Date Published: June 23, 2011
Publisher: Impact Journals LLC
Author(s): Kaoru Yasuda, Anupama Khandare, Leonid Burianovskyy, Shoichi Maruyama, Frank Zhang, Alberto Nasjletti, Michael S Goligorsky.
Although therapeutic effect of adoptive transfer of endothelial progenitor cells (EPC) has been well-substantiated, the actual engraftment is relatively low compared to a robust functional improvement of vasculopathy. Cellular mechanisms governing this action remain elusive. A recently discovered cell-cell communication via tunneling nanotube (TNT) formation is capable of transferring mitochondria and lysosomes between the cells – “organellar diakinesis”. Based on the previous demonstration of lysosomal dysfunction in endothelial cells exposed to AGE-modified collagen I, we inquired whether TNT mechanism may be involved in EPC-mediated repair of stressed endothelial cells. Here we demonstrate that EPC selectively and multiplicatively establish TNT communication with stressed endothelia. The guidance cues for the selectivity are provided by exofacially exposed phosphatidylserine moieties. Lysosomal transfer is associated with the preservation of lysosomal pH gradient, functionally reconstituting lysosomal pool of stressed cells and improving endothelial cell viability, reducing premature senescence and apoptosis. In vivo, adoptive transfer of EPC to streptozotocin-diabetic mice results in a TNT-dependent reduction of senescent endothelial cells and correction of endothelium-dependent vasorelaxation. Collectively, these data establish a selective multiplicative effect of TNT between EPC and stressed endothelia, reconstitution of the lysosomal pool, and improved viability and function of stressed endothelia.
Diseases as diverse as diabetes, atherosclerosis, chronic kidney disease and multitude of other conditions associated with oxidative stress result in stress-induced premature senescence (SIPS) of vascular endothelium, which contributes to development of vasculopathy [1-3]. We have recently demonstrated that the diabetic milieu triggers collapse of lysosomal pH gradient, lysosomal permeabilization, and frustrates autophagy – all pathogenetically linked to developing stress-induced premature senescence of vascular endothelium and vasculopathy [4, 5]. The role of autophagy in delaying cellular and organismal aging has been extensively studied [rev in: 6] Furthermore, adoptive transfer of bone marrow-derived stem cells markedly improved macro- and microvasculopathy .
The data presented herein demonstrated a) the selectivity of TNT formation, which is annexin A5-dependent, b) the ability to transfer intact lysosomes from EPC to endothelial cells exposed to a diabetes-like milieu without the loss of their integrity, which resulted in improved lysosomal-autophagosomal fusion and led to c) salvage of endothelial cells from premature senescence and apoptosis, and provided d) indirect in vivo support of the role played by TNT formation between EPC and stressed vascular endothelium in improving endothelial dysfunction. These findings raise several important issues.