1. Identification of pericyte to fibroblast differentiation and endothelial attrition as a hallmark of vascular and tissue ageing
Blood vessels provide supportive microenvironments for various cell types to maintain tissue homeostasis and organ function. Ageing is associated with alterations in tissue homeostasis and a decline in tissue functions. However, ageing of the vasculature and how it contributes to changes in tissue physiology is poorly understood. Here, we show age-related changes in vascular microenvironments. We found an age-dependent decline of capillary, artery and pericyte numbers and an increase in fibroblast abundances in mice and humans. Vascular attrition precedes the cellular hallmarks of ageing such as senescence and mitochondrial dysfunction. Endothelial cell-specific genetic experiments confirm that vascular perturbations are sufficient to stimulate cellular changes coupled with ageing. Further, genetic lineage tracing experiments reveal differentiation of pericytes to fibroblasts upon ageing. Finally, gene expression and functional analysis demonstrated that age-related molecular changes in the endothelium dictate pericyte to fibroblast differentiation. We find the contribution of pericyte-derived fibroblasts to the age-related increase in fibrosis. These findings unearth vascular attrition marked by pericyte to fibroblast differentiation as a primary hallmark of ageing tissues (Chen et al, Science Advances 2021). To facilitate further research, we provide a freely available resource of >1500 3D maps highlighting organ-specific and age-related features of vascular microenvironments
http://homeros.kennedy.ox.ac.uk/pub/chen-et-al-2021-3dOrgans(öffnet in neuem Fenster)2. Identification of gap junction communication protein Gja1 as a driver of endothelial cell ageing
Further, the comprehensive analysis of endocrine tissues shows that angiogenesis and beta-cell expansion in the pancreas during ageing showed molecularly and a functionally distinct age-dependent subset of Endothelial Cells (ECs). This EC subset support pancreatic -cells, and their decline with ageing caused by gap junction protein Gja1 led to the reduction of -cell proliferation, while their genetic or pharmacological reactivation allowed the restoration of beta-cell expansion (Chen et al, EMBO Journal 2021). These results provide a proof-of-concept for understanding age-related vascular changes for vascular targeting to restore endocrine tissue function. Towards this, our open image datasets provide a wealth of spatial information in endocrine tissues for download and exploration.
http://homeros.kennedy.ox.ac.uk/pub/chen-et-al-2020-3dEndocrine(öffnet in neuem Fenster)3. Identification of endothelial and perivascular factors regulating quiescence of disseminated tumour cells in bone
Bone marrow provides supportive microenvironments for long-lived Hematopoietic Stem Cells (HSCs), Mesenchymal Stem Cells (MSCs), and certain immune cells. Skeletal ageing is associated with a decline in HSC function and increased incidences of bone metastasis. However, the role of the ageing bone marrow microenvironment in regulating stem and cancer cell behaviour remains elusive. Here, we find that the aged bone marrow microenvironment perturbs the quiescence of HSCs and MSCs, and metastatic cancer cells in bone. In particular, the aged bone marrow microenvironment exhibits a decline in secreted factors that induce and maintain quiescence. Both radiation and chemotherapy induce bone-specific upregulation of quiescence promoting secreted factors. Cell-specific secretome screening identified the involvement of pericytes in promoting quiescent microenvironments in bone in response to radiation and chemotherapy. Administration of PDGFR inhibitor alongside radiation or chemotherapy led to the decline in quiescent cancer cells, and an increase in the susceptibility to these therapeutic strategies (Singh et al JCI Insight 2019). Thus, our study provides a framework for targeting pericytes to manipulate the bone marrow microenvironment in therapeutic interventions to manage bone metastasis.
