It is well known that vascular endothelial growth factors (VEGFs) and their receptors (vascular endothelial growth factor receptors, VEGFRs) are expressed in different tissues, and VEGF-VEGFR loops regulate a wide range of responses, including metabolic homeostasis, cell proliferation, migration and tubuleogenesis. As ligands, VEGFs act on three structurally related VEGFRs (VEGFR1, VEGFR2 and VEGFR3 [also termed FLT1, KDR and FLT4, respectively]) that deliver downstream signals. Haematopoietic stem cells (HSCs), megakaryocytic cell lines, cultured megakaryocytes (MKs), primary MKs and abnormal MKs express and secrete VEGFs. During the development from HSCs to MKs, VEGFR1, VEGFR2 and VEGFR3 are expressed at different developmental stages, respectively, and re-expressed, e.g., VEGFR2, and play different roles in commitment, differentiation, proliferation, survival and polyplodization of HSCs/MKs via autocrine, paracrine and/or even intracrine loops. Moreover, VEGFs and their receptors are abnormally expressed in MK-related diseases, including myeloproliferative neoplasms, myelodysplastic syndromes and acute megakaryocytic leukaemia (a rare subtype of acute myeloid leukaemia), and they lead to the disordered proliferation/differentiation of bone marrow cells and angiogenesis, indicating that they are closely related to these diseases. Thus, targeting VEGF-VEGFR loops may be of potential therapeutic value.

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Objectives: This study aimed to investigate the feasibility and effects of intramuscular injections of autologous bone marrow cells (BMC) combined with off-pump coronary artery bypass grafts (OPCAB) on improving cardiac function in chronic myocardial infarction patients. Methods: Ninety patients with chronic myocardial infarction were prospectively enrolled and randomized to an OPCAB with saline or an OPCAB with BMC-treatment group. After finishing CABG, patients received injections of BMC or saline into the marginal area of the infarct. The primary endpoint was incidence of emergent adverse events within 6 months. Results: There were no differences between the control and BMC-treated groups in baseline ejection fractions (EF) or wall motion score indices (WMSI) in the affected segments. At the 6-month follow-up, the ejection fraction was significantly increased in the BMC-treated group compared to controls (47.58 w 6.34 vs. 40.11 w 7.42; p < 0.05), whereas the WMSI were significantly decreased (1.25 w 0.32 vs. 1.54 w 0.53; p < 0.05), with no occurrences of life-threatening arrhythmias or death. The addition of BMC injections to OPCAB treatment increased regional perfusion to the marginal infarct area. Conclusion: These results demonstrate that BMC transplant is beneficial to the cardiac function with no adverse effects, and therefore a safe and feasible adjunct therapy providing beneficial effects in clinical practice. i 2014 S. Karger AG, Basel

CD226 molecules play an important role in maturation of the megakaryocytes in combination with LFA-1.

Studies on polyploidization of megakaryocytes have been hampered by the lack of synchronized polyploid megakaryocytes. In this study, a relatively synchronized polyploid cell model was successfully established by employing Dami cells treated with nocodazole. In nocodazole-induced cells, cyclin B expression oscillated normally as in diploid cells and polyploid megakaryocytes. By using the nocodazole-induced Dami cell model, we found that 4E-BP1 and Thr421/Ser424 of ribosomal S6 kinase 1(S6K1) were phosphorylated mostly at M-phase in cytoplasm and oscillated in nocodazole-induced polyploid Dami cells, concomitant with increased expression of p27 and cyclin D3. However, phosphorylation of 4E-BP1 and S6K1 on Thr421/Ser424 was significantly decreased in differentiated Dami cells induced by phorbol 12-myristate 13-acetate (PMA), concomitant with increased expression of cyclin D1 and p21 and cyclin D3. Overexpression of the kinase dead form of S6K1 containing the mutation Lys 100 --> Gln in PMA-induced Dami cells increased ploidy whereas overexpression of rapamycin-resistant form of S6K1 containing the mutations Thr421 --> Glu and Ser424 --> Asp significantly dephosphorylated 4E-BP1 and reduced expression of cyclin D1, cyclin D3, p21 and p27, and slightly decreased the ploidy of PMA-induced Dami cells, compared with treatment with PMA alone. Moreover, overexpression of rapamycin-resistant form of S6K1 significantly reversed polyploidization of nocodazole-induced Dami cells. Furthermore, MAP (a novel compound synthesized recently) partly blocked the phosphorylation of S6K1 on Thr421/Ser424 and decreased the expression of p27 and polyploidization in nocodazole-induced Dami cells. Taken together, these data suggested that S6K1/4E-BP1 pathway may play an important role in polyploidization of megakaryocytes.