Transcriptome reprogramming and myeloid skewing in haematopoietic stem and progenitor cells in systemic lupus erythematosus

Ann Rheum Dis. 2020 Feb;79(2):242-253. doi: 10.1136/annrheumdis-2019-215782. Epub 2019 Nov 28.


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.

Keywords: autoimmunity; inflammation; systemic lupus erythematosus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology
  • CCAAT-Enhancer-Binding Protein-delta / metabolism
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cell Cycle / immunology
  • Cellular Reprogramming / immunology*
  • Chromosome Mapping
  • DNA Damage
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Granulocyte Colony-Stimulating Factor / metabolism
  • Granulocytes / immunology
  • Hematopoietic Stem Cells / immunology*
  • Lupus Erythematosus, Systemic / immunology*
  • Lymphocytes / immunology
  • Mice
  • Myeloid Cells / immunology*
  • Transcriptome / immunology*


  • CCAAT-Enhancer-Binding Proteins
  • Cebpd protein, mouse
  • Cebpe protein, mouse
  • CCAAT-Enhancer-Binding Protein-delta
  • Granulocyte Colony-Stimulating Factor