Biology subjects

Skromna, A.

Publications and source records attributed to Skromna, A..

3 recordsLinked to original sources

bioRxiv2025

Murine limb ischaemia induces structural and functional remodelling of local and distant bone marrow

Peripheral arterial disease (PAD) can induce bone marrow (BM) ischaemia, although little is known about the implications of this for local and systemic haematopoiesis. We explored the impact of murine unilateral hind-limb ischaemia (HLI) surgery on the structure and function of the ischaemic and non-ischaemic BM, versus control mice without HLI surgery. Abnormal BM hypoxia was present in the ischaemic limb 7-days post-HLI, with normalisation by 28-days. Histological analysis revealed the ischaemic BM to undergo profound vascular remodelling at 7-days that normalised by 61-days, along with a progressive accumulation of BM lipid droplets between 7- and 61-days; no structural changes were observed in the non-ischaemic limb BM. Flow cytometry revealed increased abundance of monocytes and inflammatory monocytes in the non-ischaemic and ischaemic BM 7-days post-HLI, with this persisting at 61-days in the non-ischaemic limb. In both limbs, we observed a progressive decline in the abundance of lineage-Sca-1+c-Kit+ haematopoietic stem cells. RNA-sequencing of BM-derived macrophages (BMDMs) revealed substantial transcriptomic differences between unstimulated control, ischaemic limb and non-ischaemic limb BMDMs. Moreover, there were also substantial transcriptomic differences between lipopolysaccharide-stimulated control and ischaemic limb BMDMs. However, we observed minimal differences in chromatin accessibility of unstimulated BMDMs from the 3 groups. Collectively, our data show that BM ischaemia has transient and sustained structural implications, along with both local and systemic effects on haematopoiesis and myeloid cell function. These findings suggest that PAD may have important consequences for systemic immune responses.

immunology↗

bioRxiv2021

Paracrine role for endothelial IGF-1 receptor in white adipocyte beiging

There are at least two distinct types of thermogenic adipocyte in mammals: a pre-existing form established during development, termed classical brown adipocytes and an inducible form, beige adipocytes1-3. Various environmental cues can stimulate a process frequently referred to as beiging of white adipose tissue (WAT), leading to enhanced thermogenesis and obesity resistance 4, 5. Whilst beiging of WAT as a therapeutic goal for obesity and obesity-related complications has attracted much attention6-9; therapeutics stimulating beiging without deleterious side-effects remain elusive10. The endothelium lines all blood vessels and is therefore in close proximity to all cells. Many studies support the possibility that the endothelium acts as a paracrine organ11-14. We explored the potential role of endothelial insulin-like growth factor-1 receptor (IGF-1R) as a paracrine modulator of WAT phenotype. Here we show that a reduction in endothelial IGF-1R expression in the presence of nutrient excess leads to white adipocyte beiging, increases whole-body energy expenditure and enhances insulin sensitivity via a non-cell autonomous paracrine mechanism. We demonstrate that this is mediated by endothelial release of malonic acid, which we show, using prodrug analogues, has potentially therapeutically-relevant properties in the treatment of metabolic disease.

cell biology↗

bioRxiv2019

Reduced insulin and IGF-1 signalling synergistically extend healthspan in male mice

Reduced IGF-1 signalling is an evolutionarily conserved mediator of longevity, yet the magnitude of this effect is substantially larger in organisms retaining a common insulin and IGF-1 receptor. Whether this discrepancy reflects the failure to simultaneously reduce IGF-1 and insulin signalling in mammalian model systems remains unexplored. Moreover, studies of invertebrates cannot ascertain whether substantial effects upon lifespan are associated with preserved cognitive performance, a crucial component of healthspan. We compared the healthspan of male mice with haploinsufficiency of the insulin receptor (IRKO), IGF-1 receptor (IGF-1RKO), or both (DKO), with wildtype (WT) littermates. DKO mice survived longer than WT, with IRKO and IGF-1RKO being intermediate. At 2 years of age, DKO also exhibited preserved nesting behaviour in contrast with all other genotypes. Differential insulin sensitivity or weight gain during ageing did not explain the preserved healthspan of DKO, since these were comparable to IRKO littermates. These data provide the first demonstration that reduced insulin and IGF-1 signalling have synergistic effects upon healthspan in a mammalian model system, suggesting future mechanistic and translational studies should target insulin and IGF-1 signalling.

cell biology↗