ABO-incompatible (ABOi) hematopoietic stem cell transplantation (HSCT) is often associated with ABO discrepancies post-HSCT. Re-emergence of the patient's original type post-HSCT may signal graft loss, disease relapse, recent transfusion, or soluble ABO antigen. We present a group A pediatric patient with leukemia who underwent a minor ABOi HSCT from a group O donor with persistent and increasing A reactivity 2 years post-HSCT.

The use of immune checkpoint inhibitors (ICIs) has deeply improved the outcome of relapsed or refractory (R/R) primary mediastinal B-cell lymphoma (PMBCL) patients. However, real-world data are still limited, and several aspects, including the need for consolidation strategies, remain to be fully elucidated. We report the results of the multicenter Italian retrospective observational PRIMICI study on R/R PMBCL patients treated with ICIs in a real-life (off-label) setting. Seventy-four patients, 42 treated with pembrolizumab and 32 with nivolumab-brentuximab vedotin (nivo-BV), were enrolled. The median follow-up was 34 months. The best overall response and complete response (CR) rates were 64% (n = 50) and 50% (n = 37), respectively. Of the 37 patients in CR, 11 received a consolidation treatment and 26 patients continued ICIs; CR were stable, independently from the use of consolidation, with a 4-year disease-free survival of 100%. The estimated 5-year progression-free survival (PFS) and overall survival (OS) were 60.4% (95% confidence interval [C.I.] 48.3%-70.6%) and 77.5% (95% C.I. 65.8%-85.6%), respectively. Nivo-BV was associated with faster and higher response rates and better OS compared to pembrolizumab. OS significantly improved after 2020 due to the use of salvage treatment with CAR T-cells. In conclusion, this study supported the safety and effectiveness of pembrolizumab or nivo-BV as a salvage therapy in R/R PMBCL patients. Importantly, the chance to obtain long-lasting responses, regardless of the use of a consolidation treatment, indicates that ICIs may be used with a curative intent in a significant subset of patients.

Skeletal stem cells (SSCs), a specialized subset of mesenchymal stem cells, drive bone regeneration. This study aimed to characterize the pathological effects of ionizing radiation (IR) on osteogenic precursor cells (MC3T3-E1) and to elucidate the therapeutic efficacy and underlying molecular mechanisms of SSC-mediated rescue.

Cancer stem cells (CSCs) are a key subpopulation within tumors, characterized by their self-renewal and differentiation potential, and they drive tumor initiation, progression, metastasis, and recurrence. Recent epitranscriptomic studies have revealed that RNA modifications, including m6A, m5C, ac4C, m7G, and m1A, play critical roles in maintaining CSC stemness, determining cell fate, reprogramming metabolism, and promoting therapy resistance. This review systematically summarizes the functions of different RNA modifications and their associated enzymes in CSCs. We also discuss how RNA modifications regulate core CSC signaling pathways, such as Wnt/β-catenin, Notch, Hedgehog, PI3K-AKT-mTOR, JAK/STAT, Hippo/YAP, and TGF-β/SMAD, and we highlight strategies targeting RNA modifications for CSC intervention along with their potential challenges. These findings suggest that RNA modifications and their regulators represent promising therapeutic targets in CSCs, providing a rationale for developing highly selective or combination treatment strategies.

Leukemias are heterogeneous hematologic malignancies that involve dysregulated proliferation and impaired differentiation of hematopoietic cells. The Wnt signaling pathway, which regulates hematopoietic stem cell self-renewal and lineage commitment, is dysregulated across leukemia subtypes. Non-coding RNAs (ncRNAs), which include microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs, have been identified as important post-transcriptional and epigenetic regulators of oncogenic signaling networks. There is growing evidence for a complex, bidirectional relationship between ncRNAs and the Wnt/β-catenin pathway, but this has not yet been summarized or integrated into the context of leukemia. This study examines how ncRNA manipulation of core Wnt components - β-catenin, Frizzled receptors, and Dvl (dishevelled) proteins - affect leukemic cell survival, proliferation, stemness, and treatment resistance. Furthermore, we discuss reciprocal regulation, in which Wnt stimulation affects ncRNA production, forming feed-forward loops that promote leukemogenesis. By synthesizing disparate findings from studies investigating ncRNA and Wnt signaling mechanisms across leukemia subtypes, we identify critical mechanistic gaps in the literature, as well as opportunities and controversies that could be that could be leveraged in evaluating ncRNA-Wnt interactions as diagnostic and therapeutic targets. This review presents a comprehensive study integrating ncRNA biology and Wnt-driven leukemic development in order to identify crucial insights into disease vulnerabilities and future research initiatives.

Infertility affects approximately 15% of couples worldwide, with male factors accounting for approximately half of the cases. Low-level laser therapy (LLLT) has been increasingly considered in modern medicine due to its high efficacy, ease of use, and lack of side effects. Evidence suggests that this method can prevent DNA damage in cells and activate key genes related to fertility. This study aimed to investigate the effects of LLLT on sperm production in azoospermic mice using in vitro and in vivo experimental models.

Neural injuries affecting both the central nervous system (CNS) and peripheral nervous system (PNS) pose a great clinical challenge due to the neural tissue's limited self-regenerative capacity. Human dental pulp stem cells (hDPSCs), derived from the neural crest and easily obtained from extracted teeth, exhibit considerable potential for neural regeneration. This potential is attributed to their ability to directly differentiate into various neuronal cell types, paracrine effects, and interactions with biomaterial scaffolds. In this review, we reviewed the molecular mechanisms by which hDPSCs support neural repair, highlighting their direct neuronal differentiation function, neuroprotection function via paracrine signaling, and recent innovations in biomaterial scaffolds that enhance the viability of hDPSCs for neuroregenerative applications. Preclinical studies have shown promising therapeutic effects of hDPSCs in spinal cord injuries (SCI), strokes, Parkinson's disease (PD), Alzheimer's disease (AD), and peripheral nerve injuries. However, challenges remain, including optimizing neuronal differentiation specificity, ensuring immunological safety, and achieving scalable clinical applications. Future research should focus on standardizing manufacturing protocols, implementing strict quality control, and developing functional assays linked to neural recovery to maximize the potential of hDPSCs for nervous system regeneration.

Hepatocellular carcinoma (HCC) is a lethal malignancy with limited therapeutic options, necessitating novel treatment strategies. This study investigates the potential of emodin, a natural anthraquinone, to suppress HCC by inducing cuproptosis, a newly identified form of regulated cell death.

Relapsed/refractory RUNX1::RUNX1T1-positive acute myeloid leukemia remains a therapeutic challenge due to high relapse rates post-allogeneic hematopoietic stem cell transplantation. Preclinical evidence suggests that RUNX1::RUNX1T1 fusion proteins sensitize cells to poly ADP-ribose polymerase inhibitors by suppressing homologous recombination repair. This study explores the safety and efficacy of a novel conditioning regimen incorporating olaparib (a PARPi) for relapsed/refractory RUNX1::RUNX1T1+ AML patients undergoing allo-HSCT.

Forkhead Box A2 (FOXA2) is a transcription factor essential for endodermal development and the formation and function of several metabolic organs, including the liver and pancreas. Within the pancreatic lineage, FOXA2 plays a crucial role in orchestrating islet development, maintaining β-cell identity, and regulating genes central to glucose sensing and insulin secretion. This review provides a comprehensive overview of FOXA2's dual role in both developmental and mature stages of pancreatic islets, highlighting its function as a gatekeeper of lineage specification and metabolic homeostasis. We describe FOXA2's dynamic expression patterns during embryogenesis, its regulatory interactions with other key transcription factors, such as PDX1 and NKX6.1, and its influence on chromatin accessibility during islet cell differentiation. Furthermore, we discuss the consequences of FOXA2 dysregulation, including impaired α- and β-cell maturation, loss of functional identity, and contributions to the pathogenesis of diabetes. Insights from mouse models, human stem cell-derived islets, and patient genetics underscore the clinical relevance of FOXA2 in monogenic and complex forms of diabetes. By integrating developmental biology, genomics, and disease modeling approaches, this review highlights FOXA2 as a central regulator connecting pancreatic organogenesis with long-term metabolic control. Understanding FOXA2's regulatory networks may open new avenues for therapeutic strategies aimed at restoring or preserving β-cell function in diabetes.

Antibacterial prophylaxis has long been a cornerstone of supportive care in patients with haematological malignancies undergoing intensive chemotherapy and haematopoietic stem cell transplantation (HSCT), particularly in the setting of prolonged and profound neutropenia. However, the widespread use of fluoroquinolone (FQ) prophylaxis has increasingly raised concerns related to antimicrobial resistance, microbiota disruption, drug-related toxicity, and Clostridioides difficile infection, challenging its universal application. At the same time, the therapeutic landscape of haematology is rapidly evolving, with the introduction of novel agents and cellular therapies such as chimeric antigen receptor (CAR) T cells, bispecific antibodies (BsAbs), antibody-drug conjugates, and immune-based treatments, each associated with distinct patterns of immunosuppression and infectious risk. In this narrative review, we critically examine the role of antibacterial prophylaxis through the lens of antimicrobial stewardship, integrating evidence from traditional chemotherapy and transplantation with emerging data from innovative therapies. We summarize current guideline recommendations, real-world evidence, and recent studies questioning the net benefit of routine FQ prophylaxis, particularly in settings with high resistance prevalence. Alternative strategies, including non-FQ agents and selective omission of prophylaxis, are also discussed. Overall, available evidence supports a shift from universal prophylaxis toward a risk-adapted, individualized approach that accounts for treatment modality, expected duration and depth of neutropenia, patient-specific factors, and local epidemiology. Embedding antibacterial prophylaxis decisions within structured antimicrobial stewardship programs is essential to balance infection prevention with long-term patient safety and resistance containment in modern haematological practice.

Severe acute pancreatitis (SAP) is a complex inflammatory disorder with severe immune imbalance. This study investigates the therapeutic potential of extracellular vesicles derived from human adipose mesenchymal stem cells (hADSC-EVs) in modulating Treg differentiation and alleviating SAP. We conducted a phosphoproteomics analysis to evaluate phosphorylation levels, and administered hADSC-EVs in a mouse model of SAP and assessed their impact on Treg differentiation. Phosphoproteomics revealed a significant increase in p-STK3 following hADSC-EVs treatment, restoring Foxp3 level diminished by STK3 knockdown. HADSC-EVs promoted Treg differentiation in a concentration-dependent manner by targeting Foxp3 transcription. In the SAP mouse model, hADSC-EVs improved survival rates and mitigated histopathological alterations. In conclusion, our study revealed that STK3 effectively promotes Treg differentiation and enhances their immunosuppressive capabilities, thereby ameliorating inflammation and attenuating the pathological phenotypes associated with SAP. These findings provide valuable insights into the potential role of hADSC-EVs in regulating immune responses and promoting tissue repair.

Sponges are capable of rebuilding functional individuals from cell aggregates (primmorphs), a process termed whole-body regeneration that morphologically parallels larval development. To systematically compare these processes, we established an in vitro primmorph regeneration model in Haliclona simulans and performed multi-level analyses across planktonic, settled, and metamorphic stages. Although both processes formed similar structures (e.g., the aquiferous system), planktonic primmorphs exhibited a reduced stem cell proportion (archeocyte/choanocyte), along with the increase of seemingly dedifferentiating cells and vacuolar cells. Microbiome diverged: while sharing core symbionts (e.g., AqS1), primmorphs enriched Tenacibaculum and Vibrio species during remodeling process. Transcriptomics revealed distinct signatures: regeneration upregulated genes potentially related to DNA repair and dedifferentiation but downregulated stem cell markers. Our integrative study indicates that regeneration and development constitute distinct processes, achieving similar functional outcomes via divergent cellular, microbial, and molecular profiles that provides a foundational framework for future mechanistic studies of regeneration.

Akhunbay-Fudge et al. develop two complementary single-cell profiling methods to determine glioblastoma (GB) invasion phenotypes, focusing on the influence of host organoid developmental lineage (neural versus endodermal) and cell cycle progression on GB invasion within tumor assembloids. Notably, GB cells invaded both neural and endodermal organoid hosts, whereas non-malignant adult brain cells lacked this capacity. Single-cell mRNA sequencing revealed gene expression changes in invading tumor cells and surrounding environmental assembloid cells. Concurrently, the "DyPheT" automated tracking tool enabled real-time correlation of cell cycle phases with malignant cell migration within cerebral organoids, which can be utilized for treatment response assessment, exemplified by the investigational compound RP-6306. Collectively, these approaches identify an intrinsic (cell autonomous) gene expression signature linked to GB invasion and support a "go-and-grow" paradigm by revealing a highly migratory (and RP-6306-refractory) GB subpopulation active in the G2/M phase of cell cycle.

Following their engagement towards differentiation, tissue stem cells often transit through a precursor state that is difficult to define because of its transient nature; similarly, the precise role of lineage precursors in implementation of tissue architecture and function is unknown. In the present work, we used two mouse models of deficient feedback regulation to characterize precursors of the pituitary corticotrope lineage that regulates the stress response. Both the POMC knockout and adrenalectomized mouse models develop glucocorticoid deficiency and compensatory accumulation of corticotrope precursors that have so far eluded characterization. We found that pre-corticotrope differentiation depends on the lineage-specific factor Tpit and is repressed by glucocorticoids. We identified brain-derived neurotrophic factor (BDNF) as the signal that engages pituitary stem cells towards differentiation in these models as well as in normal pituitary development. A glucocorticoid-sensitive BDNF autocrine loop active in pre-corticotropes turns these cells into signaling hubs for maintenance of pituitary-adrenal homeostasis.

Colonic stem cells reside in a microenvironment enriched in epidermal growth factor, which is essential for their survival and can activate both PI3K-AKT and MAPK-ERK pathways. This predicts co-activation of both pathways within the growth factor-high stem cell compartment at the base of crypts. However, in patient-derived human colonic organoids and normal human tissue, stem cells maintain robust AKT activity while suppressing ERK signaling despite active EGFR engagement. As stem cells differentiate, they activate pulsatile Erk signaling, which is essential for migration, survival, and maintenance of barrier function. We show that AKT-dependent phosphorylation of Raf-1 at serine 259 establishes a post-receptor checkpoint that maintains ERK temporal dynamics in stem cells. Acute activation of ERK in stem cells triggers rapid global differentiation. Disruption of the ERK checkpoint via mutation of serine 259 leads to sustained AKT and ERK co-activation in stem cells. Unlike ERK/AKT coactivation driven by apoptosis, co-activation in the stem cell compartment results in the emergence of a neoplastic, architecturally disorganized cell population dominating the cell fate profile. Incredibly, introducing brief ERK pulses through Akt inhibition or ERK activation triggers re-differentiation of neoplastic cells. Consistent with duration-dependent MAPK encoding principles, these data demonstrate that regardless of baseline signaling amplitude, ERK signaling dynamics are epistatic to total kinase signaling load in human colonic stem cells.

Adult zebrafish exhibit scarless repair and functional recovery following spinal cord injury. Their regenerative capacity is attributed to potent stem-like progenitors that mediate neuronal and glial repair. Zebrafish are thought to lack anti-regenerative extracellular matrix (ECM) components abundant in mammalian SCI, but the positive contributions of ECM to spontaneous spinal cord repair are less understood. By employing cross-species single-cell transcriptomics, we found the hyaluran modifying enzyme Hapln1 is upregulated in zebrafish progenitors but not in mouse progenitors following injury. Loss-of-function of hapln1a/b and ablation of hapln1+ cells reduce progenitor cell activation and hinder spontaneous recovery from injury. Using a series of in vivo and in vitro assays, we show that Hapln1 is required for hyaluran- cd44b mediated progenitor cell proliferation. This study reveals that, in addition to lacking anti-regenerative ECM components around SC lesions, zebrafish can also leverage pro-regenerative ECM molecules to enhance progenitor cell potency and promote repair.

JAK2 is a key regulator of cytokine-mediated proliferative signaling in hematopoietic stem and progenitor cells. Activating mutations, most commonly JAK2 V617F, trigger aberrant cytokine signaling driving the pathogenesis of myeloproliferative neoplasms (MPNs). Phosphatidylinositol transfer proteins (PITPs) facilitate phosphoinositide synthesis by delivering phosphatidylinositol to lipid kinases, though their roles in oncogenic signaling have remained poorly defined. Here we show that PITPβ is critical for the development of JAK2V617F-driven MPN in mice. Deleting Pitp β across the hematopoietic system, but not Pitp α, prolonged 25-week survival of Jak2V617F mice from 10% to 85%. Loss of Pitp β attenuated disease-associated splenomegaly and curtailed erythroid progenitors expansion both in vivo and in vitro . Mechanistically, PITPβ is necessary for AKT hyperactivation in hematopoietic progenitors, while STAT5 and ERK signaling remain unaffected. In alignment with this role, PITPβ promotes the production of PtdIns(3,4)P ₂ , a phosphoinositide that sustains aberrant AKT signaling in Jak2V617F progenitors. Pharmacologic inhibition of AKT with the FDA-approved inhibitor capivasertib in Jak2V617F-transplanted mice similarly reduced splenomegaly and erythroid proliferation, mimicking the effects of Pitp β loss. Collectively, these results identify a novel PITPβ-PtdIns(3,4)P ₂ signaling axis that selectively maintains pathological AKT activation in JAK2V617F-driven MPN, revealing a promising therapeutic vulnerability.

The mammalian kidney relies on a branched network of collecting ducts for fluid transport and homeostasis. Replicating this network in vitro would parallelize function in synthetic replacement kidneys, yet current organoids have limited branching capacity. Here, we establish a developmentally-informed strategy to control organoid budding through optogenetic control of a receptor tyrosine kinase, RET. We first show pharmacological manipulation of RET signaling controls the extent of branching in mouse embryonic kidneys and human stem cell-derived kidney organoids. Next, we develop an optogenetic RET receptor (optoRET) that signals in a ligand-independent manner via blue light-mediated clustering. Epithelial cells expressing optoRET reproduce stereotyped RET signaling, scattering, and symmetry breaking in response to blue light. Human kidney organoids undergo budding with controllable orientation in response to spatially patterned optoRET stimulation. Our results establish ligand-free optogenetic control of branching and inspire new synthetic biology strategies for epithelial organoid design.

Carbohydrates are classically catabolized by fermentation or oxidation, a choice that impacts many cellular functions including proliferation. Proliferating cells including somatic stem and progenitor cells are thought to favor fermentation over oxidation, and most proliferating cells in vitro depend on lactate production. However, it has not been tested if fermentation and oxidation are the universal obligatory terminal fates for carbohydrates in vivo because the key enzymes, lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), have not been simultaneously deleted in any cell type. Here we show that both fermentation and oxidation are dispensable for the survival and function of hematopoietic stem cells (HSC). Combined LDHA and LDHB deletion to ablate LDH did not impair HSC function, suggesting that HSCs and rapidly proliferating hematopoietic progenitors surprisingly do not require fermentation. Combined LDHA, LDHB, and PDH deletion abolished both glucose oxidation and fermentation, but did not impair HSC function. Glycolysis was preserved, suggesting the operation of an alternative endpoint. LDH/PDH-deficient HSCs terminated glycolysis through pyruvate export. Pyruvate export by HSCs and progenitors was a physiological response to changing nutrient levels. Quadruple deletion of LDHA/B, PDH, and the pyruvate transporter MCT1 impaired HSC function. This suggested that an essential role of glycolysis termination is not to produce acetyl-CoA or lactate but to remove pyruvate. Therefore, in contrast to classical theories and to in vitro metabolism, carbohydrate metabolism in vivo does not require oxidation or fermentation but can terminate directly in pyruvate export, and this alternative pathway is sufficient to support stem cell function.