AUTHOR=Filia Anastasia , Mitroulis Ioannis , Loukogiannaki Catherine , Grigoriou Maria , Banos Aggelos , Sentis George , Giannouli Stavroula , Karali Vassiliki , Athanasiadis Emmanouil , Kokkinopoulos Ioannis , Boumpas Dimitrios T. 

TITLE=Single-cell transcriptomic analysis of hematopoietic progenitor cells from patients with systemic lupus erythematosus reveals interferon-inducible reprogramming in early progenitors

JOURNAL=Frontiers in Immunology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1383358

DOI=10.3389/fimmu.2024.1383358

ISSN=1664-3224

ABSTRACT=Introduction: Ιmmune cells that contribute to the pathogenesis of systemic lupus erythematosus (SLE) derive from adult haematopoietic stem and progenitor cells (HSPCs) within the bone marrow (BM). For this reason, we reasoned that fundamental abnormalities in SLE can be traced to a BM-derived HSPC inflammatory signature.Methods: BM samples from 4 SLE patients, 6 healthy controls and 2 umbilical cord blood (CB) samples were used. CD34+ cells were isolated from BM and CB samples and single cell RNA-sequencing was performed.Results: A total of 426 cells and 24,473 genes were used in the analysis. Clustering analysis resulted in seven distinct clusters of cell types. Mutually exclusive markers, which were characteristic of each cell type were identified. We identified three HSPC subpopulations, one of which consisted of proliferating cells (MKI67 expressing cells), one T-like, one B-like and two myeloid-like progenitor subpopulations. Differential expression analysis revealed i) cell cycle-associated signatures, in healthy BM of HSPCs clusters 3 and 4 when compared to CB and ii) interferon (IFN) signatures in SLE BM of HSPC clusters 3, 4 and myeloid-like progenitor cluster 5 when compared to healthy controls. The IFN signature in SLE appeared to be deregulated following TF regulatory network analysis and differential alternative splicing analysis between SLE and healthy controls in HSPC subpopulations.Discussion: This study revealed both quantitative-as evidenced by decreased numbers of non-proliferating early progenitors and qualitative differencescharacterised by an IFN signature in SLE, which is known to drive loss of function and depletion of HSPCs. Chronic IFN exposure affects early hematopoietic progenitors in SLE which may account for the immune aberrancies and the cytopenias in SLE.