The Regulatory Role of IFN-γ on the Proliferation and Differentiation of Hematopoietic Stem and Progenitor Cells

The replenishment of all blood cell lineages is hierarchically organized by the process of hematopoiesis, which is based on the differentiation pathways of hematopoietic stem and progenitor cells (HSPCs). Due to the ability to balance between self-renewal and differentiation, hematopoietic stem cells (HSCs) can generate the appropriate cell type that is required by the immune system and peripheral blood in response to physiological or pathological conditions. Numerous studies have shown that some proinflammatory cytokines contribute to the regulation of the various hematopoietic compartments. Of these, IFN-gamma is a type II interferon primarily produced by T cells and natural killer cells, and plays a major role in the defense against invading pathogens and transformed cancer cells; moreover, a growing amount of research indicates that it exerts negative or positive regulatory effect on hematopoiesis. Although IFN-gamma is a widely regarded negative regulator of HSC proliferation, it also participates in some chronic infections or hematological malignancies that induce bone marrow failure. Recent studies have demonstrated unexpected effects of IFN-gamma, including the promotion of HSC formation and the stimulation of myelopoiesis. Here, we review the direct and indirect effects of IFN-gamma on hematopoiesis, as well as the underlying signaling mechanisms of how IFN-gamma modulates the self-renewal, cell cycle entry, and proliferation of HSCs. Next, we describe how IFN-gamma affects different stages of the lineage differentiation from HSCs. Finally, we discuss the relationship between IFN-gamma and compensatory extramedullary hematopoiesis, as well as some related clinical diseases.