Single-cell RNA sequencing reveals important role of monocytes and macrophages during mucopolysaccharidosis treatment.

Mucopolysaccharidosis (MPS) encompasses a heterogeneous group of lysosomal storage diseases resulting from mutations in genes encoding lysosomal enzymes responsible for the degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs). Current therapeutic strategies for MPS include hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT), and symptomatic therapy. This study investigated dynamic changes in MPS type II (MPS-II) through genomic and single-cell sequencing in a patient undergoing ERT. Analysis of peripheral blood mononuclear cells (PBMCs) from one MPS-II patient of 10 year old at different disease stages through scRNA-seq identified various immune cell types, including natural killer (NK) cells, NKT cells, CD4 + and CD8 + T cells, CD14 + and CD16 + monocytes, and B cells. Monocytes and macrophages were significantly reduced during the severe stage of MPS-II but increased during the recovery stage following ERT. Notably, monocyte subtype mono3 was exclusively expressed in the severe stage, while mono1_2, a subtype of mono1, was absent during the severe stage and exhibited distinct biological functions. These findings suggest that monocytes and macrophages play critical roles in the pathogenesis of MPS-II and in the response to ERT. Pseudotime, Gene Ontology, and cell-communication analyses revealed unique functions for the different cellular subtypes. Notably, key molecules mediating cellular interactions during ERT in MPS-II included CXCR3, PF4, APP, and C5AR1 in macrophages, RPS19 in T cells, HLA-DPB1 in B cells, ADRB2 in NK cells, and IL1B, C5AR1, RPS19, and TNFSF13B in monocytes. Overall, integrative analysis delineated the expression dynamics of various cell types and identified mutations in MPS-II, providing a comprehensive atlas of transcriptional programs, cellular characterizations, and genomic variation profiles in MPS-II. This dataset, along with advanced integrative analysis, represents a valuable resource for the discovery of drug targets and the improvement of therapeutic strategies for MPS-II.