bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–08–24
eight papers selected by
William Grey, University of York
  1. Biomimetic artificial bone marrow niches for the scale up of hematopoietic stem and progenitor cells.
  2. PUMA-induced apoptosis drives bone marrow failure and genomic instability in telomerase-deficient mice.
  3. Immune composition of the mononuclear cell fraction of human umbilical cord blood.
  4. Syntenin inhibition impairs stroma-tumor communication in multiple myeloma and improves bortezomib treatment efficiency.
  5. Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis.
  6. Proteomic subtypes enrich current acute myeloid leukemia nomenclature and reflect intrinsic pathogenesis alongside aging.
  7. Metallothionein 1 mediates growth and survival of Dnmt3a;Npm1-mutant acute myeloid leukemia.
  8. Edge curvature drives endoplasmic reticulum reorganization and dictates epithelial migration mode.
  1. Biomaterials. 2025 Aug 08. pii: S0142-9612(25)00531-9. [Epub ahead of print]325 123612
    Biomimetic artificial bone marrow niches for the scale up of hematopoietic stem and progenitor cells.
    Minerva Bosch-Fortea, Daniele Marciano, Julien E Gautrot.
      Hematopoietic stem cell (HSC) transplantation to treat haematological disorders is greatly restricted by poor cell availability. Engineering of culture platforms that mimic the physiological properties of the bone marrow (BM) in a scalable format is important to enable the translation of HSC therapies. Here, we report the design of biomimetic BM niches enabling the culture of HSCs in a scalable 3D platform. Beyond cellular and biochemical components (e.g. matrix and growth factors), an important element of the BM microenvironment is its architecture, dense in adipocytes, with relatively limited matrix and anisotropic mechanical properties. To capture this context, we propose the use of bioemulsions1,2 in which oil microdroplets and associated mechanical anisotropy recreate important architectural features of the hematopoietic niche. Mesenchymal stem cells (MSCs) grown at the surface of bioemulsions assembled an interstitial matrix and secreted important factors critical to the maintenance of HSC phenotype. HSCs cultured in the resulting artificial BM niches maintained stemness whilst expanding significantly (>33-fold compared to suspension cultures) and enabling scale up of expansion in conical flask bioreactors (2 M cell batches). This platform harnesses engineered BM microenvironments and the processability of microdroplet technologies to produce HSCs in a scalable format, for application in cell-based therapies.
    Keywords:  2D nanomaterials; Liquid-liquid interface; Protein nanosheet; Self-assembly; Stem cells; Toughness
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123612
  2. Cell Death Differ. 2025 Aug 19.
    PUMA-induced apoptosis drives bone marrow failure and genomic instability in telomerase-deficient mice.
    Christian Molnar, Jovana Rajak, Julia Miriam Weiss, Irene Gonzalez-Menendez, Geoffroy Andrieux, Franziska Schreiber, Eva-Maria Kornemann, Lena Wendeburg, Gudrun Göhring, Brigitte Strahm, Fabian Beier, Doris Steinemann, Melanie Börries, Martina Rudelius, Leticia Quintanilla-Martinez, Charlotte M Niemeyer, Marena R Niewisch, Verena Labi, Sheila Bohler, Miriam Erlacher.
      Bone marrow failure is a severe complication of human telomere biology disorders and predisposes individuals to secondary leukemia. A deeper understanding of this process could offer significant clinical benefits. Using a preclinical mouse model deficient in the RNA component of the telomerase (mTerc), we demonstrate that bone marrow failure results from excessive apoptosis, predominantly mediated by the pro-apoptotic p53 target PUMA. Genetic ablation of Puma alleviates hematological phenotypes and reduces the risk of lethal bone marrow failure while preserving genomic stability. Mechanistically, PUMA deficiency decreases the sensitivity of hematopoietic cells to lethal stressors, including critically short telomeres. As a consequence, reduced compensatory turnover of hematopoietic progenitors slows down telomere shortening at the population level, delays stem cell exhaustion, and diminishes the acquisition of somatic mutations - ultimately preventing neoplastic transformation. Elevated expression of both p53 and PUMA is also observed in the bone marrow from patients with telomere biology disorders. While apoptosis resistance is traditionally associated with malignant transformation, our findings provide evidence that selective inhibition of PUMA-mediated apoptosis may represent a viable therapeutic strategy to prevent or delay leukemic transformation in this patient population.
    DOI:  https://doi.org/10.1038/s41418-025-01557-w
  3. Front Immunol. 2025 ;16 1614230
    Immune composition of the mononuclear cell fraction of human umbilical cord blood.
    Karen Kikuta, Esmond Lee, Talia Menezes, Hannah Fung, Alvaro Amorin, Aditi Agrawal, Theodore L Roth, Matthew Porteus.
      Despite its therapeutic potential and unique immunological properties, the immune composition of umbilical cord blood lacks consistent and comprehensive characterizations. Human umbilical cord blood (UCB) is often discarded after delivery and is difficult to obtain for research purposes. Furthermore, most research on UCB is focused on properties of CD34+ hematopoietic stem cells for transplantation. The Binns Program for Cord Blood Research at Stanford University has the unique advantage of regular collection and isolation of mononuclear cells (MNC) from UCB donors. This study provides a robust characterization of the immune subset compositions of the CD34-negative MNC fraction of UCB (n=50). The study also compares the UCB data to adult peripheral blood (PB) mononuclear cells to identify differences in immune maturity. Using flow cytometry and single-cell RNA sequencing (scRNA-Seq), we analyzed UCB and adult PB MNC samples to characterize the cell surface protein and transcriptomic profiles of different immune subsets. Our study findings bring a higher-definition understanding of the unique immunological properties of umbilical cord blood. Study findings reveal a distinct immune profile in UCB, such as a higher average percentage of CD19 B Lymphocytes, CD4 T Cells, CD4 Naive T Cells, CD4 Recent Thymic Emigrants, CD8 Naive T Cells, CD8 Recent Thymic Emigrants, and CD19 Naive B Cells compared to adult PB. Additionally, there were fewer CD19 Memory B Cells in UCB compared to PB. The scRNA-Seq showed concordance in the proportion of immune cell types but captured more differentiated subtypes of cells. Additionally, scRNA-Seq showed unique clustering patterns in UCB, which reflect cell types that converge in adulthood as the immune system matures. These analyses yield the intriguing possibility that the immune heterogeneity of individuals at birth gives way to more stereotyped immune subsets as the immune system is exposed to the external environment and undergoes maturation. Overall, our findings provide a robust characterization of MNC UCB immune subsets and insights into how immune function develops from birth to adulthood.
    Keywords:  Peripheral Blood Mononuclear cells (PBMCs); cell therapy; flow cytometry; immune maturation; neonatal immune system; single-cell RNA sequencing (scRNA-seq); umbilical cord blood (UCB)
    DOI:  https://doi.org/10.3389/fimmu.2025.1614230
  4. Hemasphere. 2025 Aug;9(8): e70197
    Syntenin inhibition impairs stroma-tumor communication in multiple myeloma and improves bortezomib treatment efficiency.
    Chenggong Tu, Raphael Leblanc, Arne Van der Vreken, Marnix Koops, Stephane Audebert, Lauriane Goullieux, Sofie Meeussen, Kim De Veirman, Elke De Bruyne, Karin Vanderkerken, Guido David, Tom Cupedo, Pascale Zimmermann, Eline Menu.
      Multiple myeloma (MM) remains incurable due to the development of drug resistance. We previously showed that communication between bone marrow stromal cells (BMSCs) and MM cells supports MM growth and triggers therapy resistance. This communication occurs through a plethora of mechanisms, including the release of cytokines and small extracellular vesicles (sEVs). The PDZ protein syntenin is a master regulator of intercellular communication, in particular via sEVs. In this study, we aimed to explore whether targeting syntenin, by genetic alteration or pharmacological inhibition, can disrupt BMSC-MM crosstalk, thereby rendering the MM cells more sensitive to therapy. We found that syntenin (SDCBP) is highly expressed in inflammatory BMSC of MM patients and that its expression in BM aspirates correlates with poor patient survival. Using in vitro models, we established that knockout of syntenin in BMSC alters their secretome and abolishes BMSC-induced bortezomib resistance of MM cells via regulation of STAT3, MAPK, and AKT-mTOR pathways. Pharmacological inhibition of syntenin decreases syntenin and IL-6 sorting into BMSC sEVs and enhances bortezomib-induced MM cell death. Finally, we validated the therapeutic added value of syntenin inhibition in combination with bortezomib in vivo, using the 5TGM1 MM mouse model. In conclusion, our findings show that syntenin supports the secretion of pro-tumoral factors by BMSCs and qualifies as a possible novel therapeutic target in MM.
    DOI:  https://doi.org/10.1002/hem3.70197
  5. Cell Death Dis. 2025 Aug 18. 16(1): 627
    Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis.
    Zhenghao Li, Guangci Liu, Ziren Chen, Keming Li, Zhe Yu, Chao He, Xinyu Ying, Danling Huang, Chengtian Tao, Sajid Khan, Yimeng Wang, Fang-Lin Zhang, Huan Li, Yun Chen, Jingfeng Zhou, Li Yu, Thomas J Kipps, Yongxian Cheng, Suping Zhang.
      Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis and limited therapeutic options. Leukemic stem cells (LSCs), which drive disease progression and confer resistance to therapy, pose a significant challenge to conventional treatment strategies. In this study, we identified and characterized the inhibitory mechanisms of TH37, a small molecule derived from traditional Chinese medicine, which selectively targets AML blasts and LSCs. Our analyses identified peroxiredoxin 1 (PRDX1), an enzyme that catalyzes the breakdown of hydrogen peroxide (a reactive oxygen species), as the primary molecular target of TH37. We demonstrated that TH37 directly interacts with PRDX1, inhibiting its enzymatic activity and thereby elevating intracellular reactive oxygen species levels in AML cells. PRDX1 was found to be overexpressed in AML, and its expression correlated with poor prognosis and the activation of AML- and cancer-associated pathways. Targeting PRDX1, either through lentiviral short-hairpin RNA-mediated silencing or TH37 treatment, induced apoptosis, reduced colony formation, and impaired the engraftment and growth of AML cells in immunodeficient mouse models. Furthermore, TH37 synergized with conventional chemotherapeutic agent to significantly reduce the viability and colony-forming capacity of AML cells. These findings demonstrate the critical role of PRDX1 in AML pathogenesis and highlight its potential as a key therapeutic target to improve clinical outcomes for AML patients.
    DOI:  https://doi.org/10.1038/s41419-025-07831-6
  6. Blood. 2025 Aug 19. pii: blood.2024027692. [Epub ahead of print]
    Proteomic subtypes enrich current acute myeloid leukemia nomenclature and reflect intrinsic pathogenesis alongside aging.
    Wenyan Cheng, Xiao Yi, Zhenyi Wang, Jian-Feng Li, Jun-Yi Zhang, Rui-Hong Zhang, Qian-Qian Zhang, Xiangqin Weng, Ting Huang, Yong-Mei Zhu, Chao Wang, Wei Yin, Jia-Nan Zhang, Hui-Yi Wu, Jun-Min Li, Hongming Zhu, Li Chen, Wen-Fang Wang, Yuting Dai, Chen-Xu Gao, Xuan Liu, Shan Wang, Shengyue Wang, Bo Jiao, Zhu Chen, Hai Fang, Tong Yin, Yang Shen, Sai-Juan Chen.
      Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy that increasingly affects the elderly population, with its post-transcriptional landscape remaining largely elusive. Establishing a stable proteomics-based classification system and systematically screening age-related proteins and regulatory networks are crucial for understanding the pathogenesis and outcomes of AML. In this study, we leveraged a multi-omics cohort of 374 newly diagnosed AML patients, integrating proteome, phosphoproteome, genome, transcriptome, and drug screening data. Through similarity network fusion clustering, we established eight proteomic subtypes with distinct clinical and molecular properties, including S1 (CEBPA mutations), S3 (myelodysplasia-related AML), S4 (PML::RARA), S5 (NPM1 mutations), S6 (PML::RARA and RUNX1::RUNX1T1), S8 (CBFB::MYH11), S2 and S7 (mixed), aligning well with and adding actionable value to the latest World Health Organization nomenclature of AML. Hematopoietic lineage profiling of proteins indicated that megakaryocyte/platelet- and immune-related networks characterized distinct aging patterns in AML, which were consistent with our recent findings at the RNA level. Phosphosites also demonstrated distinct age-related features. The high protein abundance of megakaryocytic signatures was observed in S2, S3, and S7 subtypes, which were associated with advanced age and dismal prognosis of patients. A hematopoietic aging score with an independent prognostic value was established based on proteomic data, where higher scores correlated with myelodysplasia-related AML, NPM1 mutations, and clonal hematopoiesis-related gene mutations. Collectively, this study provides an overview of the molecular circuits and regulatory networks of AML during the aging process, advancing current classification systems and offering a comprehensive perspective on the disease.
    DOI:  https://doi.org/10.1182/blood.2024027692
  7. Haematologica. 2025 Aug 14.
    Metallothionein 1 mediates growth and survival of Dnmt3a;Npm1-mutant acute myeloid leukemia.
    Patricia A Colom Díaz, Jayna J Mistry, Kira A Young, Chih-Hsing Chou, Nathan Boyer, Ross L Levine, Nathan Salomonis, H Leighton Grimes, Jennifer J Trowbridge.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.287662
  8. Nat Cell Biol. 2025 Aug 18.
    Edge curvature drives endoplasmic reticulum reorganization and dictates epithelial migration mode.
    Simran Rawal, Pradeep Keshavanarayana, Diya Manoj, Purnati Khuntia, Sanak Banerjee, Basil Thurakkal, Rituraj Marwaha, Fabian Spill, Tamal Das.
      From single-cell extrusion to centimetre-sized wounds, epithelial gaps of various sizes and geometries appear across organisms. Their closure involves two orthogonal modes: lamellipodial crawling at convex edges and purse string-like movements at concave edges. The mechanisms driving this curvature-dependent migration remain unclear. Here we perform an intracellular cartography to reveal that in both micropatterned and naturally arising gaps, the endoplasmic reticulum (ER) undergoes edge curvature-dependent morphological reorganizations, forming tubules at convex edges and sheets at concave edges. This reorganization depends on cytoskeleton-generated protrusive and contractile forces. Mathematical modelling reveals that these morphologies minimize strain energy under their respective geometric regime. Functionally, ER tubules at the convex edge favour perpendicularly oriented focal adhesions, supporting lamellipodial crawling, while ER sheets at the concave edge favour parallelly oriented focal adhesions, supporting purse string-like movements. Altogether, ER emerges as a central mechanotransducer, integrating signals from cytoskeletal networks to orchestrate two orthogonal modes of cell migration.
    DOI:  https://doi.org/10.1038/s41556-025-01729-3
This page is being maintained by Thomas Krichel. It was last updated on 2025‒09‒08 at 9:24.