Serum of sickle cell disease patients contains fetal hemoglobin silencing factors secreted from leukocytes

Tohru Ikuta,1 Hassan Sellak,1 Si-Yang Liu,2 Nadine Odo1 1Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA; 2Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA Background: The mechanisms that regulate fetal hemoglobin (HbF) expression in sickle cell disease (SCD) remain elusive. We previously showed that steady-state SCD patients with high HbF levels due to a γ-globin gene mutation demonstrate strong inverse correlations between HbF levels and leukocyte counts, suggesting that leukocytes play a role in regulating HbF in SCD. Materials and methods: To further investigate the role of leukocytes in HbF expression in SCD, we examined the presence of HbF silencing factors in the serum of 82 SCD patients who received hydroxyurea (HU) therapy. Results: HU-mediated HbF induction was associated with elevated total hemoglobin levels and improved red blood cell parameters, but there was no correlation with reticulocyte or platelet counts. Importantly, we again found that HU-induced HbF levels correlated with reductions in both neutrophils and lymphocytes/monocytes, indicating that these cell lineages may have a role in regulating HU-mediated HbF expression. Our in vitro studies using CD34+-derived primary erythroblasts found that patient serum preparations include HbF silencing factors that are distinct from granulocyte-macrophage colony-stimulating factor, and the activity of such factors decreases upon HU therapy. Conclusion: Together, these results demonstrate the importance of leukocyte numbers in the regulation of HbF levels for SCD patients both in steady state and under HU therapy, and that leukocytes secrete HbF silencing factors that negatively affect HbF expression in erythroid-lineage cells in SCD. Keywords: sickle cell disease, leukocytes, hydroxyurea, fetal hemoglobin, silencing factor

Mechanisms of Cardiac Repair and Regeneration

Cardiovascular regenerative therapies are pursued on both basic and translational levels. Although efficacy and value of cell therapy for myocardial regeneration can be debated, there is a consensus that profound deficits in mechanistic understanding limit advances, optimization, and implementation. In collaboration with the TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes), this review overviews several pivotal aspects of biological processes impinging on cardiac maintenance, repair, and regeneration. The goal of summarizing current mechanistic understanding is to prompt innovative directions for fundamental studies delineating cellular reparative and regenerative processes. Empowering myocardial regenerative interventions, whether dependent on endogenous processes or exogenously delivered repair agents, ultimately depends on mastering mechanisms and novel strategies that take advantage of rather than being limited by inherent myocardial biology