The hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. Although most infections are self-limiting, zoonotic genotypes can persist in immunocompromised individuals. Transmitted via the fecal-oral route, HEV has been suggested to directly infect the intestinal epithelium, a tissue with high regenerative capacity. Here, we demonstrate that HEV predominantly infects proliferative transit-amplifying and intestinal stem cells within the crypts of human pluripotent stem cell-derived intestinal organoids (hIOs). Supporting this, we detected HEV RNA in the intestinal crypts of an HEV-infected patient. We further found that HEV infection spreads through cell division and is maintained in hIOs for more than 40 days, contrasting with acute hepatitis A virus, whose infections are rapidly cleared from hIOs. Given the self-renewal ability and metabolic constraints of proliferative intestinal progenitor cells, our findings suggest that intestinal crypts could serve as reservoirs for chronic HEV infection and highlight the intestinal crypt as a primary target for viral infection in the gastrointestinal tract.

Patients with myelodysplastic syndrome (MDS) harboring SRSF2 (serine and arginine rich splicing factor 2) mutations exhibit poor prognosis and aberrant inflammatory activation, underscoring an urgent need for therapies. Here, we reveal that low messenger RNA expression of SETD2 (SET domain containing 2) in hematopoietic stem and progenitor cells (HSPCs) from patients with MDS carrying SRSF2P95 mutations (SRSF2P95-Mut MDS) correlates with adverse outcomes and increased inflammation. Multivariate analysis confirmed the correlation between low SETD2 expression and poor prognosis in patients with SRSF2P95-Mut MDS. Furthermore, Setd2 loss in the Srsf2P95H/+ mouse model resulted in lethal MDS with hyperinflammation and expansion of myeloid-derived suppressor cells (MDSCs). Mechanistically, SETD2 methylates SRSF2P95H at lysine-17 and lysine-65 to inhibit aberrant splicing of CEACAM1-4 (isoforms of carcinoembryonic antigen cell adhesion molecule), which enhances interleukin-1β (IL-1β) signaling through Slc7a11 (solute carrier family 7 member 11)-mediated cystine uptake, thereby promoting HSPC differentiation into MDSCs, establishing an IL-1β-driven immunosuppressive microenvironment. These findings identify the SRSF2P95HK17me1K65me2-CEACAM1-4 signaling axis as a promising therapeutic target in SRSF2P95-Mut MDS.

Synucleinopathies is an umbrella term for multiple neurological disorders, including Parkinson's disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA). A central pathological hallmark of synucleinopathies is the aggregation of α-synuclein (αS, a neuronal protein) and its prion-like spread. Therefore, inhibition of αS aggregation and spread is considered a viable therapeutic approach for the treatment of synucleinopathies. Foldamers are synthetic ligands that mimic the secondary structure of proteins. Using an oligoquinoline (OQ) scaffold-based foldamer approach, we have previously identified a foldamer (SK-129) that potently inhibits αS aggregation. Here, using a wide range of biophysical, cellular, and in vivo methods, we showed that SK-129 rescued synucleinopathy phenotypes in cellular, Caenorhabditis elegans, and human induced pluripotent stem cell (iPSC)-derived neuron models. SK-129 specifically bound to neurotoxic αS oligomers with ~6-fold higher affinity (Kd = 221 ± 29 nM) than to physiological αS monomer, validating αS oligomers as a therapeutic target. Furthermore, SK-129 efficiently crossed the blood-brain barrier (BBB) and exhibited favorable pharmaceutical properties in mice. Treatment with SK-129 prevented brain histopathology and increased survival in a mouse model expressing human A53T mutant αS without showing any apparent cytotoxicity. SK-129 inhibited αS aggregation mediated by exosomes derived from C. elegans or patients with PD in HEK293T reporter cells. SK-129 completely inhibited the coaggregation of αS-tau, a pathological biomarker for LBD in both cellular and mouse models. Overall, we report a potent foldamer with therapeutic potential for PD and LBD.

Vaccination is the best way to combat annual influenza epidemics, yet the breadth of vaccine-induced humoral immunity toward decades of future differentially evolving influenza A (IAV) and influenza B (IBV) viruses is unclear. Using historic 1994 influenza vaccination cohorts of young and older adults, we defined antibody responses elicited by 1994 vaccination against future influenza strains spanning three decades of differentially evolving IAV and IBV strains. Quality of antibody responses and vaccine-induced and cross-reactive B cell memory responses were investigated. Vaccination increased antibody titers against all 1994 vaccine components in younger and older adults. Antibodies to future H1N1 strains were also detected across younger and older adults, including nonneutralizing hemagglutinin (HA) stem responses. Prominent boosting against earlier B/Yamagata/16/1988 and future Yamagata lineage strains was also observed, but antibody responses toward future rapidly evolving H3N2 strains were minimal. Systems serology revealed divergent antibody signatures between younger and older adults against future antigens. However, postvaccination responses were of high quality in both age groups. Cross-reactive HA-specific memory B cells induced by 1994 vaccination bound to vaccine and future H1 and IBV strains but exhibited minimal responses against H3. Group 1 cross-reactive H1/H5 stalk-specific responses also contributed to the overall H1 future response, whereas cross-reactive H3/H7 stalk-specific B cells were not detected. Our study provides insights into the breadth of vaccine-induced humoral immunity toward future influenza viruses over 30 years of influenza virus evolution, including newly emerging pandemic strains, and highlights the unmet need to optimize future vaccines strategies, especially for H3N2.

Dengue virus infection is a major global health problem with clinical outcomes ranging from mild febrile illness to severe disease. Although a reduction in platelet counts is a common feature of dengue, the mechanisms underlying the presence of viral antigens in circulating platelets remain incompletely understood. In this study, we investigated whether infection of megakaryocytic precursors contributes to the generation of platelets carrying dengue virus proteins. Using the human megakaryocytic precursor cell lines K562 and MEG-01 cell lines as in vitro models, we show that reference strains and clinical isolates of dengue virus infect megakaryocytic precursors and modulate their differentiation, as evidenced by increased expression of the differentiation marker CD41 and the production of platelet-like particles. Flow cytometry analysis demonstrated that PLPs released from infected precursors contained precursor-derived PLP-associated dengue virus envelope protein. Correlation analyses revealed significant associations between the extent of precursor infection and both differentiation markers and PLP-associated E protein levels at early time points. Consistent with these findings, dengue virus E protein was detected in platelets from dengue patients, while no statistically significant differences were observed between clinical severity groups, a trend toward higher proportions of E+ platelets were observed in patients with dengue with warning signs or severe dengue. Spearman correlation analyses further supported an association between in vitro precursor infection and the generation of E-positive PLPs. In contrast, platelets from healthy donors incubated ex vivo with dengue virus did not acquire E protein, indicating that direct uptake or infection of circulating platelets is inefficient. Together, these results support a model in which infection of megakaryocytic precursors contributes to the generation of platelets carrying dengue virus antigens, suggesting that platelet-associated E protein may reflect bone marrow involvement during dengue infection.

Transition from a pluripotent to a differentiated cell state is accompanied by significant changes in genome organization. Activity dependent neuroprotective protein (ADNP) is a chromatin regulator with critical roles in neurodevelopment and limits the genomic occupancy of CTCF, a master architectural protein in genome organization, in embryonic stem cells. However, ADNP localization, function, and relationship with CTCF in differentiated neural lineages are not well studied. Here we develop a dual degron model which allows us to acutely deplete ADNP in neural progenitor cells (NPCs). We find that ADNP depletion does not impact NPC survival in the short term, but results in a genome organization switch, which favors the formation of short-range chromatin looping interactions coinciding with CTCF accumulation. Furthermore, ADNP localizes to active gene promoters in NPCs that are unoccupied by CTCF, where it prevents over-expression of genes that are activated upon neurodifferentiation and represses those involved in commitment to other lineages. Our findings uncover CTCF-dependent as well as CTCF-independent regulatory mechanisms of ADNP in NPC-specific chromatin organization and gene expression programs that may underlie its essential function in neurodevelopment.

PD-1+TCF1+ stem-like CD8 T cells are a progenitor population that provides a proliferative burst of effector CD8 T cells upon PD-1 blockade therapy, making them a key therapeutic target in antiviral and anticancer immunotherapy. Here, we show that IL-7 therapy preferentially expands these stem-like CD8 T cells, using NT-I7, a long-acting Fc-fused recombinant human IL-7 (efineptakin alfa). Gene profile analysis showed that a proliferating stem-like cluster induced by NT-I7 exhibited enrichment of genes related to lymphocyte migration. After NT-I7 treatment, proliferation of stem-like cells in the spleen was initiated within the white pulp, followed by egress into the red pulp. NT-I7 treatment led to an increase in stem-like CD8 T cells in circulation and peripheral tissues, contrasting with their resident property in lymphoid organs. These findings suggest NT-I7 as a promising strategy to expand and mobilize stem-like CD8 T cells to enhance antiviral and anticancer immunotherapies.

High recurrence rates, significant metastatic potential, and limited overall survival make triple-negative breast cancer (TNBC) the most challenging subtype among breast cancers. Previous studies have indicated that the downregulation of TGFB2-AS1 can enhance the stem-like properties of tumor cells, thereby promoting TNBC progression. Bioinformatics analysis has revealed the regulatory role of GATA6 in TGFB2-AS1 transcription, providing insights into the transcriptional regulation of TGFB2-AS1 by GATA6 and offering potential prognostic biomarkers and therapeutic strategies for TNBC.

Fanconi anemia (FA) is a rare inherited disorder characterized by genomic instability, bone marrow failure, and a markedly increased risk of developing acute myeloid leukemia (AML). The intrinsic hypersensitivity of FA cells to DNA-damaging agents renders conventional chemotherapy particularly toxic and often ineffective.

The prognosis of relapsed or refractory T-cell and NK-cell lymphoid proliferations and lymphomas (R/R T/NK-LPD/LYM) remains poor. Modified dendritic cell–cytokine-induced killer (DC–CIK) cells loaded with tumour stem cell (TSC) membrane microparticles (MMPs) can improve the targeted killing activity against tumours. However, the use of this treatment has not been reported for R/R T/NK-LPD/LYM. Herein, we report 3 cases. Case 1 involved an 8-year-old male who presented with bilateral cervical painless lymphadenopathy and a left elbow mass. Case 2 involved a 44-year-old man with recurrent nasal congestion and a runny nose. Case 3 involved a 49-year-old man whose bilateral cervical, axillary, and inguinal lymph nodes were enlarged. The biopsy results revealed T-lymphoblastic leukaemia/lymphoma, not otherwise specified (NOS); extranodal NK/T-cell lymphoma, nasal type; and nodal T follicular helper (TFH) cell lymphoma, angioimmunoblastic type (nTFHL-AI) for Patients 1, 2, and 3, respectively. All three patients ultimately underwent modified dendritic cell–cytokine-induced killer cell therapy loaded with tumour stem cell membrane microparticles following disease progression, relapse, and chemotherapy-associated complications after first-line therapy and multiple lines of salvage therapy. Following treatment with modified dendritic cell–cytokine-induced killer cells loaded with tumour stem cell membrane microparticles, two of these three patients achieved complete and durable remission, whereas the third patient achieved a partial response, with no treatment-related adverse events reported. At the most recent follow-up, two patients maintained stable disease (SD) with preserved quality of life, while one patient experienced progressive disease (PD) and died because of multiple organ dysfunction syndrome secondary to transplantation-associated colitis. To our knowledge, this is the first report of the use of modified dendritic cell–cytokine-induced killer cells loaded with tumour stem cell membrane microparticles for the treatment of R/R T/NK-LPD/LYM. Our findings warrant further evaluation of this novel targeted immunotherapy in future prospective clinical trials.

We have reported that trabecular meshwork stem cells (TMSCs) are effective for trabecular meshwork (TM) regeneration. This study aims to investigate different responses of TMSCs and TM cells to TGF-β2 and protective factors in TMSCs.

Stem cell-derived insulin-producing cells (Ins-PCs) hold great promise for diabetes treatment. Placenta-derived multipotent stem cells (PMSCs) are considered an ideal source of Ins-PC generation due to their immunomodulatory and differentiation properties. However, the cellular and molecular pathways underlying PMSC differentiation to Ins-PCs have not been fully elucidated. In this study, PMSCs were isolated from human placenta and successfully differentiated into Ins-PCs using miRNA-181a mimics. Differentiated Ins-PCs produced a significant amount of insulin and upregulation of C-peptide, insulin, and MAFA expression, compared to undifferentiated control PMSCs. RNA sequencing and LC-MS/MS were performed to uncover the pathways involved in the Ins-PC differentiation process. RNA sequencing revealed the transcriptional landscape of PMSC-derived Ins-PC differentiation. Pathway analysis identified important pathways involved in the differentiation process, including Notch and Wnt/ß-catenin, and so forth. Proteomics analysis further affirmed the presence of key insulin pathway-related proteins involved in the differentiation of PMSCs into Ins-PCs, including LEPR, STC2, MAP2K2, and so forth. Moreover, integrated transcriptomic and proteomic analyses further highlighted LEPR as a potential key regulator for Ins-PC differentiation. These findings demonstrated the feasibility of generating Ins-PCs from PMSCs and identified potential signaling pathways and regulators underlying Ins-PC differentiation, supporting PMSCs as a promising stem cell source of cell-based therapy for diabetes treatment.

Steroid-refractory acute graft-versus-host disease (SR-aGVHD), a severe complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) lacking standard second-line therapy, was studied in a retrospective analysis of 95 patients (2019-2024) at Third Hospital of Shanxi Medical University. We compared umbilical cord mesenchymal stem cells (UC-MSCs) plus standard care (n = 44) vs. standard care alone (n = 51). UC-MSCs were infused intravenously at 1-3 × 106 cells/kg with three infusions per patient. The MSC group had higher complete response (CR) rates than non-MSC group: 84.1% vs. 58.8% for grade II-IV SR-aGVHD (p = 0.007) and 54.5% vs. 31.4% for grade III-IV SR-aGVHD (p = 0.034) at week 4. Liver and gut CR rates improved by 31.8% and 28.1%, respectively. Multivariate analysis identified age ≥35 years, grade IV aGVHD, and hemoglobin ≤90 g/L as independent adverse prognostic factors. After median follow-up of 27 months, overall survival (OS) did not differ (HR = 1.04, p = 0.911). UC-MSCs improve early SR-aGVHD remission; prognostic factors enable risk stratification.

Cytokines mediating epithelial and immune cell interactions modulate mucosal healing-a process that goes awry with chronic inflammation as in inflammatory bowel disease. TNFSF13 is a cytokine important for B cell maturation and function, but roles for epithelial TNFSF13 and putative contribution to inflammatory bowel disease are poorly understood. We evaluated functional consequences of a novel monoallelic TNFSF13 variant using biopsies, tissue-derived colonoids and induced pluripotent stem cell (iPSC)-derived colon organoids. TNFSF13 variant colonoids exhibited a >50% reduction in secreted TNFSF13, increased epithelial proliferation, and reduced apoptosis, which was confirmed in iPSC-derived colon organoids. Single cell RNA-sequencing and flow cytometry suggested FAS as the predominant colonic epithelial receptor for TNFSF13, which was confirmed by co-immunoprecipitation and binding assays. Imaging mass cytometry revealed an increase in epithelial-associated B cells in TNFSF13 variant colon tissue sections. Finally, TNFSF13 variant colonoids co-cultured with memory B cells demonstrated a reduction in immunoglobulin-producing plasma cells compared to control colonoid cocultures. Our findings support a role for epithelial TNFSF13 as a regulator of colonic epithelial growth and epithelial crosstalk with B cells.

Cellular senescence in osteogenic mesenchymal cells contributes to age-related bone loss. The bone marrow hosts myeloid cells, the precursors of immune cells, as well as mesenchymal cells, which give rise to osteoblasts and osteocytes. The senotype and senolytic response of bone marrow cells, particularly hematopoietic cells, in age-related bone loss is unclear. In this issue, Doolittle et al. showed that of all immune cells, myeloid cells had the strongest senescence profile, yet the relative level of senescence remained lower than that of mesenchymal stromal cells. Mesenchymal cells displayed a profound senotype, rendering them susceptible to senolytic clearance protecting against bone loss. By contrast, selective clearance of p16+ myeloid cells was not long-lasting and, hence, did not fully protect against age-related bone loss. These findings underscore the challenges of developing senolytic strategies for tissues with mixed senotypes, such as bone.

Cellular senescence plays a critical role in the pathogenesis and progression of osteoarthritis (OA), contributing to articular cartilage degradation, chronic inflammation, and joint function impairment. Mesenchymal stem cells/stromal cells (MSCs) and their derivatives have emerged as potential targets for novel therapeutic strategies against cell senescence in OA, as they exert anti-aging effects in repairing damaged cartilage through multiple mechanisms-including regulating age-related signaling pathways, reducing the secretion of pro-inflammatory cytokines, and improving mitochondrial function.

Telocytes (TCs) have recently emerged as novel components of the skeletal muscle interstitium. They are distinguished from other stromal cells by their immunophenotypic profiles and, especially, unique ultrastructural traits. Specifically, TCs feature a small cell body and very long, thin telopodes with a moniliform appearance conferred by the alternation of slender segments (podomers) and small dilated portions (podoms). Experimental evidence suggests that, as part of the skeletal muscle stem cell niche, TCs may be involved in orchestrating satellite cell activation and myogenic differentiation through both direct physical interactions and paracrine signaling. Yet, further in-depth research is needed to uncover specific immunophenotypic signatures for skeletal muscle TCs within the niche, as well as to identify the signaling pathways by which they influence neighboring satellite cells and, possibly, other cellular components of the niche. In the present review, particular emphasis is placed on the putative strategic role of TCs in maintaining skeletal muscle tissue homeostasis, their involvement in muscle pathological alterations, and, most importantly, their possible role in the coordination of the regenerative response following injury. In perspective, the promising therapeutic potential of TC-based strategies to enhance skeletal muscle tissue repair/regeneration and restrain post-injury fibrosis is also discussed.

β-thalassemia is an inherited blood disorder characterized by chronic anemia, ineffective erythropoiesis, and in its most severe form, lifelong transfusion dependence. The standard of care for transfusion-dependent thalassemia (TDT) is regular red blood cell transfusions to relieve the anemia and suppress ineffective erythropoiesis and iron chelation therapy to mitigate morbidity and mortality related to iron overload. Allogeneic hematopoietic stem cell transplantation is a curative option but is only available to patients with an appropriate donor and carries risks of graft-versus-host disease and other transplant-related morbidity. In recent years, the therapeutic landscape for TDT has changed dramatically with the approval of two autologous gene therapies in the United States: betibeglogene autotemcel (beti-cel) and exagamglogene autotemcel (exa-cel). Clinical trials for both gene therapies have demonstrated high rates of sustained transfusion independence for both pediatric and adult age groups. However, despite these advances, challenges remain. Gene therapy requires myeloablative busulfan-based conditioning chemotherapy, which carries the risk of short- and long-term toxicities. Furthermore, centralized manufacturing and high treatment costs are likely to limit access to gene therapy. In this review, we discuss the available clinical trial and real-world data for beti-cel and exa-cel. We describe how gene therapy fits into the current treatment landscape and introduce areas of ongoing investigation to improve access to transformative therapy for TDT.