Tijani, A. | Search bioRxiv

bioRxiv2026

Hemoglobin C is prone to oxidative denaturation, resulting in red blood cell membrane damage in HbSC disease

Sickle-hemoglobin-C (HbSC) sickle cell disease is characterized by RBC dehydration (xerocytosis), which promotes polymerization of HbS. HbSC causes substantial morbidity despite lower sickling potential than HbSS, suggesting a critical detrimental role of HbC in the disease pathophysiology. We derived HbCC mice by interbreeding our HbSC mice, which demonstrated a similar RBC phenotype of xerocytosis as humans with HbCC. We compared RBCs from HbCC, HbSC, and HbSS mice. Oxidized ferryl (Fe4+)-Hb, and its oxidative-denaturation, which results in hemichrome formation (Heinz-bodies), was most pronounced in HbCC>HbSC>HbSS, despite significantly higher reactive oxygen species in HbSS, illustrating a higher propensity of HbC to denaturation than HbS. RBC deformability followed a similar pattern, with Elongation Index lowest in HbCC<HbSC<HbSS. Next, we determined if RBC from HbSC patients on hydroxyurea showed improved membrane damage. Hydroxyurea treatment reduced Heinz-body formation and improved RBC deformability, despite negligible/modest fetal hemoglobin (HbF) induction, compared to non-hydroxyurea HbSC controls. The antioxidant quercetin showed a similar reduction in Heinz-body burden and improvement in RBC deformability as hydroxyurea, without affecting Hb or HbF concentration, reticulocyte count, or RBC xerocytosis. HbC-driven oxidative denaturation and membrane damage represent important contributors of RBC dysfunction in HbSC disease; hence, oxidative membrane injury could be targeted besides antisickling approaches.

cell biology↗

bioRxiv2025

Mammalian oocytes receive maternal-effect RNAs from granulosa cells

It is currently thought that growing mammalian oocytes receive only small molecules via gap junctions from surrounding support cells, the granulosa cells. From the study of chimeric preantral oocyte and granulosa cell reaggregations, we provide evidence that growing mouse oocytes receive mRNAs from granulosa cells. Among the >1,000 granulosa-transcribed RNAs we identified in the oocyte, those that contribute to proper oocyte maturation and early embryo development were highly enriched. Predicted motifs for two RNA-binding proteins that function in RNA trafficking, FMRP and TDP43, were abundant in the UTRs of the granulosa-derived transcripts. Immunostaining demonstrated that both FMRP and TDP43 co-localize with the actin-rich granulosa cell protrusions that span the zone pellucida and connect to the oocyte, suggesting their role in importing mRNAs. Our results offer the possibility that oocyte failure may not always reflect an intrinsic oocyte deficiency but could arise from insufficient supply of maternal transcripts by granulosa cells during oocyte growth.

developmental biology↗