Temporal dynamics of TNF-mediated changes in hematopoietic stem cell function and recovery
Alexandra Rundberg Nilsson,
Isabel Hidalgo,
David Bryder,
Cornelis Jan Pronk
Affiliations
Alexandra Rundberg Nilsson
Medical Faculty, Division of Molecular Hematology, Institution for Laboratory Medicine, Lund University, 22184 Lund, Sweden; Medical Faculty, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden; Medical Faculty, Division of Molecular Medicine and Gene Therapy, Institution for Laboratory Medicine, Lund University, 22184 Lund, Sweden; Corresponding author
Isabel Hidalgo
Medical Faculty, Division of Molecular Hematology, Institution for Laboratory Medicine, Lund University, 22184 Lund, Sweden; Medical Faculty, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden; Wallenberg Center for Molecular Medicine, Lund University, 22184 Lund, Sweden
David Bryder
Medical Faculty, Division of Molecular Hematology, Institution for Laboratory Medicine, Lund University, 22184 Lund, Sweden; Medical Faculty, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden
Cornelis Jan Pronk
Medical Faculty, Division of Molecular Hematology, Institution for Laboratory Medicine, Lund University, 22184 Lund, Sweden; Medical Faculty, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden; Wallenberg Center for Molecular Medicine, Lund University, 22184 Lund, Sweden; Childhood Cancer Centre, Skåne University Hospital, 22185 Lund, Sweden
Summary: While tumor necrosis factor (TNF) is a critical mediator of appropriate immune response and tissue repair, its misregulation is linked to cancer, autoimmunity, bone marrow failure, and aging. Understanding the context-dependent roles of TNF is essential for elucidating normal and pathogenic conditions and to guide clinical therapy advancements. Prior studies suggested that TNF restricts the self-renewal capacity of hematopoietic stem cells (HSCs), but its long-term effect on HSCs remains unclear. Here, we demonstrate that in vivo TNF administration results in a transient exit of HSCs from quiescence, which coincides with a compromised repopulation capacity. These functional changes are; however, fully reversible even following prolonged/chronic transient exposure to TNF. Notably, antagonizing TNF signaling in transplantation recipients enhances donor HSC reconstitution. Our findings provide molecular and functional insight into HSC regulation, with implications for both acute and chronic inflammatory conditions.