Relation between factors involved in stress erythropoiesis and fetal hemoglobin production in sickle cell disease

• Grant number: 24/13972-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2025
• End date: January 31, 2026
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Renata Sesti Costa
• Grantee: Luísa dos Santos Pañella
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Sickle cell disease is a hereditary disease of high relevance worldwide caused by a mutation in the gene that encodes the b subunit of hemoglobin, which forms an anomalous hemoglobin (HbS), which polymerizes during deoxygenation, forming sickle-shaped erythrocytes. This condition can lead to several clinical complications, most of which are associated with episodes of vaso-occlusion, a phenomenon that occurs due to inflammatory processes that lead to the adhesion of sickle erythrocytes and leukocytes to activated endothelial cells, resulting in flow blockage. blood. This process involves several inflammatory mediators, such as IL-1b, IL-6, IL-8 and TNF-a, generating a chronic state of inflammation, intensified by DAMPs extravasated in intravascular hemolysis. In erythropoiesis with inflammatory stimuli, cytokines reduce the production of erythrocytes and stimulate erythrophagocytosis. In compensation, they stimulate stress erythropoiesis mechanisms, with the proliferation of extramedullary erythroblasts, intensification of the development of new erythrocytes due to the increase in erythroblastic islands (EBI) in the bone marrow and outside it, and different induction mechanisms. Erythropoiesis under stress depends on the activation of GDF15 and Wnt signaling, with GDF15 inducing the expression of BMP4 in macrophages, inducing erythroid proliferation, while Epo/STAT signaling in macrophages inhibits Wnt signaling, which generates terminal differentiation. Due to anemia, y-globin expression increases, forming HbF. Studies correlate HbF with the improvement of sickle cell disease symptoms, by reducing cell sickling and partially reversing the death of erythroblasts due to ineffective erythropoiesis, but there is still lack of information about its mechanisms. Therefore, the project intends to verify the relation between the factors that trigger erythropoiesis under stress, such as GDF25 and CCL2, and the increased production of HbF, by obtaining data and samples to do a statistical analysis. Our results could contribute to increase information about sickle cell anemia, stress erythropoiesis and fetal hemoglobin, serving as a basis for future studies of the disease.