Targeting senescence improves angiogenic potential of adipose-derived mesenchymal stem cells in patients with preeclampsia

Abstract

Background Preeclampsia is a pregnancy-specific hypertensive disorder characterized by impaired angiogenesis. We postulate that senescence of mesenchymal stem cells (MSC), multipotent cells with pro-angiogenic activities, is one of the mechanisms by which systemic inflammation exerts inhibitory effects on angiogenesis in preeclampsia. Methods MSC were isolated from abdominal fat tissue explants removed during medically indicated C-sections from women with preeclampsia (PE-MSC, n = 10) and those with normotensive pregnancies (NP-MSC, n = 12). Sections of the frozen subcutaneous adipose tissue were assessed for inflammation by staining for tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1. Viability, proliferation, and migration were compared between PE-MSC vs. NP-MSC. Apoptosis and angiogenesis were assayed before and after treatment with a senolytic agent (1 μM dasatinib) using the IncuCyte S3 Live-Cell Analysis System. Similarly, staining for senescence-associated beta galactosidase (SABG) and qPCR for gene expression of senescence markers, p16 and p21, as well as senescence-associated secretory phenotype (SASP) components, IL-6, IL-8, MCP-1, and PAI-1, were studied before and after treatment with dasatinib and compared between PE and NP. Results After in vitro exposure to TNF-alpha, MSC demonstrated upregulation of SASP components, including interleukins-6 and -8 and MCP-1. Staining of the subcutaneous adipose tissue sections revealed a greater inflammatory response in preeclampsia, based on the higher levels of both TNF-alpha and MCP-1 compared to normotensive pregnancies (p < 0.001 and 0.024, respectively). MSC isolated from PE demonstrated a lower percentage of live MSC cells (p = 0.012), lower proliferation (p = 0.005), and higher migration (p = 0.023). At baseline, PE-MSC demonstrated a senescent phenotype, reflected by more abundant staining for SABG (p < 0.001), upregulation of senescence markers and SASP components, as well as lower angiogenic potential (p < 0.001), compared to NP-MSC. Treatment with dasatinib increased significantly the number of apoptotic PE-MSC compared to NP-MSC (0.011 vs. 0.093) and decreased the gene expression of p16 and six SASP components. The mechanistic link between senescence and impaired angiogenesis in PE was confirmed by improved angiogenic potential of PE-MSC (p < 0.001) after dasatinib treatment. Conclusions Our data suggest that MSC senescence exerts inhibitory effects on angiogenesis in preeclampsia. Senolytic agents may offer the opportunity for mechanism-based therapies.

Activation of SIRT1 promotes cartilage differentiation and reduces apoptosis of nucleus pulposus mesenchymal stem cells via the MCP1/CCR2 axis in subjects with intervertebral disc degeneration

“…In addition, the present study revealed that McP1 reversed the progression of NPMSc differentiation into cartilage and inhibited SIRT1-induced cell apoptosis. It was previously reported that in NPMScs, McP1 expression is notably reduced (33). SIRT1 overexpression downregulates McP1, whereas the loss of SIRT1 increases McP1 expression, indicating a negative association between these two proteins (34).…”

Senolytic drugs: from discovery to translation

“…Senescent cells can accumulate at aetiological sites of multiple diseases throughout the lifespan. For example, in humans, senescent cells accumulate in adipose tissue in diabetes and obesity, in the hippocampi and frontal cortex in Alzheimer's disease (AD), the substantia nigra in Parkinson's disease (PD), bone and marrow in age-related osteoporosis, lungs in idiopathic pulmonary fibrosis, liver in cirrhosis, retinae in macular degeneration, plaques in psoriasis, kidneys in diabetic kidney disease, endothelium in pre-eclampsia, and the heart and major arteries in cardiovascular disease, amongst many other conditions [6,7,13,19,23,[70][71][72][73][74][75][76][77][78][79][80].…”

The role of cellular senescence in ageing and endocrine disease

“…In addition, the SASP of senescent cells seems to contribute to the initiation of parturition. However, cellular senescence might also have a role in the impaired angiogenesis associated with preeclampsia 137 . Thus, for reproductive function, cellular senescence could represent an example of antagonistic pleiotropy, whereby it contributes to proper fetal development and timely parturition during the reproductive years but also to the risk of pre-eclampsia and a decline in ovarian function with ageing 134 .…”

“…• Frailty and impaired ambulation in elderly women 143 • Progeroid syndromes in children 82,101,144 • Pre-eclampsia 137 • Macular degeneration and other eye diseases 145 • Skin conditions, including psoriasis, scleroderma, melanocytic naevi, actinic keratosis, non-healing skin wounds and other skin disorders 146 • Idiopathic pulmonary fibrosis 51,102 • Chronic obstructive pulmonary disease 147 • Inducing accumulation of senescent cells causes the phenotype.…”