Response to recombinant human granulocyte colony-stimulating factor in reticular dysgenesis.

Reticular dysgenesis (RD) is characterized by severe combined immunodeficiency and agranulocytosis with hematopoietic stem cell transplantation (HSCT) being the only curative therapy. Severe neutropenia in RD is typically unresponsive to recombinant human granulocyte colony-stimulating factor (rhG-CSF). To delineate lineage-specific transcriptional responses and cellular heterogeneity induced by rhG-CSF, we integrated single-cell RNA sequencing from seven samples, including two RD patients (with and without rhG-CSF) and three pediatric controls. We identified a moderate increase in hematopoietic stem and progenitor cells (HSPCs) and common myeloid progenitor/granulocyte-monocyte progenitor fractions following rhG-CSF. Notably, B cell fractions increased after rhG-CSF, accompanied by enhanced maturation from common lymphoid progenitors to precursor B cells. In parallel, genes involved in B cell differentiation were markedly upregulated compared with untreated cells. It also modulated the HSPC compartment by markedly suppressing interferon-γ (IFNγ) signaling pathways. RhG-CSF administration before HSCT may benefit patients with RD by modestly increasing neutrophils and supporting infection control, while suppressing IFNγ signaling in HSPCs and potentially promoting B cell differentiation.