Souradip Mallick, National Institute of Technology, Rourkela
Hematopoietic stem cell differentiation to erythroid cells occurs within the bone marrow and the process of mature RBC formation is known as erythropoiesis. This process mainly depends on specific cell interactions within the bone marrow. Erythroid differentiation in the bone marrow occurs on erythroblast islands. CD14+ monocyte-derived macrophages alter the balance between gamma and beta-globin gene expression in erythroid cultures. Downregulation of gamma-globin occurs prior to the erythroblast stage. Cultured erythroblasts are a mixture of HbA restrictive and HbA/HbF expressing cells and that the proportion of cells in the latter population depends on the starting material. Cultures started from CD34+ cells contain more HbA/HbF expressing cells compared to erythroblasts cultured from total peripheral blood mononuclear cells (PBMC).
PBMC cultures contain significant amounts of cells capable of interactions with CD34+, erythroid progenitors, and erythroblasts. Differentiating erythroblast from CD14+ depleted PBMCs showed a significantly increased frequency of HbA/HbF expressing cells and a higher HbF mean fluorescent intensity (MFI) compared to erythroid cultures derived from total PBMCs. The increased fetal hemoglobin expression did not result from overall lower hemoglobinization. Co-culture of CD34+ cells with CD14+ cells leads to a decrease in HbF expression compared to CD34+ alone. Thus CD14+ monocyte/macrophages from PBMC reduce HbF expression in erythroid cultures
Post Transcriptional control mechanisms regulate the frequency of HbF/HbA cells and differentially expressed genes is low between HbA/HbF and HbA sorted populations. CD34+ hematopoietic stem and progenitor cells (HSPC) are mixtures of hematopoietic cells at different stages of differentiation from hematopoietic stem cells to more committed lineage progenitors. Lineage specification progresses from CD34+ CD36- hematopoietic stem and progenitor cells to CD34+ CD36+ megakaryoid/erythroid common progenitors to CD34-CD36+ erythroblasts. Co-cultures with these fractions and the CD14+ cells were assessed to determine the stage at which the repression occurred. Co-culture of CD34-CD36+ erythroblasts with CD14+ monocytes did not decrease HBG1/2 expression. This supports the RNA-sequencing data results that the regulation of HBG1/2 in erythroid cultures by CD14+ cells does not occur at the committed lineage-restricted pro-erythroblast stage. Thus regulation of globin genes by CD14+ cells can occur early during hematopoiesis before the commitment to erythroid restricted progenitors.
Understanding the regulation of globin genes, mapping the signal transduction induced by macrophages on hematopoietic progenitors uncover many novel pathways. These pathways could potentially be blocked to increase gamma expression which provides novel therapeutic options to increase HbF in a sickle cell or beta-thalassemia either on its own or in combination with other HbF-inducing therapy.
Also read:PSORIASIS – A GREAT DERMATOLOGIC MYSTERY
Source – Heshusius, S., Heideveld, E., von Lindern, M. et al. CD14+ monocytes repress gamma globin expression at early stages of erythropoiesis. Sci Rep11, 1507 (2021). https://doi.org/10.1038/s41598-021-81060-7
- The Corrosion Prediction from the Corrosion Product Performance
- Nitrogen Resilience in Waterlogged Soybean plants
- Cell Senescence in Type II Diabetes: Therapeutic Potential
- Transgene-Free Canker-Resistant Citrus sinensis with Cas12/RNP
- AI Literacy in Early Childhood Education: Challenges and Opportunities
One thought on “CD14+ regulates gamma-globin gene”