来重医儿院做的第一个罕见病（2型孼多糖, MPS-II）患儿的单细胞多组学(single cell RNA/TCR/BCR)测序项目，发现了单核和巨噬细胞在疾病的治疗中有巨大的变化。这个项目来源于朱高慧老师在诊疗中的一个罕见病例，我们采用最新的组学技术，对单个患儿的多个治疗时间点进行了测序，从动态角度来研究疾病在治疗下不同细胞类群变化，为患儿用药后的细胞环境微环境及其作用靶点表达提供了一些新的视野。
罕见病的研究是典型的小样本/少样本学习问题，如何从多组学、多个时间探究单个病人治疗过程中de动态变化是一个很好的策略。罕见病难做，文章难发，从去年年初投稿到现在，经历了多轮投稿，拒稿，终于在线发表。文章虽小，罕见不应该被忽视，希望后续能结合实验做一些更要用的研究。 这个工作是我的第一个博士谢玥完成，她从一个7年制临床研究生转型到生物信息，也是她在我组里的第一篇文章。
Single-cell RNA sequencing reveals important role of monocytes and macrophages during mucopolysaccharidosis treatment
Scientific Reports volume 15, Article number: 12364 (2025)
Abstract
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.
计算基因组学研究组 