Pleiotrophin Promotes Megakaryocyte Differentiation and Thrombocytopoiesis by Regulating PTPRZ1–Fyn–Akt Signaling in Thrombocytopenia after Allo-HSCT

Post-allotransplant thrombocytopenia (PT) is associated with impaired bone marrow microenvironment function, but the underlying mechanisms remain incompletely understood. This study aimed to investigate the role of pleiotrophin (PTN), a cytokine secreted by bone marrow vascular endothelial cells, in PT treatments.The plasma PTN concentrations were measured by ELISA in thrombocytopenic or non-thrombocytopenic patients after allogeneic hematopoietic stem cell transplantation (HSCT), as well as healthy donors. To identify the therapeutic effects of PTN and its receptor, protein tyrosine phosphatase receptor zeta 1 (PTPRZ1), we conducted allo-HSCT in two mouse models: PTN-treated mice and mice transplanted with PTPRZ1-deficient hematopoietic stem cells (HSCs). A series of molecular studies were also performed to elucidate the mechanistic role of PTN on megakaryocyte (MK) differentiation and platelet production.The plasma levels of PTN were significantly reduced in PT patients compared to non-PT patients post-HSCT. In allo-HSCT mice, exogenous PTN administration enhanced MKs proliferation and accelerated platelet recovery. Mechanistically, PTN bound to PTPRZ1 and inactivated its phosphatase activity, thereby prolonging the activation of downstream signaling. PTPRZ1 knock-out (KO) mice exhibited thrombocythemia, and the transplantation of PTPRZ1 KO HSCs also boosted platelets production and MK counts in recipient mice. Further analysis revealed that PTPRZ1 interacts with Fyn, and PTPRZ1 knock-down contributes to prolonged phosphorylation of Fyn and activation of PI3K-Akt pathway.These findings demonstrated that PTN facilitates MK differentiation and platelet production by regulating PTPRZ1-Fyn-Akt axis, suggesting PTN supplementation therapies could offer a potential novel treatment approach for PT patients.