UCLA

Hematopoietic stem and progenitor cells (HSPCs) give rise to all mature blood and immune cells through a series of lineage-restricted developmental intermediates. Perturbations to these trajectories can impair immunity or promote malignant transformation. However clinical decision making rarely incorporates direct measurements of lineage state. Advances in single-cell RNA sequencing (scRNA-seq) now enable high-resolution profiling of hematopoiesis in both health and disease, offering the opportunity to connect molecular differentiation landscapes with clinical outcomes. In this dissertation, scRNA-seq analyses was applied to investigate how thymic T-cell development and bone marrow myeloid differentiation are altered in disease contexts with established clinical consequences.First, we characterize the role of RORγt-dependent regulation in human and mouse thymocyte development using single-cell expression and TCR-rearrangement signatures to map lineage progression. We demonstrate that disruption of RORC signaling affects double-positive thymocyte survival and alters the balance between positive selection and developmental arrest, providing mechanistic insight into immunodeficiency and lymphoma predisposition in mice associated with RORγt loss.Second, we examine how chronic interferon exposure reshapes hematopoietic differentiation in the context of gene therapy for chronic granulomatous disease (CGD). We show that prolonged inflammatory signaling promotes premature myeloid commitment and erodes HSPC self-renewal capacity. Using patient-derived scRNA-seq datasets, we link clinical outcomes to inflammatory pathways through the analysis of differentiation trajectories. Together, these studies establish a framework for mapping hematopoietic lineage dynamics to clinical outcomes using single-cell transcriptomics. By connecting developmental checkpoints to therapeutic response and disease risk, this work provides a mechanistic foundation for integrating lineage state into personalized treatment strategies in immunodeficiency and hematologic disease.