Interferon gamma inhibits the differentiation of mouse adult liver and bone marrow hematopoietic stem cells by inhibiting the activation of notch signaling

Yuhong Qin; Keke Fang; Nan Lu; Yuan Hu; Zhigang Tian; Cai Zhang

doi:10.1186/s13287-019-1311-0

Interferon gamma inhibits the differentiation of mouse adult liver and bone marrow hematopoietic stem cells by inhibiting the activation of notch signaling

Stem Cell Res Ther. 2019 Jul 16;10(1):210. doi: 10.1186/s13287-019-1311-0.

Authors

Yuhong Qin¹, Keke Fang¹, Nan Lu², Yuan Hu¹, Zhigang Tian³, Cai Zhang⁴

Affiliations

¹ Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China.
² Institute of Diagnostics, School of Medicine, Shandong University, Jinan, 250012, Shandong, China. lunan129@126.com.
³ Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, 230026, Anhui, China.
⁴ Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China. caizhangsd@sdu.edu.cn.

Abstract

Background: The paradigm of hematopoietic stem and progenitor cells (HSPCs) has become accepted ever since the discovery of adult mouse liver hematopoietic stem cells and their multipotent characteristics that give rise to all blood cells. However, differences between bone marrow (BM) and liver hematopoietic stem cells and the hematopoietic microenvironment remain poorly understood. In addition, the regulation of the liver hematopoietic system remains unknown.

Methods: Clone formation assays were used to confirm that the proliferation of adult mouse liver and bone marrow HSPCs. Model mice with different interferon gamma (IFN-γ) levels and a co-culture system were used to detect the differentiation of liver HSPCs. The γ-secretase inhibitor (GSI) and the JAK/STAT inhibitor ruxolitinib and cell culture assays were used to explore the molecular mechanism by which IFN-γ impairs HSPC proliferation and differentiation.

Results: The colony-forming activity of liver and bone marrow HSPCs was inhibited by IFN-γ. Model mice with different IFN-γ levels showed that the differentiation of liver HSPCs was impaired by IFN-γ. Using a co-culture system comprising liver HSPCs, we found that IFN-γ inhibited the development of liver hematopoietic stem cells into γδT cells. We then demonstrated that IFN-γ might impair liver HSPC differentiation by inhibiting the activation of the notch signaling via the JAK/STAT signaling pathway.

Conclusions: IFN-γ inhibited the proliferation of liver-derived HSPCs. IFN-γ also impaired the differentiation of long-term hematopoietic stem cells (LT-HSCs) into short-term hematopoietic stem cells (ST-HSCs) and multipotent progenitors (MPPs) and the process from LSK (Lineage^-Sca-1⁺c-Kit⁺) cells to γδT cells. Importantly, we proposed that IFN-γ might inhibit the activation of notch signaling through the JAK/STAT signaling pathway and thus impair the differentiation process of mouse adult liver and BM hematopoietic stem cells.

Keywords: Differentiation; Hematopoietic stem and progenitor cell; JAK/STAT; Liver; Notch signaling; γδT cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors
Amyloid Precursor Protein Secretases / genetics
Animals
Bone Marrow / metabolism
Cell Differentiation / genetics*
Cell Proliferation / genetics
Coculture Techniques
Hematopoietic Stem Cells / metabolism*
Humans
Interferon-gamma / genetics*
Janus Kinases / genetics
Liver / metabolism
Mice
Receptors, Notch / genetics*
Signal Transduction / genetics
Stem Cell Niche / genetics

Substances

Receptors, Notch
Interferon-gamma
Janus Kinases
Amyloid Precursor Protein Secretases