RT Journal Article
SR Electronic
T1 Transcriptome reprogramming and myeloid skewing in haematopoietic stem and progenitor cells in systemic lupus erythematosus
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 242
OP 253
DO 10.1136/annrheumdis-2019-215782
VO 79
IS 2
A1 Grigoriou, Maria
A1 Banos, Aggelos
A1 Filia, Anastasia
A1 Pavlidis, Pavlos
A1 Giannouli, Stavroula
A1 Karali, Vassiliki
A1 Nikolopoulos, Dionysis
A1 Pieta, Antigone
A1 Bertsias, George
A1 Verginis, Panayotis
A1 Mitroulis, Ioannis
A1 Boumpas, Dimitrios T
YR 2020
UL http://ard.bmj.com/content/79/2/242.abstract
AB Objectives Haematopoietic stem and progenitor cells (HSPCs) are multipotent cells giving rise to both myeloid and lymphoid cell lineages. We reasoned that the aberrancies of immune cells in systemic lupus erythematosus (SLE) could be traced back to HSPCs.Methods A global gene expression map of bone marrow (BM)-derived HSPCs was completed by RNA sequencing followed by pathway and enrichment analysis. The cell cycle status and apoptosis status of HSPCs were assessed by flow cytometry, while DNA damage was assessed via immunofluorescence.Results Transcriptomic analysis of Lin−Sca-1+c-Kit+ haematopoietic progenitors from diseased lupus mice demonstrated a strong myeloid signature with expanded frequencies of common myeloid progenitors (CMPs)—but not of common lymphoid progenitors—reminiscent of a ‘trained immunity’ signature. CMP profiling revealed an intense transcriptome reprogramming with suppression of granulocytic regulators indicative of a differentiation arrest with downregulation trend of major regulators such as Cebpe, Cebpd and Csf3r, and disturbed myelopoiesis. Despite the differentiation arrest, frequencies of BM neutrophils were markedly increased in diseased mice, suggesting an alternative granulopoiesis pathway. In patients with SLE with severe disease, haematopoietic progenitor cells (CD34+) demonstrated enhanced proliferation, cell differentiation and transcriptional activation of cytokines and chemokines that drive differentiation towards myelopoiesis, thus mirroring the murine data.Conclusions Aberrancies of immune cells in SLE can be traced back to the BM HSPCs. Priming of HSPCs and aberrant regulation of myelopoiesis may contribute to inflammation and risk of flare.Trial registration number 4948/19-07-2016.