived from HFD mice displayed enhanced myeloid colony formation which was inhibited by EX. EX reduced mesenchymal stromal cell concentrations. Conclusion: Together, these results suggest that during maintenance hematopoiesis, EX inhibits myeloid and mesenchymal stromal cell expansion while HFD opposes these effects which is similar to their effects during stress hematopoiesis.
    Keywords:  adipogenesis; bone marrow; marrow adipose tissue; myelopoiesis; physical activity
    DOI:  https://doi.org/10.1152/japplphysiol.00899.2024
  8. Blood. 2025 Apr 29. pii: blood.2024026340. [Epub ahead of print]
      Orchestrating key homeostatic functions, mitochondria likely entail cancer vulnerabilities. Moreover, due to their bacterial ancestry they can release potent immunogenic signals. Here we show that the mitochondrial protease ClpP is both a cell-intrinsic metabolic vulnerability and an actionable immunogenic trigger in multiple myeloma (MM). We found that ClpP mRNA is higher in bone marrow (BM)-purified malignant plasma cells (PC) than in normal or premalignant counterparts and that MM lines rank first for ClpP expression among human cancers. Moreover, we demonstrated that human MM cells are highly vulnerable to ClpP inhibition in vitro and in vivo. Surprisingly, MM cell dependence on ClpP was not accounted for by its acknowledged oxidative phosphorylation surveillance activity. Proteomic discovery of proteolytic targets, metabolomics, and metabolic tracing identified a critical control exerted by ClpP on ornithine aminotransferase abundance to sustain cytosolic biosynthesis of polyamines, essential to MM cells. Transcriptomics and targeted validation also revealed activation of a cyclic GMP-AMP synthase (cGAS)-dependent type-I interferon (IFN-I) response in ClpP-silenced MM cells, whose supernatants boosted dendritic cell activation and ability to stimulate IFNg production by T cells. In vivo, ClpP silencing re-shaped the BM immune environment in immunocompetent mice, significantly expanding IFNg-producing CD4+ and CD8+ T cells and CD4+ T memory cells, while containing exhausted CD4+ T cells and myeloid derived suppressor cells. Thus, ClpP is a novel addiction of MM cells, whose inhibition not only exerts cell-intrinsic toxicity, but also triggers otherwise indolent anti-tumoral immunity. Our findings yield a novel immunogenic chemotherapeutic framework of potential relevance against myeloma.
    DOI:  https://doi.org/10.1182/blood.2024026340
  9. Commun Biol. 2025 Apr 26. 8(1): 666
      Understanding cellular diversity and disease mechanisms requires a global analysis of proteins and their modifications. While next-generation sequencing has advanced our understanding of cellular heterogeneity, it fails to capture downstream signalling networks. Ultrasensitive mass spectrometry-based proteomics enables unbiased protein-level analysis of low cell numbers, down to single cells. However, phosphoproteomics remains limited to high-input samples due to sample losses and poor reaction efficiencies associated with processing low cell numbers. Isobaric stable isotope labelling is a promising approach for reproducible and accurate quantification of low abundant phosphopeptides. Here, we introduce SPARCE (Streamlined Phosphoproteomic Analysis of Rare CElls) for multiplexed phosphoproteomic analysis of low cell numbers. SPARCE integrates cell isolation, water-based lysis, on-tip TMT labelling, and phosphopeptide enrichment. SPARCE outperforms traditional methods by enhancing labelling efficiency and phosphoproteome coverage. To demonstrate the utility of SPARCE, we analysed four patient-derived glioblastoma stem cell lines, reliably quantifying phosphosite changes from 1000 FACS-sorted cells. This workflow expands the possibilities for signalling analysis of rare cell populations.
    DOI:  https://doi.org/10.1038/s42003-025-08068-x
  10. Haematologica. 2025 Apr 30.
      In acute myeloid leukemia, the burden of CD34+CD38- leukemia stem cells (LSC) has prognostic value at diagnosis and after induction chemotherapy. Since different methods of LSC quantification have been proposed, we determined the prognostic value on overall survival and incidence of relapse of these methods across ELN2017 risk groups, using data from the HOVON-SAKK132 trial. In addition, we have evaluated the optimal number of acquired white blood cells for accurate LSC detection and the prognostic value of individual LSC markers. Results show that acquiring 1 million white blood cells is essential for accurate LSC-negativity assessment. Among different LSC markers, CD44 overexpression on CD34+CD38- cells was the only insignificant marker in our panel. Testing the impact of several published variations on the analysis for LSC assessments on prognostic value for overall survival and cumulative incidence of relapse, showed marginal differences, demonstrating the robust prognostic value of LSC burden. For further clinical implementation, the optimal LSC assessment may differ among ELN risk groups. In conclusion, LSC burden is a robust prognostic factor and insight in the different methods of LSC definition can facilitate the clinical implementation.
    DOI:  https://doi.org/10.3324/haematol.2024.287090
  11. BioData Min. 2025 May 02. 18(1): 32
      Acute myeloid leukemia (AML) is caused by proliferation of mutated myeloid progenitor cells. The standard chemotherapy regimen does not efficiently cause remission as there is a high relapse rate. Resistance acquired by leukemic stem cells is suggested to be one of the root causes of relapse. Therefore, there is an urgency to develop new drugs for therapy. Repurposing approved drugs for AML can provide a cost-friendly, time-efficient, and affordable alternative. The multiscale interactome network is a computational tool that can identify potential therapeutic candidates by comparing mechanisms of the drug and disease. Communities that could be potentially experimentally validated are detected in the multiscale interactome network using the algorithm CRank. The results are evaluated through literature search and Gene Ontology (GO) enrichment analysis. In this research, we identify therapeutic candidates for AML and their mechanisms from the interactome, and isolate prioritized communities that are dominant in the therapeutic mechanism that could potentially be used as a prompt for pre-clinical/translational research (e.g. bioinformatics, laboratory research) to focus on biological functions and mechanisms that are associated with the disease and drug. This method may allow for an efficient and accelerated discovery of potential candidates for AML, a rapidly progressing disease.
    Keywords:  Acute myeloid leukemia (AML); Community detection; Drugs; Human interactome; Networks; Therapeutic targets
    DOI:  https://doi.org/10.1186/s13040-025-00444-x
  12. Nucleic Acids Res. 2025 Apr 22. pii: gkaf344. [Epub ahead of print]53(8):
      To improve ex vivo gene therapy strategies involving hematopoietic stem and progenitor cells (HSPCs), we propose a novel knock-in strategy (named KI-Ep) aiming to achieve transgene regulation of the inserted cassette through the acquisition of naturally occurring epigenetic marks. Based on this hypothesis, we selected CX3CR1 (a myeloid-specific gene presenting a poised histone signature on primitive HSPCs) as safe harbor to generate KI-Ep HSPCs. We demonstrated that, unlike the expression pattern achieved with lentiviral vectors (LVs), the insertion of a constitutive expression cassette into the intron 1 of the CX3CR1 locus (CX3CR1-I) in HSPCs resulted in very low expression levels in the more primitive HSPCs but, crucially, strong expression in HSPC-differentiated populations (especially myeloid cells), both in vitro and in vivo. Furthermore, we showed that the promoter of the expression cassette inserted into CX3CR1-I acquired epigenetic marks associated with poised genes during the HSPC stage. These marks transitioned to activated histone states upon KI-Ep HSPCs differentiation. In summary, here, we introduce the KI-Ep concept which enables the epigenetic modulation of the inserted transgene during the HSPCs stem cell stages and its subsequent activation upon differentiation.
    DOI:  https://doi.org/10.1093/nar/gkaf344
  13. Cell Death Discov. 2025 Apr 25. 11(1): 201
      Multiple myeloma (MM) is an incurable hematologic malignancy. While recent therapies have significantly improved survival in MM patients, drug resistance and refractory phenomenon underscores the urgent need of new therapeutic targets. Methylenetetrahydrofolate dehydrogenase 2(MTHFD2) has been widely reported as a potential and promising anti-cancer target, but its role and underlying mechanisms remain unclear in MM. We aimed to investigate the biologic function and mechanisms of MTHFD2 in MM. First, we demonstrated that MTHFD2 is overexpressed in MM and associated with poor prognosis. We then illustrated that targeting MTHFD2 exhibits anti-MM effects in vitro and in vivo. Mechanistically, targeting MTHFD2 inhibited glycolysis and mitochondrial respiration in MM cells. For the nonmetabolic function of MTHFD2, we found that MTHFD2 knockdown affected the unfolded protein response (UPR) via decreasing expression of the splice form of X-box binding protein 1 (XBP1s). Importantly, the level of MTHFD2 in MM cells was associated with sensitivity of bortezomib, and targeting MTHFD2 synergizes with bortezomib against MM in vitro and in vivo. In summary, our innovative findings suggest that MTHFD2 is a promising target for MM, targeting it alters metabolic homeostasis of MM and synergizes with bortezomib to inhibit MM.
    DOI:  https://doi.org/10.1038/s41420-025-02498-6
  14. medRxiv. 2025 Apr 26. pii: 2025.04.11.25325281. [Epub ahead of print]
      Therapeutic advances in immunotherapy have significantly improved outcomes in lymphomas and myelomas, yet patients with TP53-mutant acute myeloid leukemia (AML) continue to be challenged. While TP53 mutations in leukemic blasts have been extensively characterized, their incidence and impact within immune cells remain largely unexplored. Here, using single-cell multi-omics and integrated phenotypic analyses, we identify TP53 mutations in T and NK cells from AML patients. Notably, T cells harboring monoallelic TP53 mutations exhibited elevated proliferative markers yet showed reduced cytotoxic capacity and increased expression of inhibitory receptors, including PD-1, TIGIT, and TIM-3. To investigate the functional consequences of p53-mutant immune cells, we engineered CAR-T cells carrying clinically relevant p53 mutations (Y220C and R175H). These mutant p53 CAR-T cells exhibited a pronounced exhaustion phenotype, with diminished cytokine secretion and impaired tumor cytolysis both in vitro and in PDX mouse models. Crucially, restoring mutant p53 to a wild-type conformation using a targeted small-molecule reactivator rescued CAR-T functionality, reduced exhaustion marker expression, and prolonged survival in AML PDX mouse models, revealing a direct mechanistic link between TP53 mutations in T cells and therapeutic resistance. Our findings establish TP53-mutant T cells as a previously unrecognized driver of immune escape in AML, highlighting the importance of immune-cell genotyping and p53 reactivation strategies. By demonstrating that mutant p53 can be selectively corrected to restore T-cell function, this study opens new avenues for immunotherapeutic intervention in TP53-mutant AML.
    DOI:  https://doi.org/10.1101/2025.04.11.25325281
  15. Nat Commun. 2025 Apr 26. 16(1): 3932
      Selective inheritance of sub-cellular components has emerged as a mechanism guiding stem cell fate after asymmetric cell divisions. Peroxisomes play a crucial role in multiple metabolic processes such as fatty acid metabolism and reactive oxygen species detoxification, but the apportioning of peroxisomes during stem cell division remains understudied. Here, we develop a mouse model and labeling technique to follow the dynamics of distinct peroxisome age-classes, and find that old peroxisomes are inherited by the daughter cell retaining full stem cell potency in mammary and epidermal stem cell divisions. Old peroxisomes carry Glucose-6-phosphate-dehydrogenase, whose specific location on the peroxisomal membrane promotes stem cell function by facilitating peroxisomal ether lipid synthesis. Our study demonstrates age-selective apportioning of peroxisomes in vivo, and unveils how functional heterogeneity of peroxisomes is utilized by asymmetrically dividing cells to metabolically divert the fate of the two daughter cells.
    DOI:  https://doi.org/10.1038/s41467-025-58752-z
  16. Methods Mol Biol. 2025 ;2908 33-50
      Within the complex interplay of proteins, lipids and carbohydrates at the cell surface is the surfaceome, a dense layer of proteins and their posttranslationally modified counterparts that serves as a hub for cell signaling and signal transduction. The surfaceome plays crucial roles in mediating interactions between cells and the extracellular environment, which combined with their availability at the cell surface make it an attractive therapeutic target. Despite its importance, the development of technologies to selectively target cell surface proteins for empirical identification is challenged by their structural complexity. Here, we describe a proximity labeling-based technique to covalently label proteins at the cell surface with a biotin handle, enabling downstream streptavidin-based enrichment and manipulation in a variety of modalities, including fluorescence imaging, western blotting, and mass spectrometry-based proteomics.
    Keywords:  Cell surface; Lipid remodeling; Proteomics; Proximity labeling; Surfaceome
    DOI:  https://doi.org/10.1007/978-1-0716-4434-8_3
  17. bioRxiv. 2025 Apr 13. pii: 2025.04.13.648568. [Epub ahead of print]
      Understanding protein distribution patterns across tissue architecture is crucial for deciphering organ function in health and disease. Here, we applied single-cell Deep Visual Proteomics to perform spatially-resolved proteome analysis of individual cells in native tissue. We combined this with a novel strategic cell selection pipeline and a continuous protein gradient mapping framework to investigate larger clinical cohorts. We generated a comprehensive spatial map of the human hepatic proteome by analyzing hundreds of individual hepatocytes from 18 individuals. Among more than 2,500 proteins per cell about half exhibited zonated expression patterns. Cross-species comparison with mouse data revealed conserved metabolic functions and human-specific features of liver zonation. Analysis of fibrotic samples demonstrated widespread disruption of protein zonation, with pericentral proteins being particularly susceptible. Our study provides a comprehensive resource of human liver organization while establishing a broadly applicable framework for spatial proteomics analyses along tissue gradients.
    DOI:  https://doi.org/10.1101/2025.04.13.648568