bims-emyelo 2026-10-18 papers

Issue of 2026–10–18
five papers selected by
Robbin Kramer, Radboudumc

J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70403

Aberrant Myelopoiesis and Haematopoietic Stem Cell Niche Remodelling Precedes Cancer Cachexia Onset in a Sex-Dependent Manner.

Alice Tate, Alex Brown, Lisa Ek Orloff, James Vanhie, Nicolas Collao, Cooper Brabrook, Victoria Moghadam, Vedrana Rajaković, Nadine Wiper-Bergeron, Michael De Lisio.

BACKGROUND: Male cancer patients are 30% more likely to develop cachexia compared to females; however, the underlying aetiology remains unknown. Myelopoiesis induces inflammation in cancer cachexia, which contributes to muscle atrophy. Whether differences in myelopoiesis during cancer cachexia initiation contribute to sex-based differences in cachexia incidence remains unknown.
METHODS: Male and female C57BL/6 and B6(C)-Ccr2tm1.1Cln/J mice were randomized into sham (PBS) or were inoculated subcutaneously with Lewis lung carcinoma (LLC) to induce cachexia. Mice were sacrificed 2 (14 days), 2.5 (17 days) and 3.5 weeks (24 days) post-inoculation. Changes in body composition, haematopoietic stem and progenitor cells (HSPCs), myeloid immune cell migration, bone marrow niche cellular dynamics and CCL2 expression were assessed.
RESULTS: LLC inoculation reduced tumour-free body weight, lean mass, gastrocnemius-soleus mass and myofiber cross-sectional area (CSA) in males at 3.5 weeks (p < 0.05), while females maintained tumour-free body weight, lean mass and CSA. Within the bone marrow, haematopoietic stem cells (HSCs) were increased at 2, 2.5 and 3.5 weeks compared to sham in males and at 2.5 weeks compared to 2 and 3.5 weeks in females (p < 0.05). Multipotent progenitors (MPPs) were significantly increased at 2, 2.5 and 3.5 weeks compared to sham in males and at 2.5 weeks compared to sham, 2 and 3.5 weeks in females (p < 0.05). Downstream, common myeloid progenitors (CMPs) and granulocyte-monocyte progenitors (GMPs) were elevated in males at 2.5 weeks, with CCR2+GMPs peaking at 2.5 weeks in males and 3.5 weeks in females (p < 0.05). Sex differences in HSC niche composition were also observed with osteoprogenitors, osteoblasts and endothelial cells increased at 2 weeks in males, while females showed increased osteoprogenitors and endothelial progenitors at 2.5 weeks in tumour-bearing mice (p < 0.05). Plasma C-C motif chemokine ligand 2 (CCL2) concentrations increased with tumour progression in both sexes; however, CCR2+-progenitors and macrophages were decreased at 2.5 and 3.5 weeks compared to 2 weeks (p < 0.05). In skeletal muscle, CCL2 concentration increased at 3.5 weeks, and the proportion of CCR2+/CD206- macrophages increased, while total macrophage abundance remained unchanged (p < 0.05). Macrophage subpopulations were related to decreasing CSA in males but not females.
CONCLUSION: Our study suggests that aberrant myelopoiesis and sex-specific HSC niche remodelling precede muscle atrophy during cachexia development in males. These findings provide an important first step in understanding the role aberrant myelopoiesis plays in cancer cachexia and establish myeloid skewing as a potential therapeutic target.

Keywords: CCR2‐CCL2 signalling; Lewis lung carcinoma; bone marrow; haematopoietic stem cells; inflammation; muscle wasting

DOI: https://doi.org/10.1002/jcsm.70403

bioRxiv. 2026 Sep 29. pii: 2026.09.24.754168. [Epub ahead of print]

Sexual dimorphism in adult zebrafish marrows regulates blood cell composition and immune response.

Shannon E Paquette, Carolyn L Winston, Elizabeth A Jones, Dionna M Kasper.

Hematopoiesis sustains lifelong blood production and immunity and is strongly influenced by biological sex. Males and females differ in their hematopoietic composition and susceptibility to infection and hematologic disease. Because current models cannot readily disentangle the independent contributions of sex chromosomes versus hormones, the mechanisms underlying sexual dimorphism remain poorly understood. Zebrafish have proven to be a powerful, translatable system for studying hematopoiesis, and offer a unique opportunity to isolate hormonal contributions due to their absence of sex chromosomes. However, whether sex is regulated in the zebrafish hematopoietic system remained unknown. Here, we discovered pronounced sexual dimorphism in the adult zebrafish marrow, with compositional differences peaking at reproductive age. Transcriptome analysis of marrows revealed conservation of sex-specific programs between zebrafish and human datasets. Upon immune challenge with lipopolysaccharide, all major blood lineages exhibited sex-biased changes in their composition and transcriptomes with the largest responses in erythroid and myeloid cell types. Among these sex differences was an unexpected immunoregulation of the erythroid lineage across maturation states. These findings establish biological sex as a major regulator of zebrafish hematopoiesis and immunity, paralleling humans, and lay the groundwork necessary for future mechanistic studies on sexual dimorphism in hematologic health and disease.

DOI: https://doi.org/10.64898/2026.09.24.754168

Geroscience. 2026 Oct 10.

Bone marrow myeloid skewing and preserved immunoregulation in hip osteoarthritis of elderly patients.

Ada Tushe, Eleonora Binatti, Elisa Belluzzi, Assunta Pozzuoli, Samuela Francescato, Barbara Buldini, Carlo Biz, Pietro Ruggieri, Susanna Mandruzzato.

Osteoarthritis (OA) is increasingly recognized as a disease involving low-grade inflammation and immune remodeling, yet the contribution of the bone marrow (BM) myeloid compartment to hip OA remains poorly defined. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with immunoregulatory activity and potential roles in inflammatory bone disease. Here, we investigated ex vivo BM myeloid composition and the functional properties of BM-MDSCs in elderly patients with hip OA compared with patients undergoing surgery for proximal femoral fracture. BM aspirates from both cohorts were analyzed by flow cytometry and cultured with G-CSF and GM-CSF to induce BM-MDSCs. Despite the lower mean age of the hip osteoarthritis cohort, these patients showed a significantly higher proportion of BM myeloid cells than fracture patients, whereas lymphoid cell frequencies were not significantly different. Analysis of myeloid maturation stages revealed enrichment of CD11b⁺/CD16low metamyelocyte-like cells in hip OA samples both ex vivo and after cytokine-driven expansion. Functional assays demonstrated that inhibition of activated T cell proliferation was confined to the most immature myeloid fraction, which displayed promyelocyte-like features. This suppressive activity was preserved in both hip OA and fracture cohorts, with no significant difference between groups. These findings indicate that hip OA is associated with BM myeloid skewing and selective enrichment of myeloid subsets reassembling metamyelocytes-like cells, while maintaining conserved immunoregulatory function. The BM may represent an active immunological compartment linked to the balance between chronic inflammation and immune regulation in hip OA.

Keywords: Bone marrow; Hip osteoarthritis; Immunology; Inflammaging; Myeloid-derived suppressor cells

DOI: https://doi.org/10.1007/s11357-026-02578-0

Aging Dis. 2026 Oct 09.

Aging as a Potential Modulator of Extramedullary Hematopoiesis: A Hypothesis-Generating Niche-HSPC Competence-Trigger Model.

Zoe Bezirgiannidou, Iliana Stamatiou, Konstantinos Liapis, Emmanouil Spanoudakis, Evdokia Mandala, Ioannis Kotsianidis, Timoleon-Achilleas Vyzantiadis, Efthymia Vlachaki.

Extramedullary hematopoiesis (EMH) is a compensatory response to hematopoietic stress that occurs unevenly across disorders with ineffective erythropoiesis (IE). The mechanisms underlying differing EMH patterns despite similarly severe IE remain poorly understood. Thalassemia and congenital dyserythropoietic anemias frequently develop overt EMH, whereas myelodysplastic syndromes (MDS), despite severe IE, rarely show overt EMH. We propose the Niche- HSPC Competence-Trigger Model as a hypothesis-generating framework in which EMH expression reflects the interaction among erythropoietic trigger load, intrinsic hematopoietic stem and progenitor cell (HSPC) competence, and extramedullary niche fitness. Erythropoietic trigger load reflects the intensity and persistence of erythropoietic stress, particularly anemia and hypoxia, in disorders characterized by ineffective erythropoiesis. HSPC competence refers to the intrinsic capacity of HSPCs for proliferation and differentiation, whereas extramedullary niche fitness denotes the capacity of target tissues to support HSPC homing, engraftment, survival, expansion, and productive hematopoiesis; this capacity is shaped by stromal and vascular integrity, inflammatory and fibrotic remodeling, metabolic support, and iron availability. Within this framework, overt EMH is hypothesized to be favored when erythropoietic drive coincides with preserved HSPC competence and extramedullary niche fitness. Conversely, impaired HSPC competence or reduced niche fitness may limit overt EMH, while whether subclinical extramedullary hematopoietic activity occurs in MDS remains unresolved. We hypothesize that aging may modulate this balance by influencing both HSPC competence and niche fitness, thereby potentially contributing to the rarity of overt EMH in MDS. These hypotheses, including the contribution of aging and the possible occurrence of subclinical extramedullary hematopoietic activity, require experimental and clinical validation.

DOI: https://doi.org/10.14336/AD.2026.0896

Int J Mol Sci. 2026 Sep 30. pii: 8763. [Epub ahead of print]27(19):

Multiple Myeloma Cell-Derived Secretome Modulates Bone Marrow Mesenchymal Stromal Cell Migration In Vitro.

Maria João Fernandes, Andrea Giestinhas, Sara Reis Moura, Maria Helena Vasconcelos, Susana Gomes Santos, Maria José Oliveira, Maria Inês Almeida.

Multiple myeloma (MM) depends on a permissive bone marrow microenvironment that supports malignant plasma cell survival and disease progression. Bone marrow mesenchymal stromal cells (BM-MSCs) are key components of this niche, but the mechanisms by which they are recruited by MM cells remain unclear. Here, we show that the MM-derived secretome (MM-Sec) promotes BM-MSC wound closure and transwell migration-associated responses in vitro. A small extracellular vesicle (sEV)-enriched pellet was isolated from MM.1S-Sec by differential ultracentrifugation and characterized, and the relative contributions of the sEV-enriched fraction and sEV-depleted secretome (post-100,000× g) to BM-MSC migration were assessed. The results show that the sEV-depleted secretome is more effective than the sEV-enriched fraction in promoting BM-MSC recruitment. Chemokine profiling of MM.1S-Sec identified CCL3 (MIP-1α) and CCL5 (RANTES) as abundant secreted factors and exploratory candidate contributors. Recombinant CCL3 and CCL5 increased the BM-MSC transwell migration response at high concentrations. Priming with MM.1S-Sec was associated with increased transwell migration-associated responses in the presence of CCL3 and CCL5. Together, these exploratory findings suggest that both vesicle-associated and soluble non-vesicular components may contribute to BM-MSC migration, while CCL3 and CCL5 may participate as candidate contributors within a broader network of soluble mediators. These findings identify secretome-mediated modulation of stromal migration as a relevant component of MM-microenvironment crosstalk that warrants further mechanistic investigation.

Keywords: bone marrow niche; cytokines/chemokines; extracellular vesicles; secretome

DOI: https://doi.org/10.3390/ijms27198763