{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:03:32Z","timestamp":1792789412980,"version":"4.5.0"},"reference-count":144,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Association for the Advancement of Blood &amp; Biotherapies","award":["AABB Foundation Early-career Research Grant"],"award-info":[{"award-number":["AABB Foundation Early-career Research Grant"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Megakaryocytes (MKs) are specialized hematopoietic cells long recognized for their ability to produce platelets. Increasing evidence now highlights MKs as multifunctional immune effectors that bridge hematopoiesis with host immunity. In the bone marrow (BM), MKs arise through thrombopoietin (TPO)-mediated differentiation of hematopoietic stem cells (HSCs) and show substantial heterogeneity, with discrete subsets specialized for platelet production (thrombopoiesis), HSC niche maintenance, or immune modulation. Outside the BM, MKs in the lungs and spleen perform tissue-specific immune functions, including pathogen recognition, phagocytosis, antigen presentation, and secretion of cytokines. During bacterial infections and sepsis, infectious or inflammatory cues reprogram MKs to amplify immune signaling and host responses, but can also drive coagulopathy and contribute to organ failure. Collectively, these findings redefine MKs as dynamic immunomodulatory cells positioned at the interface of thrombopoiesis and innate and adaptive immunity. In this review, we synthesize emerging literature on MK biogenesis, functional diversity, and immune modulation, with a special focus on their roles in bacterial infections and sepsis.<\/jats:p>","DOI":"10.3390\/ijms262211191","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T15:03:15Z","timestamp":1763564595000},"page":"11191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Beyond Thrombopoiesis: The Immune Functions of Megakaryocytes in Bacterial Infections and Sepsis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5252-6272","authenticated-orcid":false,"given":"Marina","family":"Leardini-Trist\u00e3o","sequence":"first","affiliation":[{"name":"Molecular Medicine Program, University of Utah Health, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5139-5861","authenticated-orcid":false,"given":"Meenakshi","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Molecular Medicine Program, University of Utah Health, Salt Lake City, UT 84112, USA"},{"name":"Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah Health, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1083\/jcb.201304054","article-title":"The incredible journey: From megakaryocyte development to platelet formation","volume":"201","author":"Machlus","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1111\/j.1365-2141.2006.06215.x","article-title":"Megakaryocyte development and platelet production","volume":"134","author":"Deutsch","year":"2006","journal-title":"Br. J. Haematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1172\/JCI26674","article-title":"The molecular mechanisms that control thrombopoiesis","volume":"115","author":"Kaushansky","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/cyto.a.22438","article-title":"Improved quantitative analysis of primary bone marrow megakaryocytes utilizing imaging flow cytometry","volume":"85","author":"Niswander","year":"2014","journal-title":"Cytom. A"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.stem.2020.11.006","article-title":"Decoding Human Megakaryocyte Development","volume":"28","author":"Wang","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/s41467-017-00201-7","article-title":"Thrombopoiesis is spatially regulated by the bone marrow vasculature","volume":"8","author":"Stegner","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/jcp.10035","article-title":"Roads to polyploidy: The megakaryocyte example","volume":"190","author":"Ravid","year":"2002","journal-title":"J. Cell Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/j.1365-2141.1993.tb03210.x","article-title":"The relationship between human megakaryocyte nuclear DNA content and gene expression","volume":"85","author":"Hancock","year":"1993","journal-title":"Br. J. Haematol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1182\/blood-2002-05-1553","article-title":"Megakaryocyte polyploidization is associated with a functional gene amplification","volume":"101","author":"Raslova","year":"2003","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3868","DOI":"10.1182\/blood-2005-07-2755","article-title":"Characterization of the megakaryocyte demarcation membrane system and its role in thrombopoiesis","volume":"107","author":"Schulze","year":"2006","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1182\/blood-2013-03-492330","article-title":"Biogenesis of the demarcation membrane system (DMS) in megakaryocytes","volume":"123","author":"Eckly","year":"2014","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3348","DOI":"10.1172\/JCI26891","article-title":"The biogenesis of platelets from megakaryocyte proplatelets","volume":"115","author":"Patel","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1007\/s00018-014-1813-y","article-title":"The secret life of a megakaryocyte: Emerging roles in bone marrow homeostasis control","volume":"72","author":"Malara","year":"2015","journal-title":"Cell Mol. Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Singh, S.V., Lucerne, A., and Ravid, K. (2025). Immune and Inflammatory Properties of Megakaryocytes. Cells, 14.","DOI":"10.3390\/cells14141053"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1182\/bloodadvances.2020004112","article-title":"CRISPR-edited megakaryocytes for rapid screening of platelet gene functions","volume":"5","author":"Montenont","year":"2021","journal-title":"Blood Adv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e153014","DOI":"10.1172\/JCI153014","article-title":"IFITM3 regulates fibrinogen endocytosis and platelet reactivity in nonviral sepsis","volume":"132","author":"Campbell","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s40560-023-00672-5","article-title":"The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation","volume":"11","author":"Iba","year":"2023","journal-title":"J. Intensive Care"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Frydman, G.H., Ellett, F., Jorgensen, J., Marand, A.L., Zukerberg, L., Selig, M.K., Tessier, S.N., Wong, K.H.K., Olaleye, D., and Vanderburg, C.R. (2023). Megakaryocytes respond during sepsis and display innate immune cell behaviors. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1083339"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1182\/blood-2015-07-607945","article-title":"Hematopoietic stem\/progenitor cell commitment to the megakaryocyte lineage","volume":"127","author":"Woolthuis","year":"2016","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/ncb3493","article-title":"Human haematopoietic stem cell lineage commitment is a continuous process","volume":"19","author":"Velten","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1055\/s-0038-1642732","article-title":"Thrombopoietin: The primary regulator of megakaryocyte and platelet production","volume":"74","author":"Kaushansky","year":"1995","journal-title":"Thromb. Haemost."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/0092-8674(94)90450-2","article-title":"Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl","volume":"77","author":"Bartley","year":"1994","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/369533a0","article-title":"Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand","volume":"369","author":"Hass","year":"1994","journal-title":"Nature"},{"key":"ref_26","first-page":"1883","article-title":"Thrombopoietin maintains cell numbers of hematopoietic stem and progenitor cells with megakaryopoietic potential","volume":"106","author":"Chin","year":"2021","journal-title":"Haematologica"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Khatib-Massalha, E., and Mendez-Ferrer, S. (2022). Megakaryocyte Diversity in Ontogeny, Functions and Cell-Cell Interactions. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.840044"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1083\/jcb.147.6.1299","article-title":"Blood platelets are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes","volume":"147","author":"Italiano","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nm.3770","article-title":"The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling","volume":"21","author":"Grozovsky","year":"2015","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1182\/blood-2017-12-820779","article-title":"GPIbalpha is required for platelet-mediated hepatic thrombopoietin generation","volume":"132","author":"Xu","year":"2018","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2720","DOI":"10.1182\/blood.V98.9.2720","article-title":"Interleukin-6 stimulates thrombopoiesis through thrombopoietin: Role in inflammatory thrombocytosis","volume":"98","author":"Kaser","year":"2001","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1182\/blood-2015-05-644583","article-title":"CCL5 derived from platelets increases megakaryocyte proplatelet formation","volume":"127","author":"Machlus","year":"2016","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/nm973","article-title":"Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis","volume":"10","author":"Avecilla","year":"2004","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.devcel.2017.03.020","article-title":"Hematopoiesis Lineage Tree Uprooted: Every Cell Is a Rainbow","volume":"41","author":"Hirschi","year":"2017","journal-title":"Dev. Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.stem.2011.04.021","article-title":"All hematopoietic cells develop from hematopoietic stem cells through Flk2\/Flt3-positive progenitor cells","volume":"9","author":"Boyer","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1161\/ATVBAHA.119.312129","article-title":"New Insights Into the Differentiation of Megakaryocytes From Hematopoietic Progenitors","volume":"39","author":"Noetzli","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/nature12495","article-title":"Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy","volume":"502","author":"Macaulay","year":"2013","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.cell.2013.08.007","article-title":"Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells","volume":"154","author":"Yamamoto","year":"2013","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e00202","DOI":"10.1097\/BS9.0000000000000202","article-title":"Adult megakaryopoiesis: When taking a short-cut results in a different final destination","volume":"6","author":"Zhu","year":"2024","journal-title":"Blood Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.immuni.2024.02.006","article-title":"Differentiation route determines the functional outputs of adult megakaryopoiesis","volume":"57","author":"Li","year":"2024","journal-title":"Immunity"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nature25168","article-title":"Clonal analysis of lineage fate in native haematopoiesis","volume":"553","author":"Wolock","year":"2018","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1182\/blood.2021010697","article-title":"Single-cell analysis of ploidy and the transcriptome reveals functional and spatial divergency in murine megakaryopoiesis","volume":"138","author":"Sun","year":"2021","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e2100921","DOI":"10.1002\/advs.202100921","article-title":"Characterization of Cellular Heterogeneity and an Immune Subpopulation of Human Megakaryocytes","volume":"8","author":"Liu","year":"2021","journal-title":"Adv. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1182\/blood.2019000067","article-title":"Sepsis alters the transcriptional and translational landscape of human and murine platelets","volume":"134","author":"Middleton","year":"2019","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.stem.2015.07.007","article-title":"Inflammation-Induced Emergency Megakaryopoiesis Driven by Hematopoietic Stem Cell-like Megakaryocyte Progenitors","volume":"17","author":"Haas","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nature21706","article-title":"The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors","volume":"544","author":"Lefrancais","year":"2017","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1152\/physiol.00017.2019","article-title":"Platelet Biogenesis in the Lung Circulation","volume":"34","author":"Lefrancais","year":"2019","journal-title":"Physiology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3975","DOI":"10.1182\/blood-2002-02-0490","article-title":"The spleen is a major site of megakaryopoiesis following transplantation of murine hematopoietic stem cells","volume":"100","author":"Slayton","year":"2002","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1182\/blood.V3.8.934.934","article-title":"The significance of megakaryocytes in the peripheral circulation","volume":"3","author":"Whitby","year":"1948","journal-title":"Blood"},{"key":"ref_50","first-page":"212","article-title":"Megakaryocytes in Peripheral Blood Smears","volume":"36","author":"Garg","year":"2019","journal-title":"Turk. J. Haematol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/BF01924893","article-title":"Ueber capill\u00e4re Embolie von riesenkernhaltigen Zellen","volume":"134","author":"Aschoff","year":"1893","journal-title":"Arch. Pathol. Anat. Physiol. Klin. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e137377","DOI":"10.1172\/JCI137377","article-title":"Lung megakaryocytes are immune modulatory cells","volume":"131","author":"Pariser","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"120602","DOI":"10.1016\/j.lfs.2022.120602","article-title":"Megakaryocytes in pulmonary diseases","volume":"301","author":"Huang","year":"2022","journal-title":"Life Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"100053","DOI":"10.1016\/j.rpth.2023.100053","article-title":"Megakaryocytes in the lung: History and future perspectives","volume":"7","author":"Livada","year":"2023","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6204","DOI":"10.1182\/bloodadvances.2020002843","article-title":"Lung megakaryocytes display distinct transcriptional and phenotypic properties","volume":"4","author":"Yeung","year":"2020","journal-title":"Blood Adv."},{"key":"ref_56","first-page":"11","article-title":"Expression of interleukin 6 and its specific receptor by untreated and PMA-stimulated human erythroid and megakaryocytic cell lines","volume":"19","author":"Navarro","year":"1991","journal-title":"Exp. Hematol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1158\/1078-0432.CCR-06-2108","article-title":"Toll-like receptor-4 is up-regulated in hematopoietic progenitor cells and contributes to increased apoptosis in myelodysplastic syndromes","volume":"13","author":"Maratheftis","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1111\/j.1538-7836.2011.04530.x","article-title":"Expression and functionality of type I interferon receptor in the megakaryocytic lineage","volume":"9","author":"Negrotto","year":"2011","journal-title":"J. Thromb. Haemost."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1182\/bloodadvances.2017007021","article-title":"Mature murine megakaryocytes present antigen-MHC class I molecules to T cells and transfer them to platelets","volume":"1","author":"Zufferey","year":"2017","journal-title":"Blood Adv."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Gelon, L., Fromont, L., and Lefrancais, E. (2022). Occurrence and role of lung megakaryocytes in infection and inflammation. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1029223"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1084\/jem.2015005711172015c","article-title":"Correction: CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow","volume":"212","author":"Takubo","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1182\/blood-2017-12-823369","article-title":"Platelets play an essential role in murine lung development through Clec-2\/podoplanin interaction","volume":"132","author":"Tsukiji","year":"2018","journal-title":"Blood"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"33985","DOI":"10.1074\/jbc.M113.511881","article-title":"Early growth response-1 (EGR-1) and nuclear factor of activated T cells (NFAT) cooperate to mediate CD40L expression in megakaryocytes and platelets","volume":"288","author":"Crist","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1182\/blood.V67.2.285.285","article-title":"Immunohistochemical localization of membrane and alpha-granule proteins in human megakaryocytes: Application to plastic-embedded bone marrow biopsy specimens","volume":"67","author":"Beckstead","year":"1986","journal-title":"Blood"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Bury, L., Malara, A., Gresele, P., and Balduini, A. (2012). Outside-in signalling generated by a constitutively activated integrin alphaIIbbeta3 impairs proplatelet formation in human megakaryocytes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034449"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1126\/science.8073287","article-title":"Thrombocytopenia in c-mpl-deficient mice","volume":"265","author":"Gurney","year":"1994","journal-title":"Science"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2978","DOI":"10.1182\/blood.2024024636","article-title":"cMPL-based purification and depletion of human hematopoietic stem cells: Implications for pretransplant conditioning","volume":"145","author":"Araki","year":"2025","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1182\/blood.V87.6.2162.bloodjournal8762162","article-title":"Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl","volume":"87","author":"Alexander","year":"1996","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1365-2141.1995.tb05241.x","article-title":"Quantitation of soluble and membrane-bound Fc gamma RIIA (CD32A) mRNA in platelets and megakaryoblastic cell line (Meg-01)","volume":"91","author":"Markovic","year":"1995","journal-title":"Br. J. Haematol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s40164-022-00273-2","article-title":"The GPIb-IX complex on platelets: Insight into its novel physiological functions affecting immune surveillance, hepatic thrombopoietin generation, platelet clearance and its relevance for cancer development and metastasis","volume":"11","author":"Bendas","year":"2022","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.imlet.2014.11.013","article-title":"Human megakaryocyte progenitors derived from hematopoietic stem cells of normal individuals are MHC class II-expressing professional APC that enhance Th17 and Th1\/Th17 responses","volume":"163","author":"Finkielsztein","year":"2015","journal-title":"Immunol. Lett."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1111\/imcb.12035","article-title":"Splenic hematopoietic stem cells display a pre-activated phenotype","volume":"96","author":"Coppin","year":"2018","journal-title":"Immunol. Cell Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.chom.2014.05.004","article-title":"Infection mobilizes hematopoietic stem cells through cooperative NOD-like receptor and Toll-like receptor signaling","volume":"15","author":"Burberry","year":"2014","journal-title":"Cell Host Microbe"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S0074-7696(06)50005-1","article-title":"New insights into the cell biology of the marginal zone of the spleen","volume":"250","author":"Kraal","year":"2006","journal-title":"Int. Rev. Cytol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e153920","DOI":"10.1172\/JCI153920","article-title":"Sepsis promotes splenic production of a protective platelet pool with high CD40 ligand expression","volume":"132","author":"Valet","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1172\/JCI84538","article-title":"Neutrophil extracellular traps\u2014The dark side of neutrophils","volume":"126","author":"Sorensen","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1002\/JLB.MR0718-261RR","article-title":"Megakaryocytes as immune cells","volume":"105","author":"Cunin","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e78662","DOI":"10.7554\/eLife.78662","article-title":"CXCR4(high) megakaryocytes regulate host-defense immunity against bacterial pathogens","volume":"11","author":"Wang","year":"2022","journal-title":"Elife"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1186\/s13054-024-05221-6","article-title":"Megakaryocyte in sepsis: The trinity of coagulation, inflammation and immunity","volume":"28","author":"Hua","year":"2024","journal-title":"Crit. Care"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1182\/blood-2017-08-803635","article-title":"Unusual finding of a megakaryocyte in a peripheral blood smear","volume":"130","author":"Ku","year":"2017","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1084\/jem.20121090","article-title":"A novel role of sphingosine 1-phosphate receptor S1pr1 in mouse thrombopoiesis","volume":"209","author":"Zhang","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Pawig, L., Klasen, C., Weber, C., Bernhagen, J., and Noels, H. (2015). Diversity and Inter-Connections in the CXCR4 Chemokine Receptor\/Ligand Family: Molecular Perspectives. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00429"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.exphem.2021.11.007","article-title":"Integrins and their role in megakaryocyte development and function","volume":"106","author":"Yang","year":"2022","journal-title":"Exp. Hematol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1038\/s41417-022-00476-z","article-title":"Global characterization of megakaryocytes in bone marrow, peripheral blood, and cord blood by single-cell RNA sequencing","volume":"29","author":"Zhang","year":"2022","journal-title":"Cancer Gene Ther."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.thromres.2009.11.004","article-title":"The role of inflammation in regulating platelet production and function: Toll-like receptors in platelets and megakaryocytes","volume":"125","author":"Beaulieu","year":"2010","journal-title":"Thromb. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1111\/jth.14605","article-title":"Activation of toll-like receptors 2 and 4 on CD34(+) cells increases human megakaryo\/thrombopoiesis induced by thrombopoietin","volume":"17","author":"Rodriguez","year":"2019","journal-title":"J. Thromb. Haemost."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1172\/JCI84598","article-title":"Megakaryocytes compensate for Kit insufficiency in murine arthritis","volume":"127","author":"Cunin","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1182\/blood.2020008958","article-title":"Platelet MHC class I mediates CD8+ T-cell suppression during sepsis","volume":"138","author":"Guo","year":"2021","journal-title":"Blood"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"916","DOI":"10.4049\/jimmunol.1200580","article-title":"Platelets present antigen in the context of MHC class I","volume":"189","author":"Chapman","year":"2012","journal-title":"J. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1182\/blood.V79.3.619.619","article-title":"Transforming growth factor beta inhibits megakaryocyte growth and endomitosis","volume":"79","author":"Kuter","year":"1992","journal-title":"Blood"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1182\/blood.V94.6.1961","article-title":"Transforming growth factor-beta1 (TGF-beta1) induces thrombopoietin from bone marrow stromal cells, which stimulates the expression of TGF-beta receptor on megakaryocytes and, in turn, renders them susceptible to suppression by TGF-beta itself with high specificity","volume":"94","author":"Sakamaki","year":"1999","journal-title":"Blood"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1182\/blood-2007-01-067116","article-title":"Platelet factor 4 is a negative autocrine in vivo regulator of megakaryopoiesis: Clinical and therapeutic implications","volume":"110","author":"Lambert","year":"2007","journal-title":"Blood"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1084\/jem.20021897","article-title":"An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4","volume":"197","author":"Lasagni","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nri.2016.112","article-title":"Immunoregulation by members of the TGFbeta superfamily","volume":"16","author":"Chen","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.7150\/thno.40559","article-title":"Megakaryocytes promote bone formation through coupling osteogenesis with angiogenesis by secreting TGF-beta1","volume":"10","author":"Tang","year":"2020","journal-title":"Theranostics"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"4584","DOI":"10.1073\/pnas.78.7.4584","article-title":"Platelet factor 4 is chemotactic for neutrophils and monocytes","volume":"78","author":"Deuel","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","first-page":"313","article-title":"Enhancement of human neutrophil survival and activation by TGF-beta 1","volume":"43","author":"Lagraoui","year":"1997","journal-title":"Cell Mol. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.4049\/jimmunol.147.5.1600","article-title":"Type I transforming growth factor-beta receptors on neutrophils mediate chemotaxis to transforming growth factor-beta","volume":"147","author":"Brandes","year":"1991","journal-title":"J. Immunol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"4349","DOI":"10.1182\/blood-2010-09-308387","article-title":"G-CSF-mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands","volume":"117","author":"Kohler","year":"2011","journal-title":"Blood"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.blre.2009.04.001","article-title":"Platelet alpha-granules: Basic biology and clinical correlates","volume":"23","author":"Blair","year":"2009","journal-title":"Blood Rev."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"3169","DOI":"10.1182\/blood-2003-11-3861","article-title":"Potential role of APRIL as autocrine growth factor for megakaryocytopoiesis","volume":"104","author":"Bonci","year":"2004","journal-title":"Blood"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1161\/ATVBAHA.113.302700","article-title":"Interleukin 1 receptor 1 and interleukin 1beta regulate megakaryocyte maturation, platelet activation, and transcript profile during inflammation in mice and humans","volume":"34","author":"Beaulieu","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"4151","DOI":"10.1182\/blood.V84.12.4151.bloodjournal84124151","article-title":"Cytokine production by primary bone marrow megakaryocytes","volume":"84","author":"Jiang","year":"1994","journal-title":"Blood"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1182\/blood.V78.6.1467.1467","article-title":"Effects of human interleukin-6 on megakaryocyte development and thrombocytopoiesis in primates","volume":"78","author":"Stahl","year":"1991","journal-title":"Blood"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1097\/MOH.0b013e32833e77ee","article-title":"Clinical relevance of microparticles from platelets and megakaryocytes","volume":"17","author":"Italiano","year":"2010","journal-title":"Curr. Opin. Hematol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1182\/blood-2008-06-163832","article-title":"Megakaryocyte-derived microparticles: Direct visualization and distinction from platelet-derived microparticles","volume":"113","author":"Flaumenhaft","year":"2009","journal-title":"Blood"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1182\/blood-2014-05-572818","article-title":"CLEC-2 expression is maintained on activated platelets and on platelet microparticles","volume":"124","author":"Gitz","year":"2014","journal-title":"Blood"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/j.1365-2141.1956.tb06700.x","article-title":"Biological interaction between lymphocytes and other cells","volume":"2","author":"Humble","year":"1956","journal-title":"Br. J. Haematol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1093\/ajcp\/53.4.485","article-title":"Emperipolesis of granular leukocytes within megakaryocytes in human hemopoietic bone marrow","volume":"53","author":"Larsen","year":"1970","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/j.1600-0609.1976.tb01110.x","article-title":"Marrow cell uptake by megakaryocytes in routine bone marrow smears during blood loss","volume":"16","author":"Sahebekhitiari","year":"1976","journal-title":"Scand. J. Haematol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1111\/j.1365-2141.1985.tb07429.x","article-title":"Emperipolesis of granulocytes within megakaryocytes","volume":"60","author":"Paterlini","year":"1985","journal-title":"Br. J. Haematol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/BF01695470","article-title":"The frequency and significance of megakaryocytic emperipolesis in myeloproliferative and reactive states","volume":"64","author":"Cashell","year":"1992","journal-title":"Ann. Hematol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/BF00716989","article-title":"Histomorphometry of bone marrow biopsies in chronic myeloproliferative disorders with associated thrombocytosis\u2014Features of significance for the diagnosis of primary (essential) thrombocythaemia","volume":"413","author":"Thiele","year":"1988","journal-title":"Virchows Arch. A"},{"key":"ref_114","first-page":"93","article-title":"Ultrastructure of bone marrow tissue in so-called primary (idiopathic) myelofibrosis-osteomyelosclerosis (agnogenic myeloid metaplasia). I. Abnormalities of megakaryopoiesis and thrombocytes","volume":"23","author":"Thiele","year":"1991","journal-title":"J. Submicrosc. Cytol. Pathol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1292\/jvms.58.663","article-title":"Morphological observations of megakaryocytic emperipolesis in the bone marrow of rats treated with lipopolysaccharide","volume":"58","author":"Tanaka","year":"1996","journal-title":"J. Vet. Med. Sci."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.thromres.2018.09.053","article-title":"Hypermucoviscous Klebsiella pneumoniae infections induce platelet aggregation and apoptosis and inhibit maturation of megakaryocytes","volume":"171","author":"Wang","year":"2018","journal-title":"Thromb. Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e0010223","DOI":"10.1128\/iai.00102-23","article-title":"Fusobacterium nucleatum Promotes Megakaryocyte Maturation in Patients with Gastric Cancer via Inducing the Production of Extracellular Vesicles Containing 14-3-3epsilon","volume":"91","author":"Liu","year":"2023","journal-title":"Infect. Immun."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1111\/1348-0421.12685","article-title":"Pseudomonas aeruginosa infection stimulates mitogen-activated protein kinases signaling pathway in human megakaryocytes","volume":"63","author":"Sethumadhavan","year":"2019","journal-title":"Microbiol. Immunol."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Lin, G.L., Chang, H.H., Lin, W.T., Liou, Y.S., Lai, Y.L., Hsieh, M.H., Chen, P.K., Liao, C.Y., Tsai, C.C., and Wang, T.F. (2024). Dachshund Homolog 1: Unveiling Its Potential Role in Megakaryopoiesis and Bacillus anthracis Lethal Toxin-Induced Thrombocytopenia. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25063102"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1097\/SHK.0000000000001699","article-title":"The Hematopoietic Stem\/Progenitor Cell Response to Hemorrhage, Injury, and Sepsis: A Review of Pathophysiology","volume":"56","author":"Kelly","year":"2021","journal-title":"Shock"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Tang, X., Xu, Q., Yang, S., Huang, X., Wang, L., Huang, F., Luo, J., Zhou, X., Wu, A., and Mei, Q. (2023). Toll-like Receptors and Thrombopoiesis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021010"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1111\/jth.14788","article-title":"Large and small platelets-(When) do they differ?","volume":"18","author":"Handtke","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Velez-Paez, J.L., Legua, P., Velez-Paez, P., Irigoyen, E., Andrade, H., Jara, A., Lopez, F., Perez-Galarza, J., and Baldeon, L. (2022). Mean platelet volume and mean platelet volume to platelet count ratio as predictors of severity and mortality in sepsis. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0262356"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"6047","DOI":"10.1113\/JP284879","article-title":"The role of platelets and megakaryocytes in sepsis and ARDS","volume":"602","author":"Leung","year":"2024","journal-title":"J. Physiol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.thromres.2023.05.015","article-title":"Alterations in the megakaryocyte transcriptome impacts platelet function in sepsis and COVID-19 infection","volume":"231","author":"Ajanel","year":"2023","journal-title":"Thromb. Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1055\/s-0039-3400256","article-title":"Immature Platelets As a Predictor of Disease Severity and Mortality in Sepsis and Septic Shock: A Systematic Review","volume":"46","author":"Thorup","year":"2020","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Qiu, X.R., Nair, M.G., Jaroszewski, L., and Godzik, A. (2024). Deciphering Abnormal Platelet Subpopulations in COVID-19, Sepsis and Systemic Lupus Erythematosus through Machine Learning and Single-Cell Transcriptomics. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115941"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"12825","DOI":"10.2147\/JIR.S535701","article-title":"The Crucial Roles of Platelets as Immune Mediators in Sepsis","volume":"18","author":"Yang","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1182\/bloodadvances.2017011817","article-title":"Platelet HMGB1 is required for efficient bacterial clearance in intra-abdominal bacterial sepsis in mice","volume":"2","author":"Zhou","year":"2018","journal-title":"Blood Adv."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1177\/08850666211024188","article-title":"Hypercoagulability in Septic Shock Patients With Thrombocytopenia","volume":"37","author":"Kim","year":"2022","journal-title":"J. Intensive Care Med."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"8S","DOI":"10.1177\/1076029618806424","article-title":"Disseminated Intravascular Coagulation: An Update on Pathogenesis, Diagnosis, and Therapeutic Strategies","volume":"24","author":"Papageorgiou","year":"2018","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"e2010024","DOI":"10.4084\/mjhid.2010.024","article-title":"Sepsis-associated disseminated intravascular coagulation and thromboembolic disease","volume":"2","author":"Semeraro","year":"2010","journal-title":"Mediterr. J. Hematol. Infect. Dis."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Cox, D. (2023). Sepsis\u2014It is all about the platelets. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1210219"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.thromres.2019.05.008","article-title":"Modulation of megakaryopoiesis and platelet production during inflammation","volume":"179","author":"Couldwell","year":"2019","journal-title":"Thromb. Res."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"eaau6762","DOI":"10.1126\/sciadv.aau6762","article-title":"Engineering human megakaryocytic microparticles for targeted delivery of nucleic acids to hematopoietic stem and progenitor cells","volume":"4","author":"Kao","year":"2018","journal-title":"Sci. Adv."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1002\/jcp.29166","article-title":"Microvesicles promote megakaryopoiesis by regulating DNA methyltransferase and methylation of Notch1 promoter","volume":"235","author":"Chattapadhyaya","year":"2020","journal-title":"J. Cell Physiol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1182\/bloodadvances.2019000753","article-title":"Human megakaryocytic microparticles induce de novo platelet biogenesis in a wild-type murine model","volume":"4","author":"Escobar","year":"2020","journal-title":"Blood Adv."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1182\/bloodadvances.2017007914","article-title":"Infused factor VIII-expressing platelets or megakaryocytes as a novel therapeutic strategy for hemophilia A","volume":"3","author":"Lyde","year":"2019","journal-title":"Blood Adv."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"274","DOI":"10.2119\/molmed.2015.00235","article-title":"Generation of HLA-Universal iPSC-Derived Megakaryocytes and Platelets for Survival Under Refractoriness Conditions","volume":"22","author":"Borger","year":"2016","journal-title":"Mol. Med."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.jtha.2024.09.008","article-title":"Genetic engineering of megakaryocytes from blood progenitor cells using messenger RNA lipid nanoparticles","volume":"23","author":"Leung","year":"2025","journal-title":"J. Thromb. Haemost."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1056\/NEJMoa073275","article-title":"Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura","volume":"357","author":"Bussel","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"123","DOI":"10.2478\/jccm-2019-0019","article-title":"The Use of High Dose Eltrombopag in the Management of Sepsis-Associated Thrombocytopenia in Critically Ill Patients","volume":"5","author":"Hasan","year":"2019","journal-title":"J. Crit. Care Med."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1111\/cts.12788","article-title":"Good Manufacturing Practice-Grade of Megakaryocytes Produced by a Novel Ex Vivo Culturing Platform","volume":"13","author":"Guan","year":"2020","journal-title":"Clin. Transl. Sci."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/sctm.18-0160","article-title":"Enabling Large-Scale Ex Vivo Production of Megakaryocytes from CD34(+) Cells Using Gas-Permeable Surfaces","volume":"8","author":"Martinez","year":"2019","journal-title":"Stem Cells Transl. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11191\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T05:22:03Z","timestamp":1763702523000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":144,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262211191"],"URL":"https:\/\/doi.org\/10.3390\/ijms262211191","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,19]]}}}