Decoding lymphomyeloid divergence and immune hyporesponsiveness in G-CSF-primed human bone marrow by single-cell RNA-seq

Abstract

Granulocyte colony-stimulating factor (G-CSF) has been widely used to mobilize bone marrow hematopoietic stem/progenitor cells for transplantation in the treatment of hematological malignancies for decades. Additionally, G-CSF is also accepted as an essential mediator in immune regulation, leading to reduced graft-versus-host disease following transplantation. Despite the important clinical roles of G-CSF, a comprehensive, unbiased, and high-resolution survey into the cellular and molecular ecosystem of the human G-CSF-primed bone marrow (G-BM) is lacking so far. Here, we employed single-cell RNA sequencing to profile hematopoietic cells in human bone marrow from two healthy donors before and after 5-day G-CSF administration. Through unbiased bioinformatics analysis, our data systematically showed the alterations in the transcriptional landscape of hematopoietic cells in G-BM, and revealed that G-CSF-induced myeloid-biased differentiation initiated from the stage of lymphoid-primed multipotent progenitors. We also illustrated the cellular and molecular basis of hyporesponsiveness of T cells and natural killer (NK) cells caused by G-CSF stimulation, including the potential direct mechanisms and indirect regulations mediated by ligand–receptor interactions. Taken together, our data extend the understanding of lymphomyeloid divergence and potential mechanisms involved in hyporesponsiveness of T and NK cells in human G-BM, which might provide basis for optimization of stem cell transplantation in hematological malignancy treatment.

In vivo G-CSF treatment activates the GR-SOCS1 axis to suppress IFN-γ secretion by natural killer cells

“…The role of SOCS1 in regulating IFN-g secretion by NK cells has also been confirmed in mouse models (Zawislak et al, 2013;Zhao et al, 2016). G-CSF treatment of murine 32D cells expressing the wild-type form of the human G-CSF-R resulted in rapid induction of SOCS1 transcripts (Zhuang et al, 2005), indicating that G-CSF may reduce IFN-g secretion by upregulating SOCS1 and single-cell sequencing data suggest that G-CSF may directly upregulate SOCS1 expression in T/NK cells (You et al, 2022). However, there is limited understanding of how G-CSF treatment upregulates SOCS1.…”

TRPV4 mRNA is elevated in the caudate nucleus with NPH but not in Alzheimer’s disease

“…There are immunological cells such as T lymphocytes in the CSF ( Evans et al, 2019 ) that can be analyzed by single cell techniques ( Esaulova et al, 2020 ; Guan et al, 2022 ; Piper et al, 2022 ; You et al, 2022 ). To study CSF and compare that with the brain tissue finding is thus highly relevant.…”

Role of Granulocyte-Colony Stimulating Factor (G-CSF) in Immune Regulation and Neuroprotection

“…This implies that, mTOR/p70S6K may be one of the signaling pathways by which G-CSF exerts its neuroprotective effect as well as other important physiological functions including modulation of immune response, gene regulation, protein synthesis and neurogenesis. The role of G-CSF in regulation of the immune system through gene regulation is best illustrated in a recent paper by You et al [13] using single -cell RNA sequence to decode lymphomyeloid divergence and immune hyporesponsiveness in G-CSF -primed human bone marrow.…”