{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThrombopoietin (THPO) is a pleiotropic cytokine that plays a central role in regulating hematopoiesis through its effects on megakaryocytic development, platelet production, and hematopoietic stem cell (HSC) maintenance. THPO is produced in the liver and other tissues and is subject to a feedback regulation mechanism whereby aged or desialylated platelets bind the hepatic Ashwell‐Morell receptor to induce THPO synthesis, thus modulating thrombopoiesis. At the cellular level, THPO activates signaling cascades—including JAK2/STAT, PI3‐kinase, and mTOR—that promote megakaryocyte survival via anti‐apoptotic mediators such as Bcl‐xL and direct the expression and nuclear import of key transcription factors (for example, HOX family members and GATA‐1) necessary for stem cell self‐renewal and lineage commitment. Moreover, THPO cooperates with other cytokines such as FLT3‐ligand to expand interferon‐producing dendritic cell precursors and enhances HSC engraftment in xenogeneic models, underscoring its essential role in normal and regenerative hematopoiesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role in hematopoiesis, THPO exerts additional functions that impact diverse biological processes. In some contexts, THPO acts as a mediator in extrahematopoietic settings—affecting cardiovascular function by modulating myocardial contractility through nitric oxide pathways and influencing inflammatory responses in sepsis, while also priming platelets for activation. In the realm of malignancy, aberrant THPO signaling (for example through its receptor CD110) has been implicated in promoting self‐renewal, metabolic reprogramming, and metastasis of tumor‐initiating cells in colorectal cancer. Moreover, studies on developmental variations have revealed that THPO signaling differs between neonatal and adult megakaryocytes, and genetic alterations in THPO or its receptor are now recognized as causative in inherited thrombocytopenia or thrombocythemia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural insights into THPO and its receptor interactions have furthered our understanding of the cytokine’s biology and have significant clinical implications. Detailed crystallographic and mutational analyses have delineated the receptor‐binding domain of THPO and its interaction with c‐Mpl, while studies have uncovered regulatory mechanisms—including alternative splicing events and receptor–ligand feedback via platelet-mediated clearance—that fine‐tune its activity. Genetic studies have identified both loss‐of‐function and gain‐of‐function mutations in the THPO gene that underlie conditions such as congenital amegakaryocytic thrombocytopenia, aplastic anemia, and hereditary thrombocythemia. Moreover, animal models engineered to express the human THPO or its agonists have demonstrated improved HSC engraftment and multilineage differentiation, paving the way for targeted therapeutic strategies in bone marrow failure and myeloproliferative disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Keita Kirito, Tomoko Watanabe, Ken-ichi Sawada, et al. 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