A novel mouse model of hemoglobin SC disease reveals mechanisms underlying beneficial effects of hydroxyurea

Blood. 2025 Jul 3;146(1):13-28. doi: 10.1182/blood.2024028136.

Abstract

Sickle cell hemoglobin C (HbSC) disease results from compound heterozygosity of hemoglobin S (HbS) and hemoglobin C (HbC), comprising 30% of sickle cell disease (SCD). HbC induces red blood cell (RBC) dehydration/xerocytosis, which promotes sickling. HbSC-SCD causes significant morbidity despite being milder than homozygous HbSS-SCD. Current research/treatment strategies have focused on HbSS-SCD, whereas patients with HbSC are deprived of disease-modifying/transformative therapies because of lack of preclinical models. We generated HbSC mice, which resemble human HbSC-SCD: HbSC erythrocytes showed marked xerocytosis. Anemia, hemolysis, inflammation, and organ damage were milder than HbSS mice but hypoxia/reperfusion injury was similar. Retinopathy developed at higher frequency than HbSS mice (66.7% vs 16.7%; P < .05), as in patients with HbSC-SCD. Although HbSC RBCs sickled at lower oxygen tension than HbSS RBCs, they did not completely recover deformability after hypoxia/reoxygenation. Using the HbSC mice, we studied the mechanism by which hydroxyurea causes significant clinical benefit in patients with HbSC-SCD, despite minimal/modest increases in fetal Hb (HbF). We found hydroxyurea had distinct non-HbF and HbF effects. Hydroxyurea did not increase HbF in adult HbSC/HbSS mice but reduced RBC reactive oxygen species, ferryl Hb, and Heinz-body formation, thereby reducing membrane damage; however, RBC hydration was unaffected. When given to unborn pups before γ-globin expression was switched off, and continued postnatally, we could induce HbF in both HbSC and HbSS mice (higher HbF in HbSS vs HbSC mice). Minimal increases in HbF (∼1%) improved HbSC RBC hydration. Peak HbF levels of 7% in HbSC mice abrogated sickling. Overall, this HbSC model will help bridge the knowledge gap in mechanistic/therapeutic studies in this neglected disease.

MeSH terms

  • Anemia, Sickle Cell* / blood
  • Anemia, Sickle Cell* / drug therapy
  • Anemia, Sickle Cell* / genetics
  • Anemia, Sickle Cell* / pathology
  • Animals
  • Antisickling Agents* / pharmacology
  • Antisickling Agents* / therapeutic use
  • Disease Models, Animal*
  • Erythrocytes / drug effects
  • Erythrocytes / metabolism
  • Erythrocytes / pathology
  • Erythrocytes, Abnormal / drug effects
  • Erythrocytes, Abnormal / metabolism
  • Erythrocytes, Abnormal / pathology
  • Hemoglobin C / genetics
  • Hemoglobin C / metabolism
  • Hemoglobin, Sickle / genetics
  • Hemoglobin, Sickle / metabolism
  • Humans
  • Hydroxyurea* / pharmacology
  • Hydroxyurea* / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL

Substances

  • Hydroxyurea
  • Antisickling Agents
  • Hemoglobin, Sickle
  • Hemoglobin C