Blockade of TGF-ß signalling alleviates human adipose stem cell senescence induced by native ECM in obesity visceral white adipose tissue.

BACKGROUND: Abdominal obesity is appreciated as a major player in insulin resistance and metabolically dysfunctional adipose tissue. Inappropriate extracellular matrix (ECM) remodelling and functional alterations in human adipose stromal/stem cells (hASCs) have been linked with visceral white adipose tissue (vWAT) dysfunction in obesity. Understanding the interactions between hASCs and the native ECM environment in obese vWAT is required for the development of future therapeutic approaches for obesity-associated metabolic complications. METHODS: The phenotypes and transcriptome properties of hASCs from the vWAT of obese patients and lean donors were assessed. The hASC-derived matrix from vWAT of obese or lean patients was generated in vitro using a decellularized method. The topography and the major components of the hASC-derived matrix were determined. The effects of the obese hASC-derived matrix on cell senescence and mitochondrial function were further determined. RESULTS: We showed that hASCs derived from the vWAT of obese patients exhibited senescence and were accompanied by the increased production of ECM. The matrix secreted by obese hASCs formed a fibrillar suprastructure with an abundance of fibronectin, type I collagen, and transforming growth factor beta 1 (TGF-ß1), which resembles the native matrix microenvironment of hASCs in vWAT derived from obese patients. Furthermore, the obese hASC-derived matrix promoted lean hASC ageing and induced mitochondrial dysfunction compared to the lean hASC-derived matrix. Blockade of TGF-ß1 signalling using an anti-TGF-ß1 neutralizing antibody alleviated the lean hASC senescence and mitochondrial dysfunction induced by the obese hASC-derived matrix. CONCLUSIONS: Native ECM in obesity vWAT initiates hASC senescence through TGF-ß1-mediated mitochondrial dysfunction. These data provide a key mechanism for understanding the importance of cell-ECM interactions in hASCs senescence in obesity.

Distal end side-to-side anastomosis of sequential coronary bypass for size mismatched saphenous vein grafts and coronary arteries.

INTRODUCTION: The distal end anastomosis is critical to the entire sequential grafts in coronary artery bypass grafting (CABG), but caliber mismatch diminishes the quality of the anastomosis. We aimed to introduce a modified distal end side-to-side (deSTS) anastomosis to handle the size mismatch and compared with classic distal end end-to-side (deETS) anastomosis. METHODS: From January 2014 to December 2018, 185 patients who underwent off-pump CABG with size mismatched sequential vein grafts (≥3.5 mm) and target coronaries (1.0-1.5 mm) at the distal end anastomoses were included. We retrospectively reviewed the data of the patients, perioperative and follow-up outcomes were analyzed. RESULTS: The deSTS group (n = 67) showed higher anastomotic flow (19.8 ± 8.0 vs 14.9±6.8 mL/min; p < 0.001) and lower pulsatility index (2.7 ± 0.8 vs 3.2 ± 1.0; p = 0.001) than the deETS group (n = 118). Higher incidence of in-hospital myocardial infarction (MI) was found in the deETS group but without significant difference (9.0% vs. 15.3%; p = 0.220). Kaplan-Meier analysis illustrated a relatively lower MI and major adverse cardiovascular and cerebrovascular events (MACCE) incidence in the deSTS group, and the deSTS group was associated with a reduction in long-term death, MI and MACCE in the adjusted Cox regression model. In addition, relatively higher graft patency was found in the deSTS group. CONCLUSIONS: The deSTS anastomosis showed superiority in solving size mismatch in sequential CABG, including better intraoperative flow dynamics, ideal long-term graft patency and reduced the incidence of perioperative and follow-up adverse events especially in MI.