bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–02–16
fifteen papers selected by
William Grey, University of York
  1. Development of an efficient differentiation culture system of murine HSC into megakaryocytes.
  2. Bone marrow mesenchymal stromal cells support translation in refractory acute myeloid leukemia.
  3. Protection of CD33-modified hematopoietic stem cell progeny from CD33-directed CAR T cells in nonhuman primates.
  4. Hematopoietic stem cells: Understanding the mechanisms to unleash the therapeutic potential of hematopoietic stem cell transplantation.
  5. Resolving Leukemia Heterogeneity and Lineage Aberrations with HematoMap.
  6. Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution.
  7. SOCS1 protects acute myeloid leukemia against allogeneic T cell-mediated cytotoxicity.
  8. UM171 glues asymmetric CRL3-HDAC1/2 assembly to degrade CoREST corepressors.
  9. Lactoferrin-Derived Peptide Chimera Induces Caspase-Independent Cell Death in Multiple Myeloma.
  10. Intercellular adhesion boots collective cell migration through elevated membrane tension.
  11. Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation.
  12. ArfGAP2 promotes STING proton channel activity, cytokine transit, and autoinflammation.
  13. Directing autophagy to degrade cell surface receptors.
  14. Immunophenotypic and Functional Interindividual Variability in Banked Cord Blood Cells: Insights for Advanced Therapies.
  15. Intrinsic electrical activity drives small-cell lung cancer progression.
  1. Biochem Biophys Res Commun. 2025 Feb 07. pii: S0006-291X(25)00177-9. [Epub ahead of print]752 151463
    Development of an efficient differentiation culture system of murine HSC into megakaryocytes.
    Yue Chai, Chong Yang, Fang Dong, Hideo Ema, Toshio Suda.
      Despite significant progress in the cultivation of hematopoietic stem cells (HSCs), the establishment of lineage-specific cell culture systems remains inadequately developed. This study compares the effects of recombinant human serum albumin (r-HSA) and polyvinyl alcohol (PVA) in serum-free culture systems on the differentiation of HSCs into multiple lineages. Both single-cell and multi-cellular culture systems are used, and differentiation is evaluated by flow cytometry and slides-based techniques under various cytokine conditions. Our results show that r-HSA strongly promotes differentiation into megakaryocytes (MKs) compared to PVA. The findings indicate that r-HSA outperforms PVA in supporting MK differentiation through both early expansion and later differentiation. This study provides insights into optimizing megakaryocyte generation and offers a more effective culture system for clinical applications.
    Keywords:  Hematopoietic stem cells; Megakaryocytes differentiation; PVA; Serum-free culture; r-HSA
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151463
  2. Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01502-X. [Epub ahead of print]44(1): 115151
    Bone marrow mesenchymal stromal cells support translation in refractory acute myeloid leukemia.
    Livia E Lisi-Vega, Alice Pievani, María García-Fernández, Dorian Forte, Tim L Williams, Marta Serafini, Simón Méndez-Ferrer.
      In acute myeloid leukemia (AML), malignant cells surviving chemotherapy rely on high mRNA translation and their microenvironmental metabolic support to drive relapse. However, the role of translational reprogramming in the niche is unclear. Here, we found that relapsing AML cells increase translation in their bone marrow (BM) niches, where BM mesenchymal stromal cells (BMSCs) become a source of eIF4A-cap-dependent translation machinery that is transferred to AML cells via extracellular vesicles (EVs) to meet their translational demands. In two independent models of highly chemo-resistant AML driven by MLL-AF9 or FLT3-ITD (internal tandem duplication) and nucleophosmin (NPMc) mutations, protein synthesis levels increase in refractory AML dependent on nestin+ BMSCs. Inhibiting cap-dependent translation in BMSCs abolishes their chemoprotective ability, while EVs from BMSCs carrying eIF4A boost AML cell translation and survival. Consequently, eIF4A inhibition synergizes with conventional chemotherapy. Together, these results suggest that AML cells rely on BMSCs to maintain an oncogenic translational program required for relapse.
    Keywords:  CP: Cancer; acute myeloid leukemia; bone marrow mesenchymal stromal cells; chemotherapy; extracellular vesicles; microenvironment; niche; protein synthesis; refractory; relapse; translation
    DOI:  https://doi.org/10.1016/j.celrep.2024.115151
  3. Blood Adv. 2025 Feb 10. pii: bloodadvances.2024015016. [Epub ahead of print]
    Protection of CD33-modified hematopoietic stem cell progeny from CD33-directed CAR T cells in nonhuman primates.
    Nicholas E Petty, Stefan Radtke, Greta Kanestrom, Emily Fields, Olivier Humbert, Salvatore Fiorenza, Mallory J Llewellyn, George S Laszlo, Justin Thomas, Zach Burger, Kyle Swing, Haiying Zhu, Keith R Jerome, Cameron J Turtle, Roland B Walter, Hans-Peter Kiem.
      The treatment of monogenetic disorders, such as hemoglobinopathies and lysosomal storage diseases, has markedly improved with the advent of cell and gene therapies, particularly allogeneic or gene-modified autologous stem cell transplantations. However, therapeutic efficacy is reliant on maintaining engraftment above a critical threshold. To maintain such engraftment levels, we and others have pursued approaches to shield edited cells from antibody or CAR T-cell mediated selection. Here we focused on CD33, which is expressed early on hematopoietic stem and progenitor cells (HSPC) as well as on myeloid progenitors. Rhesus macaques were engrafted with HSPCs edited to ablate CD33 utilizing either CRISPR/Cas9 or adenine base editor. Both editing strategies showed similar post-transplant recovery kinetics and yielded equivalent levels of engraftment. We then created a V-set domain specific chimeric antigen receptor construct (CAR33), validated its functionality in vitro, and treated both animals with autologous CAR33 T cells. CAR33 T cells expanded after infusion and caused specific depletion of CD33WT but not CD33null progeny - leading to a transient enrichment for gene-edited cells in the blood. No depletion was seen in the bone marrow stem cell compartment with CD34+CD90+ HSCs expressing lower levels of CD33 in comparison to monocytes. Thus, we show proof of concept and safety of an epitope editing based enrichment/protection strategy in macaques.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015016
  4. Stem Cell Res Ther. 2025 Feb 10. 16(1): 60
    Hematopoietic stem cells: Understanding the mechanisms to unleash the therapeutic potential of hematopoietic stem cell transplantation.
    Amjad Ahmed Aljagthmi, Amal Kamal Abdel-Aziz.
      Hematopoietic stem cell transplantation (HSCT) is a promising approach in regenerative medicine and serves as a standard treatment for different malignant and non-malignant conditions. Despite its widespread applications, HSCT is associated with various complications that compromise patients' lives and pose considerable risks of morbidity and mortality. Understanding the molecular physiology of HSCs is fundamental to ultimately enhance the mobilization, engraftment and differentiation of HSCs, thus unleashing the full therapeutic potential of HSCT in the treated patients. This review outlines the current understanding of HSC biology and its relevance to the clinical challenges associated with HSCT. Furthermore, we critically discuss the pros and cons of the preclinical murine models exploited in the HSCT field. Understanding the molecular physiology of HSCs will ultimately unleash the full therapeutic potential of HSCT. HSCs derived from induced pluripotent stem cells (iPSCs) might present an attractive tool which could be exploited preclinically and clinically. Nonetheless, further studies are warranted to systematically evaluate their potential in terms of improving the therapeutic outcome and minimizing the adverse effects of HSCT.
    Keywords:  GVHD; HSC; HSCT; Humanized models; Murine models; iPSC
    DOI:  https://doi.org/10.1186/s13287-024-04126-z
  5. Genomics Proteomics Bioinformatics. 2025 Feb 13. pii: qzaf005. [Epub ahead of print]
    Resolving Leukemia Heterogeneity and Lineage Aberrations with HematoMap.
    Yuting Dai, Wen Ouyang, Wen Jin, Fan Zhang, Wenyan Cheng, Jianfeng Li, Shuo He, Junqi Zong, Shijia Cao, Chenxin Zhou, Junchen Luo, Gang Lu, Jinyan Huang, Hai Fang, Xiaojian Sun, Kankan Wang, Saijuan Chen.
      Precise mapping of leukemic cells onto the known hematopoietic hierarchy is important for understanding the cell-of-origin and mechanisms underlying disease initiation and development. However, this task remains challenging because of the high interpatient and intrapatient heterogeneity of leukemia cell clones as well as the differences existed between leukemic and normal hematopoietic cells. Using single-cell RNA sequencing (scRNA-seq) data with a curated clustering approach, we constructed a comprehensive reference hierarchy of normal hematopoiesis. This reference hierarchy was accomplished through multistep clustering and annotating over 100,000 bone marrow mononuclear cells derived from 25 healthy donors. We further employed the cosine distance algorithm to develop a likelihood score, determining the similarities of leukemic cells to their putative normal counterparts. Using our scoring strategies, we mapped the cells of acute myeloid leukemia (AML) and B cell precursor acute lymphoblastic leukemia (BCP-ALL) samples to their corresponding counterparts. The reference hierarchy also facilitated bulk RNA sequencing (RNA-seq) analysis, enabling the development of a least absolute shrinkage and selection operator (LASSO) score model to reveal subtle differences in lineage aberrancy within AML or BCP-ALL patients. To facilitate interpretation and application, we have established an R-based package (HematoMap) that offers a fast, convenient, and user-friendly tool for identifying and visualizing lineage aberrations in leukemia from scRNA-seq and bulk RNA-seq data. Our tool provides curated resources and data analytics for understanding leukemogenesis, with the potential to enhance leukemia risk stratification and personalized treatments. The HematoMap is available at https://github.com/NRCTM-bioinfo/HematoMap.
    Keywords:  Acute leukemia; Bioinformatics; Hematopoietic hierarchy; Lineage aberration; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1093/gpbjnl/qzaf005
  6. Cell. 2025 Feb 03. pii: S0092-8674(25)00050-9. [Epub ahead of print]
    Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution.
    Alan Y Hsu, Qingxiang Huang, Xiong Pi, Jianing Fu, Krishnan Raghunathan, Laxman Ghimire, Arumugam Balasubramanian, Xuemei Xie, Hongbo Yu, Fabien Loison, Viraga Haridas, Jiali Zha, Fei Liu, Shin-Young Park, Kamal Bagale, Qian Ren, Yuping Fan, Yi Zheng, Jose A Cancelas, Li Chai, Sean R Stowell, Kanchao Chen, Rong Xu, Xiaoxue Wang, Yuanfu Xu, Lianghui Zhang, Tao Cheng, Fengxia Ma, Jay R Thiagarajah, Hao Wu, Sizhou Feng, Hongbo R Luo.
      Although subsets with immunosuppressive properties exist, neutrophils are typically known for their pro-inflammatory role and pathogen clearance capabilities. Here, we reveal that neutrophils can paradoxically aid in resolving inflammation by actively producing anti-inflammatory extracellular vesicles. These large aging-neutrophil-derived vesicles (LAND-Vs) do not fit into classical vesicle categorizations due to their specific size, structure, or biogenesis pathway. They are protected from efferocytotic clearance by phagocytes due to surface "do not eat me" signals and accumulate in the resolution phase of inflammation. CD55 on LAND-Vs exerts a robust, sustained anti-inflammatory effect by inhibiting complement 3 convertase, thereby reducing neutrophil recruitment and tissue damage. CD55+ LAND-Vs originate in ordered lipid raft domains, where CD55 accumulates asymmetrically during neutrophil aging, and are subsequently formed through RhoA-dependent budding. Collectively, LAND-V emerges as a pivotal physiological immunomodulator and showcases functions that transcend the limited lifespan of neutrophils, offering a therapeutic target for inflammatory and infectious diseases.
    Keywords:  CD55; COVID-19; aging; complement; do not eat me signal; extracellular vesicles; inflammation resolution; lung injury; neutrophils; pneumonia
    DOI:  https://doi.org/10.1016/j.cell.2025.01.021
  7. Blood Cancer Discov. 2025 Feb 10.
    SOCS1 protects acute myeloid leukemia against allogeneic T cell-mediated cytotoxicity.
    Enoch Tin, Sergio Rutella, Ismat Khatri, Yoosu Na, Yongran Yan, Neil MacLean, Jayakumar Vadakekolathu, Mark D Minden, Aaron D Schimmer, JongBok Lee, Li Zhang.
      Despite the curative potential of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML), its efficacy is limited by intrinsic resistance of cancer cells to donor-derived T-cell cytotoxicity. Using a genome-wide CRISPR screen, we identified the SOCS1-JAK1-STAT1 pathway as a mediator of AML susceptibility to T cells. SOCS1 knockdown in AML cells sensitized them to killing by allogeneic T cells, whereas SOCS1 overexpression in AML cells induced resistance to T-cell anti-leukemic activity. Mechanistically, SOCS1 protected AML cells from T-cell killing by antagonizing IFNγ-JAK1-induced ICAM-1 expression. Furthermore, primary AML cells with lower SOCS1 expression correlated with better overall survival in patients, especially those with a lower exhausted CD8+ T-cell score. Thus, this study reveals SOCS1 and its downstream mediators as a potential targetable pathway to enhance T cell-based immunotherapy for AML.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-24-0140
  8. Nature. 2025 Feb 12.
    UM171 glues asymmetric CRL3-HDAC1/2 assembly to degrade CoREST corepressors.
    Megan J R Yeo, Olivia Zhang, Xiaowen Xie, Eunju Nam, N Connor Payne, Pallavi M Gosavi, Hui Si Kwok, Irtiza Iram, Ceejay Lee, Jiaming Li, Nicholas J Chen, Khanh Nguyen, Hanjie Jiang, Zhipeng A Wang, Kwangwoon Lee, Haibin Mao, Stefan A Harry, Idris A Barakat, Mariko Takahashi, Amanda L Waterbury, Marco Barone, Andrea Mattevi, Steven A Carr, Namrata D Udeshi, Liron Bar-Peled, Philip A Cole, Ralph Mazitschek, Brian B Liau, Ning Zheng.
      UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal1. By co-opting KBTBD4, a substrate receptor of the CUL3-RING E3 ubiquitin ligase (CRL3) complex, UM171 promotes the degradation of the LSD1-CoREST corepressor complex, thereby limiting haematopoietic stem cell attrition2,3. However, the direct target and mechanism of action of UM171 remain unclear. Here we show that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1/2 to promote corepressor degradation. Through proteomics and chemical inhibitor studies, we identify the principal target of UM171 as HDAC1/2. Cryo-electron microscopy analysis of dimeric KBTBD4 bound to UM171 and the LSD1-HDAC1-CoREST complex identifies an asymmetric assembly in which a single UM171 molecule enables a pair of KELCH-repeat propeller domains to recruit the HDAC1 catalytic domain. One KBTBD4 propeller partially masks the rim of the HDAC1 active site, which is exploited by UM171 to extend the E3-neosubstrate interface. The other propeller cooperatively strengthens HDAC1 binding through a distinct interface. The overall CoREST-HDAC1/2-KBTBD4 interaction is further buttressed by the endogenous cofactor inositol hexakisphosphate, which acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces is demonstrated by base editor scanning of KBTBD4 and HDAC1. By delineating the direct target of UM171 and its mechanism of action, we reveal how the cooperativity offered by a dimeric CRL3 E3 can be leveraged by a small molecule degrader.
    DOI:  https://doi.org/10.1038/s41586-024-08532-4
  9. Cells. 2025 Feb 03. pii: 217. [Epub ahead of print]14(3):
    Lactoferrin-Derived Peptide Chimera Induces Caspase-Independent Cell Death in Multiple Myeloma.
    Young-Saeng Jang, Shima Barati Dehkohneh, Jaewon Lim, Jaehui Kim, Donghwan Ahn, Sun Shim Choi, Seung Goo Kang.
      Lactoferrin-derived peptide chimera is a synthetic peptide that mimics the functional unit of lactoferrin with antibacterial activity. Although LF has anticancer effects, to the best of our knowledge, its effects on multiple myeloma have not yet been studied. We explored the potential of a lactoferrin-derived chimera for multiple myeloma treatment, a malignant clonal plasma cell bone marrow disease. The lactoferrin-derived chimera effectively inhibited MM1S, MM1R, and RPMI8226 multiple myeloma cell growth, and induced the early and late phases of apoptosis, but not in normal peripheral blood mononuclear cells. Furthermore, the lactoferrin-derived chimera modulates the relative expression of genes involved in survival, apoptosis, and mitochondrial dysfunction at the transcriptional level. Mitochondrial analysis revealed that lactoferrin-derived chimera triggered oxidative stress in multiple myeloma cells, leading to reactive oxygen species generation and a decline in mitochondrial membrane potential, resulting in mitochondrial dysfunction. Although lactoferrin-derived chimera did not cause caspase-dependent cell death, it induced nuclear translocation of apoptosis-inducing factor and endonuclease G, indicating the initiation of caspase-independent apoptosis. Overall, the lactoferrin-derived chimera induces caspase-independent programmed cell death in multiple myeloma cell lines by increasing the nuclear translocation of apoptosis-inducing factor/endonuclease G. Therefore, it has potential for multiple myeloma cancer therapies.
    Keywords:  apoptosis-inducing factor; lactoferrin; lactoferrin chimera; multiple myeloma
    DOI:  https://doi.org/10.3390/cells14030217
  10. Nat Commun. 2025 Feb 12. 16(1): 1588
    Intercellular adhesion boots collective cell migration through elevated membrane tension.
    Brent M Bijonowski, Jongkwon Park, Martin Bergert, Christina Teubert, Alba Diz-Muñoz, Milos Galic, Seraphine V Wegner.
      In multicellular systems, the migration pattern of individual cells critically relies on the interactions with neighboring cells. Depending on the strength of these interactions, cells either move as a collective, as observed during morphogenesis and wound healing, or migrate individually, as it is the case for immune cells and fibroblasts. Mediators of cell-cell adhesions, such as cadherins coordinate collective dynamics by linking the cytoskeleton of neighboring cells. However, whether intercellular binding alone triggers signals that originate from within the plasma membrane itself, remains unclear. Here, we address this question through artificial photoswitchable cell-cell adhesions that selectively connect adjacent plasma membranes without linking directly to cytoskeletal elements. We find that these intercellular adhesions are sufficient to achieve collective cell migration. Linking adjacent cells increases membrane tension, which activates the enzyme phospholipase D2. The resulting increase in phosphatidic acid, in turn, stimulates the mammalian target of rapamycin, a known actuator of collective cell migration. Collectively, these findings introduce a membrane-based signaling axis as promotor of collective cell dynamics, which is independent of the direct coupling of cell-cell adhesions to the cytoskeleton.
    DOI:  https://doi.org/10.1038/s41467-025-56941-4
  11. Elife. 2025 Feb 12. pii: RP100541. [Epub ahead of print]13
    Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation.
    Kelsey R Baron, Samantha Oviedo, Sophia Krasny, Mashiat Zaman, Rama Aldakhlallah, Prerona Bora, Prakhyat Mathur, Gerald Pfeffer, Michael J Bollong, Timothy E Shutt, Danielle A Grotjahn, R Luke Wiseman.
      Excessive mitochondrial fragmentation is associated with the pathologic mitochondrial dysfunction implicated in the pathogenesis of etiologically diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) - comprising the four eIF2α kinases PERK, GCN2, PKR, and HRI - is a prominent stress-responsive signaling pathway that regulates mitochondrial morphology and function in response to diverse types of pathologic insult. This suggests that pharmacologic activation of the ISR represents a potential strategy to mitigate pathologic mitochondrial fragmentation associated with human disease. Here, we show that pharmacologic activation of the ISR kinases HRI or GCN2 promotes adaptive mitochondrial elongation and prevents mitochondrial fragmentation induced by the calcium ionophore ionomycin. Further, we show that pharmacologic activation of the ISR reduces mitochondrial fragmentation and restores basal mitochondrial morphology in patient fibroblasts expressing the pathogenic D414V variant of the pro-fusion mitochondrial GTPase MFN2 associated with neurological dysfunctions, including ataxia, optic atrophy, and sensorineural hearing loss. These results identify pharmacologic activation of ISR kinases as a potential strategy to prevent pathologic mitochondrial fragmentation induced by disease-relevant chemical and genetic insults, further motivating the pursuit of highly selective ISR kinase-activating compounds as a therapeutic strategy to mitigate mitochondrial dysfunction implicated in diverse human diseases.
    Keywords:  cell biology; human; integrated stress response; mitochondrial fragmentation; mitochondrial morphology; mouse; stress signaling
    DOI:  https://doi.org/10.7554/eLife.100541
  12. Cell. 2025 Feb 05. pii: S0092-8674(25)00096-0. [Epub ahead of print]
    ArfGAP2 promotes STING proton channel activity, cytokine transit, and autoinflammation.
    Subhajit Poddar, Samuel D Chauvin, Christopher H Archer, Wei Qian, Jean A Castillo-Badillo, Xin Yin, W Miguel Disbennett, Cathrine A Miner, Joe A Holley, Teresa V Naismith, W Alexander Stinson, Xiaochao Wei, Yue Ning, Jiayuan Fu, Trini A Ochoa, Nehalee Surve, Shivam A Zaver, Kimberly A Wodzanowski, Katherine R Balka, Rajan Venkatraman, Canyu Liu, Kelly Rome, Will Bailis, Yoko Shiba, Sara Cherry, Sunny Shin, Clay F Semenkovich, Dominic De Nardo, Sunnie Yoh, Elisha D O Roberson, Sumit K Chanda, David J Kast, Jonathan J Miner.
      Stimulator of interferon genes (STING) transmits signals downstream of the cytosolic DNA sensor cyclic guanosine monophosphate-AMP synthase (cGAS), leading to transcriptional upregulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (STING-associated vasculopathy with onset in infancy [SAVI]) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi apparatus. Because pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell-type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.
    Keywords:  ArfGAP2; Golgi trafficking; SAVI; STING; antiviral immunity; autoinflammation; cGAS; chemokines; cytokines; interferon
    DOI:  https://doi.org/10.1016/j.cell.2025.01.027
  13. Nat Rev Drug Discov. 2025 Feb 10.
    Directing autophagy to degrade cell surface receptors.
    M Teresa Villanueva.
      
    Keywords:  Biotechnology; Cancer; Chemical biology; Drug discovery
    DOI:  https://doi.org/10.1038/d41573-025-00026-w
  14. Int J Mol Sci. 2025 Jan 30. pii: 1208. [Epub ahead of print]26(3):
    Immunophenotypic and Functional Interindividual Variability in Banked Cord Blood Cells: Insights for Advanced Therapies.
    Diana María Vanegas Lozano, Bellaneth Devia Mejia, Catalina Machuca Acevedo, Valentina Jaramillo Mejia, Andrea Marisol Moreno González, Anita Krisko, Sandra Milena Quijano Gómez, Ana María Perdomo-Arciniegas.
      Umbilical cord blood (UCB) is an alternative therapeutic resource for treating both hematological and non-hematological diseases, especially for pediatric patients. However, UCB transplantation faces challenges, including delayed engraftment, increased risk of graft failure, and slower immune recovery. To maximize its clinical potential, it is essential to understand the variability and functionality of its nucleated cells. This study focused on characterizing UCB cellular populations, viability, and functionality at three key processing stages: freshly collected, post-volume reduction, and post-thawing. Using EuroFlow-based flow cytometry, significant changes were observed in granulocyte and T-cell populations during processing. Additionally, integrating EuroFlow data with hematology counts revealed variability that could affect the yield of specific cell populations, potentially influencing therapeutic decisions. An in vitro migration assay, designed to mimic the vascular niche, was employed to study donor variability in cellular migratory patterns. Notably, thawed UCB cells displayed two distinct migration profiles, distinguishing lymphocyte-like cells from monocyte-like cells. These findings underscore the importance of reproducible cellular quality control measures, such as immunophenotypic and functional donor characterization, to ensure the integrity of UCB composition. A better understanding of these parameters could improve the consistency and reliability of UCB as a starting material for the development of advanced therapies.
    Keywords:  EuroFlow; advanced cellular therapies; hematology analyzer; hematopoietic stem cells; migration profiles
    DOI:  https://doi.org/10.3390/ijms26031208
  15. Nature. 2025 Feb 12.
    Intrinsic electrical activity drives small-cell lung cancer progression.
    Paola Peinado, Marco Stazi, Claudio Ballabio, Michael-Bogdan Margineanu, Zhaoqi Li, Caterina I Colón, Min-Shu Hsieh, Shreoshi Pal Choudhuri, Victor Stastny, Seth Hamilton, Alix Le Marois, Jodie Collingridge, Linus Conrad, Yinxing Chen, Sheng Rong Ng, Margaret Magendantz, Arjun Bhutkar, Jin-Shing Chen, Erik Sahai, Benjamin J Drapkin, Tyler Jacks, Matthew G Vander Heiden, Maksym V Kopanitsa, Hugh P C Robinson, Leanne Li.
      Elevated or ectopic expression of neuronal receptors promotes tumour progression in many cancer types1,2; neuroendocrine (NE) transformation of adenocarcinomas has also been associated with increased aggressiveness3. Whether the defining neuronal feature, namely electrical excitability, exists in cancer cells and impacts cancer progression remains mostly unexplored. Small-cell lung cancer (SCLC) is an archetypal example of a highly aggressive NE cancer and comprises two major distinct subpopulations: NE cells and non-NE cells4,5. Here we show that NE cells, but not non-NE cells, are excitable, and their action potential firing directly promotes SCLC malignancy. However, the resultant high ATP demand leads to an unusual dependency on oxidative phosphorylation in NE cells. This finding contrasts with the properties of most cancer cells reported in the literature, which are non-excitable and rely heavily on aerobic glycolysis. Additionally, we found that non-NE cells metabolically support NE cells, a process akin to the astrocyte-neuron metabolite shuttle6. Finally, we observed drastic changes in the innervation landscape during SCLC progression, which coincided with increased intratumoural heterogeneity and elevated neuronal features in SCLC cells, suggesting an induction of a tumour-autonomous vicious cycle, driven by cancer cell-intrinsic electrical activity, which confers long-term tumorigenic capability and metastatic potential.
    DOI:  https://doi.org/10.1038/s41586-024-08575-7
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