Abstract
Skeletal aging is associated with reduced proliferative potential of bone marrow (BM) multipotential stromal cells (MSCs). Recent data suggest the involvement of type 1 interferon (IFN1) signalling in hematopoietic stem cell (HSC) senescence. Considering that BM-HSCs and BM-MSCs share the same BM niche, we investigated IFN1 expression profile in human BM-MSCs in relation to donor age, culture-expansion and IFN1 (α and β) stimulation. Fluorescence-activated cell sorting was used to purify uncultured BM-MSCs from younger (19–41, n = 6) and older (59–89, n = 6) donors based on the CD45lowCD271+ phenotype, and hematopoietic-lineage cells (BM-HLCs, CD45+CD271−) were used as controls. Gene expression was analysed using integrated circuits arrays in sorted fractions as well as cultured/stimulated BM-MSCs and Y201/Y202 immortalised cell lines. IFN1 stimulation led to BM-MSC growth arrest and upregulation of many IFN1-stimulated genes (ISGs), with IFNβ demonstrating stronger effects. Uncultured MSCs were characterised by a moderate-level ISG expression similar to Y201 cells. Age-related changes in ISG expression were negligible in BM-MSCs compared to BM-HLCs, and intracellular reactive oxygen species (ROS) levels in BM-MSCs did not significantly correlate with donor age. Antiaging genes Klotho and SIRT6 correlated with more ISGs in BM-MSCs than in BM-HLCs. In patients with osteoarthritis (OA), BM-MSCs expressed considerably lower levels of several ISGs, indicating that their IFN1 signature is affected in a pathological condition. In summary, BM-MSCs possess homeostatic IFN1 gene expression signature in health, which is sensitive to in vitro culture and external IFN1 stimulation. IFN signalling may facilitate in vivo BM-MSC responses to DNA damage and combating senescence and aberrant immune activation.
Highlights
Aging-associated health and well-being concerns have increased in the last two to three decades [1]owing to the global demographic shift towards people aged over 60 [2]
Certain bones contain active bone marrow (BM), which is the site of haematopoiesis, where various cell types are formed owing to the activity of BM-resident hematopoietic stem cells (BM-HSCs) and multipotential stromal cells (BM-MSCs) [5]
This study investigated the IFN1 gene expression profile of human BM-MSCs in their native state and upon culture and IFN1 stimulation
Summary
Aging-associated health and well-being concerns have increased in the last two to three decades [1]owing to the global demographic shift towards people aged over 60 [2]. Biomedicines 2020, 8, 214 leading to deterioration of health at advanced age, including decline in immunity and increased frailty are yet to be established. Inflamm-aging conceptually postulates an intrinsic decline of the proliferation potential and increase in senescence and DNA damage in immune-lineage cells. This is accompanied by the reduction of protective extrinsic mechanisms within the cellular microenvironment that aim at removal of senescent cells and accumulated damage, that is, autophagy [7]. Age-related bone loss, on the other hand, is associated with inefficient bone remodelling processes [9] and cell senescence, mainly due to oxidative stress and DNA damage, as well as telomere erosion [10,11]
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