Interferon-Gamma Impairs Maintenance and Alters Hematopoietic Support of Bone Marrow Mesenchymal Stromal Cells

Abstract

Bone marrow (BM) mesenchymal stromal cells (MSCs) provide microenvironmental support to hematopoietic stem and progenitor cells (HSPCs). Culture-expanded MSCs are interesting candidates for cellular therapies due to their immunosuppressive and regenerative potential which can be further enhanced by pretreatment with interferon-gamma (IFN-γ). However, it remains unknown whether IFN-γ can also influence hematopoietic support by BM-MSCs. In this study, we elucidate the impact of IFN-γ on the hematopoietic support of BM-MSCs. We found that IFN-γ increases expression of interleukin (IL)-6 and stem cell factor by human BM-MSCs. IFN-γ-treated BM-MSCs drive HSPCs toward myeloid commitment in vitro, but impair subsequent differentiation of HSPC. Moreover, IFN-γ-ARE-Del mice with increased IFN-γ production specifically lose their BM-MSCs, which correlates with a loss of hematopoietic stem cells' quiescence. Although IFN-γ treatment enhances the immunomodulatory function of MSCs in a clinical setting, we conclude that IFN-γ negatively affects maintenance of BM-MSCs and their hematopoietic support in vitro and in vivo.

IFN-γ and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis

“…9,11,13,14 Because we also observed a low reticulocyte count (Fig 5), IFN-g might also function through disrupting bone marrow support of erythroid lineage differentiation. 36 Thus although the ongoing clinical trials of anti-IFN-g antibody in patients with HLH are likely to reverse anemia, they might not be effective as a monotherapy, with the inflammatory aspects requiring a distinct approach. This adjunct therapy will need to target the consumption of IL-2 by CD8 1 T cells, the collapse of Treg cells, or the downstream (IFNg-independent) inflammatory cascade that drives the immune aspects of the disease.…”

CD8 T cells induce destruction of bone marrow stromal niches and hematopoietic stem cell dysfunction in chronic viral infections

“…Viral agents such as HIV and CMV, which are associated with strong hematological manifestations, directly infect BM stromal cells and impair their function, thereby suggesting that cytotoxic killing could be a potential mechanism contributing to BM suppression in clinical settings (Moses et al, 1996;Scadden et al, 1990;Bahner et al, 1997;Apperley et al, 1989;SIMMONS et al, 1990). Nonetheless, recent work demonstrates that immunopathological loss of SLO FRCs in acute LCMV infection is exclusively driven by cytokines (Scandella et al, 2008), and abnormally high IFNg production functionally impairs and partially depletes the BM mesenchymal stromal cell compartment in transgenic mouse models (Goedhart et al, 2018). Thus, it seems reasonable to speculate that cytokine-mediated mechanisms may also directly operate to either destroy the CARc network, alter its function, or prevent its regeneration upon damage.…”

Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers

“…Other proinflammatory cytokines secreted by BM-MSCs could impair hematopoiesis. Indeed, although IFN-γ promotes stem cell factor (SCF) expression in mouse BM-MSCs, an important factor for the support of hematopoiesis, chronic exposure of BM-MSCs to this cytokine leads to a decrease in the total number of BM-MSCs, diminishing their hematopoietic support [ 65 ]. In a recent paper, Gnani and colleagues showed a clonogenic impairment of young hematopoietic stem and progenitor cells (HSPCs) due to the activation of a proinflammatory program when they are exposed to compounds secreted by aged BM-MSCs [ 52 ].…”