Stitt, A. | Search bioRxiv

bioRxiv2025

Cell-cell communication analysis demonstrates early-stage common pathways linking ageing, Alzheimers disease, and Type 2 diabetes-related brain dysfunction

Ageing promotes to the development of age-related diseases and cognitive decline. In this study, we integrated and analysed four single-cell RNA sequencing (scRNA-seq) datasets encompassing Alzheimers disease, type 2 diabetes, and ageing in mouse brain tissue to identify early pathological factors that may drive normal ageing toward disease through alterations in cell-cell communication (CCC). Building on our previously established CCC change modelling framework, we found that both Alzheimers disease and ageing were characterized by a loss of intercellular communication, whereas type 2 diabetes exhibited an overall gain of new communication pathways. Notably, vascular communication changes were more prominent in age-related diseases than in normal ageing. Furthermore, we identified a series of CCC molecules that play key roles in brain ageing and disease through pseudo covariance and conflicting resolving CCC algorithms. Among them, the LRP1 receptor on astrocytes emerged as a central CCC hub implicated in both ageing and disease pathology.

bioinformatics↗

bioRxiv2025

An Assessment of the Functional State of Endothelial Colony Forming Cells from Patients with Diabetes Mellitus and Chronic Limb Threatening Ischemia

Chronic limb threatening ischemia (CLTI) is the most severe form of peripheral vascular disease which can lead to amputation with a high associated mortality rate. Endothelial colony forming cells (ECFCs) show potential as a cell therapy to revascularize the limbs of individuals with CLTI. However, autologous ECFCs from patient peripheral blood (PB) have been reported to have a dysfunctional phenotype. We investigated this disease phenotype in individuals with CLTI, with and without diabetes mellitus (DM), to determine ECFC suitability as an autologous cell therapy. PB-ECFCs were isolated from age-matched controls, individuals with DM, and individuals with CLTI, with and without DM. The frequency of isolating ECFCs from this donor cohort was calculated. Furthermore, in vitro characterization assays were performed (growth kinetics, angiogenic properties, and reactive oxygen species (ROS) levels) and compared between donor groups. We report a significantly increased frequency of ECFCs from individuals with CLTI, with and without DM. Furthermore, our results demonstrate no significant disease related effect on the in vitro functional properties of ECFCs between cohorts. However, there is a significantly higher in vitro angiogenic capacity in individuals with DM vs age-matched controls. Our results demonstrate that ECFCs can be isolated in individuals with CLTI, with and without DM, and that ECFC functionality is similar between cohorts. Therefore, if the 70% isolation efficiency from CLTI cohorts is overcome, then autologous PB-ECFCs may be a suitable therapeutic for CLTI. Further analysis is needed to determine the critical quality attributes of ECFCs from this patient population. Significance StatementTo the authors knowledge, this paper shows for the first time that endothelial colony forming cells can be isolated from individuals with chronic limb threatening ischemia, with and without diabetes. Additionally, we show a significantly higher frequency of endothelial colony forming cells isolated from chronic limb threatening ischemia patient cohorts. There is no significant difference in endothelial colony forming cells between age-matched controls and chronic limb threatening ischemia patient with and without diabetes mellitus in vitro, potentially suggesting an autologous approach may be a viable therapeutic option in the future.

cell biology↗

bioRxiv2023

Regulatory T cells limit age-associated retinal inflammation and neurodegeneration

Aging is the principal risk factor for retinal degenerative diseases, which are the commonest cause of blindness in the developed countries. These conditions include age-related macular degeneration or diabetic retinopathy. Regulatory T cells play a vital role in immunoregulation of the nervous system by limiting inflammation and tissue damage in health and disease. Because the retina was long-considered an immunoprivileged site, the precise contribution of regulatory T cells in retinal homeostasis and in age-related retinal diseases remains unknown. Our study shows that regulatory T cell elimination leads to retinal pigment epithelium cell dysmorphology, and accumulation of phagocytes in the subretinal space of young and aged mice. However, only aged mice experience retinal neurodegeneration and gliosis. Surprisingly, adoptive transfer of young but not aged regulatory T cells reverse these changes. This study reveals a previously unknown protective role of regulatory T cells in maintaining aged retinal homeostasis.

neuroscience↗