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At least 19 recordsLinked to original sources

PubMed2026

Mitochondrial translocation of DNMT3L suppresses oxidative phosphorylation and restrains megakaryopoiesis.

DNMT3L, a catalytically inactive member of the DNA methyltransferase family, is identified here as a negative regulator of megakaryopoiesis. In K562 cells undergoing PMA-induced megakaryocytic differentiation, DNMT3L protein levels declined progressively, and shRNA-mediated depletion enhanced differentiation, whereas overexpression attenuated it. Consistent with these findings, Dnmt3l-knockout mice exhibited elevated peripheral blood platelet counts and expanded bone marrow megakaryocytes. Mechanistically, megakaryocytic differentiation triggered rapid mitochondrial translocation of DNMT3L within 6 h; mitochondrial DNMT3L suppressed oxidative phosphorylation (OXPHOS) capacity and ATP production and downregulated mitochondrial-encoded genes spanning Complex I, III, IV, and ATP synthase, without altering mitochondrial DNA copy number. This metabolic suppression was mediated through compartment-specific remodeling of DNMT3L-containing protein complexes: upon differentiation, DNMT3L selectively dissociated from DNMT1 and DNMT3B in mitochondria, relieving the repressive constraint on OXPHOS, whereas in the nucleus DNMT3L remained associated with DNMT3A, which concomitantly accumulated during differentiation. These findings reveal a previously unrecognized mechanism by which a catalytically inactive epigenetic co-regulator spatially redistributes to coordinate mitochondrial metabolic output with nuclear epigenetic control, thereby facilitating terminal megakaryocytic maturation.

Animals↗

PubMed2026

Inherited Platelet GPIV Deficiency: First Description of a Series of Unrelated Patients with Bleeding Diathesis.

GPIV (CD36) is a multifunctional membrane protein expressed on various cells, including platelets, where it plays a role in adhesion and activation through the interaction with its ligands, including collagen types I and III and thrombospondin 1. Inherited GPIV deficiency, historically recognized in anti-Naka alloimmunized East Asian donors, is considered asymptomatic and associated with normal platelet aggregation, although impaired adhesion under high-flow conditions has been reported. Here, we reconsider the molecular basis, epidemiology and functional consequences of GPIV deficiency and report four unrelated patients in whom heterozygous CD36 variants are associated with markedly reduced platelet GPIV expression and a clinically relevant mucocutaneous bleeding diathesis. Patients suffered lifelong bleeding symptoms despite normal light-transmission aggregometry and platelet granule content and release and displayed decreased GPIV expression. Three of them showed slightly decreased VWF. Platelet adhesion to Type I collagen was reduced at high shear. These cases suggest for the first time an association between CD36 gene variants and bleeding and underscore the importance of including GPIV in the diagnostic workup of inherited platelet disorders, particularly when conventional assays do not reveal abnormalities.

Humans↗

PubMed2026

A novel G13-RAPGEF2-RAP1 signaling pathway critical for platelet adhesion and aggregation.

Hemostasis and thrombosis are strongly dependent on the unique ability of platelets to rapidly activate integrin receptors and to firmly adhere to sites of injury under shear stress conditions. Central to integrin activation is the small GTPase RAP1, which itself is activated by guanine nucleotide exchange factors (GEFs). CalDAG-GEFI (RASGRP2) is the highest expressed and functionally dominant platelet RAP-GEF. However, a genome-wide association study also suggested a significant role for RAPGEF2 (PDZ-GEFI), a low-expressed RAP-GEF, in human platelet aggregation. Here, we used mice deficient in RAPGEF2 (megakaryocyte-specific, Rapgef2mKO), CalDAG-GEFI (Caldaggef1-/-), or both RAPGEF2 and CalDAG-GEFI (DKO) to characterize the contribution of RAPGEF2 signaling to platelet function, hemostasis, and thrombosis. RAPGEF2 protein was detected in murine and human platelets. Compared with control or Caldaggef1-/- platelets, both RAP1 activation and integrin αIIbβ3-mediated aggregation were significantly diminished in DKO platelets. When compared with controls, Rapgef2mKO platelets exhibited reduced integrin activation, a more reversible aggregation response, and impaired adhesion under conditions of shear stress ex vivo and in vivo. Mechanistic studies strongly suggest that RAPGEF2 operates downstream of receptors coupled to the heterotrimeric G protein G13 (GNA13), such as αIIbβ3 and the thromboxane receptor. Together, our studies provide genetic evidence that RAPGEF2 in platelets operates downstream of G13 as an important regulator of RAP1 signaling and integrin activation, especially under conditions of elevated shear stress. These findings markedly improve our understanding of G protein signaling and integrin function in platelets, with potential implications for the development of improved platelet-targeted therapies for cardiovascular disease.

Animals↗

PubMed2026

Tanshinone IIA impairs platelet function and thrombus formation.

BACKGROUND: Tanshinone IIA (T-IIA) is a fat-soluble active ingredient derived from the traditional Chinese medicine Danshen and possesses cardioprotective property. However, its exact role in platelet function is unknown. OBJECTIVES: This study investigated T-IIA's role in platelet aggregation, granules release, spreading, clot retraction, as well as in vivo hemostasis and thrombus formation. METHODS: Human platelets were treated with different doses of T-IIA (10, 50, and 100 μM) to measure platelet function and activation. In addition, T-IIA was administrated into wild-type mice to evaluate hemostasis and thrombus formation. RESULTS: T-IIA significantly impaired platelet aggregation, adenosine triphosphate secretion, P-selectin expression, and spreading and clot retraction dose dependently without affecting the expression profiles of αIIbβ3 and glycoprotein VI or Ibα. Administration of T-IIA significantly prolonged mice tail bleeding time and inhibited arterial and venous thrombosis. Further analysis showed that T-IIA dose dependently reduced platelet reactive oxygen species generation. Quantitative proteomic and phosphoproteimic assays analyzing T-IIA-treated vs vehicle-treated platelets after stimulation identified dysregulated phosphorylation of several proteins, which were enriched in platelet activation. Among the downregulated phosphoproteins, Rho-associated protein kinase (ROCK)1, integrin β3, and talin1 exhibited the lower fold change of phosphorylation in T-IIA-treated platelets compared with those in vehicle-treated platelets. Consistently, T-IIA treatment inhibited the phosphorylation of ROCK1, p47phox, integrin β3, and talin1 in activated platelets. CONCLUSION: T-IIA impairs platelet function and thrombosis via inhibition of several signaling pathways including ROCK1/p47phox, β3, and talin1, implying that T-IIA may represent a promising therapeutic candidate for treating thrombotic diseases.

Animals↗

PubMed2026

Dynamic lysine acetylation and succinylation of platelet proteins regulates platelet storage lesion: mechanistic insights from multi-omics.

OBJECTIVES: Platelet storage lesion (PSL) severely impairs platelet function during storage, presenting a major hurdle in transfusion medicine; however, the dynamic interplay between global proteomic changes and post-translational modifications (PTMs) underlying these functional deteriorations remains insufficiently characterized. Here, we report the first comprehensive multi-omics analysis integrating global proteomics, acetylomics, and succinylomics to dissect the molecular dynamics during platelet storage. METHODS: We performed quantification of global proteomics, acetylome and succinylome based on TMT-labeled LC-MS/MS analysis, combined with antibody-affinity enrichment and purification. Dynamic molecular changes and functional transformation of platelet were also characterized under proper conditions stored for 1, 3, 5, 7 days, respectively. RESULTS: We systematically characterized 3,609 proteins, 1,308 acetylation sites, and 1,947 succinylation sites across multiple storage time points (D1, D3, D5, D7). We distinct temporal patterns of post-translational modifications, with succinylation showing more extensive coverage than acetylation in platelets. Pathway enrichment analysis revealed extensive metabolic reprogramming involving complement activation, energy metabolism, and cellular detoxification processes. The identification of specific motif patterns provided mechanistic insights into the functional specificity of these modifications. Random forest machine learning identified 20 core regulatory proteins representing critical nodes in PSL development. Furthermore, we employed real - time quantitative polymerase chain reaction (RT - QPCR) to measure the expression levels of key genes related to platelet function and PTM - associated pathways. CONCLUSION: By mapping the interplay between proteomic abundance shifts and PTM dynamics, this study provides a multidimensional understanding of PSL, establishing a foundational framework for optimizing storage protocols and enhancing transfusion safety.

Blood Platelets↗

PubMed2026

Platelet triggering receptor expressed on myeloid cells-like transcript 1 regulation in healthy donors and patients at risk of bleeding and thrombosis.

BACKGROUND: Triggering receptor expressed on myeloid cells-like transcript 1 (TLT-1), a platelet-specific α-granule protein, is implicated in hemostasis, but its regulation remains unclear. Platelet dysfunction contributes to trauma-induced coagulopathy (TIC) and thrombotic complications in trauma or mechanical circulatory support (MCS); however, underlying mechanisms remain poorly understood. OBJECTIVES: This study investigated the molecular mechanisms underlying soluble TLT (sTLT)-1 release and its role as a biomarker of platelet dysfunction in patients with severe trauma or receiving MCS. METHODS: TLT-1 dynamics on platelets exposed to glycoprotein (GP)VI ligand, coagulation, or shear stress in vitro were evaluated by ELISA and immunoblotting. sTLT-1 was measured in plasma from trauma or MCS-treated patients and healthy donors. Associations with TIC, injury severity, and mortality were assessed. RESULTS: Proteolysis of TLT-1 to release a 10- to 17-kDa fragment was metalloproteinase dependent and blocked by ADAM10 and ADAM17 inhibition. Unlike GPVI, platelet TLT-1 exposure increased following PAR-1 activation. sTLT-1 was elevated in trauma patients compared with controls and correlated with TIC (P < .05) and injury severity (P < .01). Receiver-operating characteristic analysis demonstrated discriminatory performance for TIC (area under the curve, 0.78; P = .011), with a Youden cutoff of 1.180 ng/mL yielding 89% sensitivity and 73% specificity. Platelet TLT-1 was basally expressed, mobilized 2.5-fold with activation, and shed in response to GPVI ligation and plasma recalcification. Shear-exposed platelets and plasma from MCS-treated patients exhibited elevated sTLT-1 levels. CONCLUSION: Unlike GPVI, TLT-1 increased on activated platelets and was regulated by ADAM10 and ADAM17. TLT-1 release is triggered by shear stress, GPVI ligands or activated factor X. Plasma sTLT-1 was associated with trauma severity and TIC.

Humans↗

PubMed2026

Targeting ACKR3/CXCR7 enhances platelet anticoagulant acylcarnitines and modulates procoagulant function.

Targeting ACKR3/CXCR7 regulates enzymatic generation of prothrombotic lipids while favoring antithrombotic lipids that inhibit platelets through the AC-cAMP-PKA pathway in coordination with prostacyclin IP receptor. This investigation validated the effect of CXCR7 in modulating nonenzymatic lipid (per)oxidation, platelet response to lipoproteins, mitochondrial metabolism, and procoagulant functions. CXCR7 agonist VUF11207 preserved mitochondrial membrane integrity, counteracted activation-induced mitochondrial superoxide generation, and reduced nonenzymatic lipid (per)oxidation. Moreover, it regulated lipoprotein-induced platelet adhesion to thrombogenic matrices, degranulation, αIIbβIII-integrin activation, aggregation, and thrombotic responses by reducing lipoprotein uptake through CD36 and ApoER2. CXCR7 ligation triggered the activation of AMP-dependent kinaseSer-172 and prompted AMPK-mediated inhibitory phosphorylation of acetyl-coenzyme A carboxylaseSer-79 to foster lipolysis over lipogenesis. Consequently, the AMPKSer-172-ACCSer-79 pathway increased generation of anticoagulant FXa-inhibitory long-chain acylcarnitines (LC-CAR) in platelets of healthy subjects and patients with coronary artery disease. Enrichment of intraplatelet LC-CARs was not attributable to dysregulated mitochondrial respiration because VUF11207 improved maximal respiration, spare respiratory capacity, and ATP-linked respiration in thrombin-activated platelets, suggesting sustained mitochondrial metabolism. Exerting a 2-pronged effect on procoagulant function, VUF11207 downregulated phosphatidylserine exposure on activated platelets and reduced FX/FXa binding, while platelet-derived anticoagulant LC-CARs regulated thrombin generation. VUF11207 administration reduced thrombus formation, platelet degranulation, αIIbβIII-integrin activation, procoagulant activity, and circulating platelet-leukocyte aggregates in murine venous thrombosis model, also decreased plasma procoagulant lipids derived from platelet cyclooxygenase-1 and 12-lipooxygenase (LOX), and leukocyte 5/15-LOX, decreased thromboinflammatory mediators (IL-1β, IL-6, IFN-γ, TNF-α, and MCP-1), and increased plasma LC-CAR levels. Therefore, pharmacological targeting of CXCR7 could regulate (non)enzymatic lipid processing and promote anticoagulant LC-CAR generation to limit platelet-driven thrombotic propensity and hypercoagulability, also replenish reduced levels of circulatory LC-CARs in patients with STEMI and VTE.

Humans↗

PubMed2024

Platelet-derived mitochondria regulate lipid metabolism in nonalcoholic steatohepatitis through extracellular vesicles.

BACKGROUND AND AIMS: Immune system activation, along with lipotoxicity due to excessive lipid droplet (LD) accumulation in the liver, are key drivers of NASH. Extracellular vesicles (EVs) released by cells that carry biological signals contribute to intercellular communication. However, the roles of immune cell-derived EVs in the pathogenesis of NASH are unclear. APPROACH AND RESULTS: Platelets are abundant in blood. We explored the role of platelet-derived EVs (pEVs) in LD accumulation from 30 patients with nonalcoholic fatty liver disease of different severity as well as 20 healthy subjects, a rat model, and an in vitro cell-based assay. There was increased platelet activation, accompanied by pEVs release, in NASH patients/rat model, and palmitate-treated cells. The mitochondria in the platelets and pEVs from NASH patients/rats were increased but dysfunctional, including a reduction in fatty acid β-oxidation, inactivated acetyl-CoA carboxylase 2, and suppressed oxidative phosphorylation system complex II/III/IV activity. These damaged mitochondria could be transferred to hepatocytes through pEVs to increase the number of lipid droplet-bound mitochondria. An increase in dysfunctional lipid droplet-bound mitochondria in hepatocytes affects lipid metabolism, resulting in excessive LD accumulation, elevated mitochondrial reactive oxygen species production, and apoptosis. CONCLUSIONS: We offer a novel molecular mechanism that connects platelets, pEVs, and excessive LD accumulation to the development of NASH. Our results suggest that NASH progression may be alleviated by specifically inhibiting the production and release of pEVs, or by targeting pEV components and inhibiting their uptake. Additional experiments are required to confirm this potentiality.

Non-alcoholic Fatty Liver Disease↗

PubMed2026

The alarmin interleukin-33 modulates platelet proteome, function, and biogenesis.

Platelets, traditionally recognized for their involvement in hemostasis and wound healing, also play a central role in immune regulation and inflammation. Their function and production adapt in response to inflammatory cues such as cytokines and danger-associated molecular patterns. Interleukin-33 (IL-33), an alarmin released during tissue damage, particularly in lung inflammation, has been implicated in influencing platelet biology, though its exact effects remain poorly understood. To clarify IL-33's role, we examined its impact on platelet production, proteome, adhesion, secretion, and aggregation using platelets from IL-33-deficient (IL-33 knockout [IL-33KO]) mice and IL-33 stimulation in vivo. Our results reveal that although platelets themselves do not express IL-33, platelets isolated from IL-33KO mice display altered proteomic signatures and reduced adhesion to fibrinogen, podoplanin, and laminin, alongside impaired thrombus formation under shear stress. IL-33 administration in vivo led to proteomic remodeling characterized by increased expression of inflammatory proteins, as well as changes in platelet morphology, including increased size, typically associated with de novo production. Using lung intravital microscopy, we visualized platelet fragmentation within the lung vasculature in real time, and observed enhanced fragmentation following IL-33 stimulation. Interestingly, ST2, the receptor for IL-33, is expressed in subsets of mouse and human megakaryocytes and hematopoietic progenitors, particularly those involved in a noncanonical pathway of thrombopoiesis that enables the rapid replenishment of platelets during inflammation, infection, and aging. Together, these findings identify IL-33 as a pivotal regulator of platelet function and production, linking inflammatory signaling to the dynamic regulation of thrombopoiesis.

Interleukin-33↗

PubMed2026

Reduced platelet formation associated with serine metabolic dysregulation in integrin αIIbβ3-deficient megakaryocytes.

Glanzmann thrombasthenia (GT) is characterized by absent platelet aggregation in response to all agonists except ristocetin and is caused by recessive inactivating variants in ITGA2B or ITGB3. Although patients with GT typically are described as having normal platelet counts, autosomal dominant activating variants in ITGA2B or ITGB3 cause macrothrombocytopenia. Interestingly, in our cohort of 16 patients with GT, 8 consistently exhibited platelet counts at the lower end of the normal range. We studied the role of integrin αIIbβ3 in platelet formation using megakaryocytes (MKs) derived from genetically modified immortalized MK cell lines (imMKCLs), focusing on 2 modifications of ITGB3: ITGB3-/- (inactivating) and ITGB3WT/D673_E713del (activating). In static differentiation cultures, ITGB3-/- and ITGB3WT/D673_E713del imMKCLs exhibited normal MK differentiation but reduced proplatelet formation. Platelet production was also impaired in a 3-dimensional silk-based bone marrow system and in shaking cultures, confirming a quantitative role for ITGB3 in platelet production independent of the type of variant. Although thrombin receptor activating protein-activated, in vitro-generated platelets lacking αIIbβ3 failed to bind the activation-dependent PAC-1 antibody, ITGB3WT/D673_E713del platelets bound PAC-1 before activation, mimicking the patient's phenotype. Transcriptome profiling and metabolomic analyses of integrin αIIbβ3-deficient MKs revealed impaired serine metabolism and downregulation of SLC3A2 (CD98hc), an amino acid transporter chaperon known to interact with the β3 subunit. Flow cytometry confirmed decreased CD98hc in mutant MKs, whereas reexpression of wild-type ITGB3 in ITGB3-/- MKs restored αIIbβ3 and CD98hc expression, normalized proplatelet formation, and enhanced serine uptake. These results uncover a previously unrecognized role of integrin αIIbβ3 in coupling serine metabolism to platelet biogenesis.

Humans↗

PubMed2025

Studying the Role of HOX Genes in Thrombocyte Development.

In our laboratory, we study thrombopoiesis and hemostasis using zebrafish as a model organism to unravel the mechanisms of differentiation and development of thrombocytes. We have shown in our earlier work that thrombocytes are functional equivalents of platelets and have transcriptional machinery similar to megakaryocytes. We recently found evidence that hox genes play a role in their development. We used piggyback gene knockdown and thrombocyte quantification assays to understand the influence of these ancient developmental regulators on thrombopoiesis. In this chapter, we describe methods used to discover these hox genes.

Animals↗

PubMed2025

Circulating miRNAs and inflammatory markers - Associations between miRNAs and cytokine levels point to miRNA-mediated sCD40L release from platelets.

MicroRNAs (miRNAs) are gaining increasing attention, particularly because of their involvement in immune-related signaling pathways. We investigated the association between 179 plasma-circulating miRNAs (Plasma Focus microRNA PCR Panel) and 47 cytokines ("MILLIPLEX® panel) in 692 participants of the population-based SHIP-TREND cohort (age range 21-79) and two additional cohorts to present a comprehensive map of miRNA-cytokine relations. Multivariate linear regression models identified Bonferroni-corrected significant associations between miRNAs and cytokines for EGF (pro-epidermal growth factor), PDGF-AA, PDGF-AB/BB (platelet-derived growth factor subunit A and B), VEGF-A (vascular endothelia growth factor A), and sCD40L (soluble CD40 ligand) with sCD40L showing the most robust pattern. These models were adjusted for age, sex, platelet count, BMI, smoking, and technical parameters. In the follow-up sample (N = 191, 7 years after initial sampling), we confirmed that the observed associations were stable over time and replicated our findings in an independent clinical cohort (N = 74). Furthermore, the causal mediation results provide evidence for the involvement of platelet activity in the regulation of sCD40L mediated by five miRNAs in the range of 25 %-69 % of the effect being mediated (strongest mediation for hsa-miR-223-3p). Our study highlights a strong and stable miRNA-mediated modulation of sCD40L, at the stage of platelet activation with potential subsequent effects on the interaction of immune cells and haemostasis pointing to a complex regulatory mechanism. Future research is needed to determine the clinical relevance of our observations in the context of vascular thrombosis, immunological disorders, and neurodegeneration.

Humans↗

PubMed2026

Monocytes Defined by Platelet Interactions and Oxidative Stress Signaling Underlie HIV-Associated Atherosclerosis.

BACKGROUND: Monocytes contribute to atherosclerosis by migrating into inflamed endothelium and differentiating into lipid-laden macrophages. In people living with HIV, chronic inflammation increases atherosclerosis risk, yet the role of specific monocyte subsets remains unclear. We investigated how distinct monocyte populations contribute to vascular pathology in early HIV-associated atherosclerosis. METHODS: We profiled 123 965 circulating monocytes using single-cell RNA sequencing and integrated plasma microparticle proteomics in 32 individuals stratified by HIV and atherosclerosis status. Supervised learning identified cluster- and disease-specific signatures, validated by platelet-monocyte cocultures, reverse transcription-quantitative polymerase chain reaction, bulk RNA sequencing, flow cytometry, and ELISA. RESULTS: Seven monocyte clusters were identified, including a subset characterized by platelet-monocyte complexes. Bulk RNA sequencing of platelet-monocyte cocultures revealed platelet-driven upregulation of genes involved in inflammation, lipid metabolism, oxidative stress, and endothelial adhesion. Platelet-monocyte complex-derived macrophages secreted higher levels of TGF-β (transforming growth factor-β) and IL-10 (interleukin-10), displayed decreased CD14 and increased CD80/CD86 while retaining CD36, and promoted endothelial-to-mesenchymal transition (decreased expression of CDH5 and PECAM1; increased expression of S100A4 and markers of vascular inflammation (ICAM1), VCAM), and IL-6 (interleukin-6), and CCL2 (C-C motif chemokine ligand 2) secretion). Additionally, CD14+ monocytes from HIV+ atherosclerosis-negative and HIV+ atherosclerosis-positive groups showed enhanced ROS-NRF2 (reactive oxygen species-nuclear factor erythroid 2-related factor 2) pathway activities, supported by increased basal and H2O2-induced p90RSK phosphorylation, indicating oxidative stress priming. CONCLUSIONS: Two monocyte clusters contribute independently to vascular immune dysregulation in people living with HIV. Platelet-monocyte complex-derived macrophages promote endothelial dysfunction while adopting a profibrotic cytokine profile. CD14+ monocytes show heightened oxidative signaling and stress responses, consistent with vascular activation. Together, these mechanisms may accelerate atherosclerosis development in HIV, even in the absence of traditional cardiovascular risk factors.

Humans↗

PubMed2025

Impact of Race on Profiles of Platelet Reactivity and Clinical Outcomes in Clopidogrel-Treated Participants.

Black individuals undergoing percutaneous coronary intervention (PCI) experience higher rates of major adverse cardiovascular events (MACE) than non-Black individuals. This study assessed the racial differences in platelet reactivity and clinical outcomes among clopidogrel-treated participants. Two cohorts were analyzed. The pharmacodynamic (PD) cohort involved patients with atherosclerotic cardiovascular disease on maintenance clopidogrel therapy undergoing platelet function testing. The primary outcome was high platelet reactivity (HPR, i.e., P2Y12 reaction unit [PRU] > 208). The PCI cohort included participants undergoing PCI on clopidogrel-based dual antiplatelet therapy. The primary outcome was 1-year MACE, defined as the composite of cardiovascular death, myocardial infarction (MI), ischemic stroke, or stent thrombosis. Data on clinically significant bleeding and CYP2C19 genotyping alleles were collected. The PD and PCI cohorts included 728 (32.1% Black) and 2,770 (20.5% Black) participants, respectively. Black participants had higher PRU levels (184 [IQR 128-234] vs. 144 [IQR 88-195]; P < 0.001) and higher prevalence of HPR (39.3% vs. 20.6%; P < 0.001). Independent predictors of HPR included Black race, hemoglobin levels, and presence of CYP2C19 loss-of-function allele. In the PCI cohort, Black participants had a higher risk of MACE (HR 1.47; 95% CI 1.02-2.11; P = 0.037), primarily driven by MI (HR 1.71; 95% CI 1.09-2.67; P = 0.019), with no significant difference in clinically significant bleeding (HR 1.08; 95% CI 0.65-1.80; P = 0.768). Black participants on clopidogrel exhibit higher platelet reactivity, increased rates of HPR, and an elevated risk of MACE within 1 year after PCI, without significant differences in bleeding compared to non-Black participants.

Aged↗

PubMed2026

Trans-Mitochondrial Cybrid Generation from mtDNA Patient Platelets: An Efficient Protocol Optimizing Colony Selection and Functional Validation.

Trans-mitochondrial cybrid cell line generation represents the gold-standard method for determining pathogenicity by enabling biochemical analyses of a specific mitochondrial DNA (mtDNA) variant of interest at high and low percentages (heteroplasmy levels) within an otherwise identical mtDNA and nuclear genome background. Historically, the cybrid generation process has been tedious and poorly efficient. Here, we describe a highly efficient and effective protocol for generating trans-mitochondrial cybrid cell lines by fusing human platelets with a standard osteosarcoma 143B cell line to provide an isogenic nuclear background depleted of mtDNA (Rho0 cells). Cell isolates capture a given mtDNA genome of interest to establish stable cell lines harboring different degrees of heteroplasmy, or to compare divergent effects of distinct mitochondrial haplogroups. Because cybrids from mitochondrial patients may be more difficult to establish with standard protocols, this current methodology focuses on isolating mtDNA variants where the electron transport chain activity is affected. We here demonstrate that colony selection techniques reduce time and improve the yield of generating high-level heteroplasmy mtDNA mutant cybrid lines. A case study is provided of cybrid generation for a variant of unknown significance in MT-ND1, m.3985G>A (p.E227K). We analyze the efficiency of the cybrid generation process using this protocol and run functional studies performed by high-resolution respirometry. High-level heteroplasmy MT-ND1 m.3985G>A cybrid mutants generated by this protocol are shown to have impaired complex I-dependent mitochondrial respiration relative to wild-type control, demonstrating m.3985G>A is likely pathogenic.

Humans↗

PubMed2026

Preemptive hematopoietic stem cell transplantation in RUNX1 familial platelet disorder: a shared decision-making framework.

RUNX1 familial platelet disorder (RUNX1-FPD) is associated with a 35-50% lifetime risk of hematologic malignancy (HM). Like all germline HM predisposition syndromes, RUNX1-FPD can only be cured with allogeneic hematopoietic stem cell transplantation (HSCT). Current genetic screening techniques allow for early detection of germline predisposition and, consequently, the opportunity for HSCT before overt development of HM (i.e., preemptive HSCT). However, there is as yet no consensus on the use of preemptive HSCT for RUNX1-FPD. Described here is the case of an individual with RUNX1-FPD and a family history of HM who underwent preemptive HSCT. We introduce a shared decision-making framework designed to support individuals with RUNX1-FPD, their families, and their multidisciplinary clinical teams in evaluating whether and when to pursue preemptive HSCT versus continued surveillance. The framework reviews key medical factors that influence the decisions regarding timing of HSCT, including germline and somatic variants, clonal changes over time, familial history of HM, early morphologic or hematologic features, impacts on bleeding-related quality of life, and donor availability. The framework also summarizes the major risks and uncertainties potentially associated with preemptive HSCT while highlighting the associated ethical challenges. Together, the case and framework provide a structured, patient-centered approach for navigating the complex clinical decision of preemptive HSCT. Ongoing collaborative efforts to define cytogenetic and clonal changes preceding malignant transformation in RUNX1-FPD will refine the framework and bolster individualized treatment strategies aimed at preventing HM and improving the quality of life of individuals with RUNX1-FPD.

Humans↗

PubMed2025

Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA.

Platelets are anucleate blood cells vital for hemostasis and immunity. During cell death and aberrant mitosis, nucleated cells release DNA, resulting in "cell-free" DNA in plasma (cfDNA). An excess of cfDNA is deleterious. Given their ability to internalize pathogen-derived nucleic acids, we hypothesized that platelets may also clear endogenous cfDNA. We found that, despite lacking a nucleus, platelets contained a repertoire of DNA fragments mapping across the nuclear genome. We detected fetal DNA in maternal platelets and cancer-derived DNA in platelets from patients with premalignant and cancerous lesions. As current liquid biopsy approaches utilize platelet-depleted plasma, important genetic information contained within platelets is being missed. This study establishes a physiological role for platelets that has not previously been highlighted, with broad translational relevance.

Female↗

PubMed2025

Engraftment and persistence of HBB base-edited hematopoietic stem cells in nonhuman primates.

Sickle cell disease (SCD) is caused by a single nucleotide change in the β-globin gene that adenine base editors can convert to the nonpathogenic Makassar β-globin variant. Here, we evaluated the long-term efficiency and off-target editing potential of autologous Makassar base editing in three rhesus macaques as a step toward human translation. Base editing of CD34+CD90+ hematopoietic stem cells (HSCs) at the Makassar locus reached greater than 60% efficiency using a bystander nucleotide as a proxy for the sickle cell target in cells from healthy macaques. No impact on myeloid and erythroid colony formation was seen, and clonal analysis revealed that >90% of HSCs were edited, >20% with biallelic editing. After transplantation of autologous gene-edited HSCs, all three macaques rapidly recovered neutrophils, red blood cells, and platelets with stable editing of 25.6%, on average, observed across nucleated blood cells. Similarly, the bone marrow stem cell compartment maintained over 20% of cells harboring mono- or biallelic edits. Off-target editing was assessed at over 900 candidate sites, with editing observed at eight sites, but no selection for or impact of these edits was observed throughout engraftment. These data support further translation of base editing of autologous HSCs for the treatment of patients with SCD.

Animals↗