Abstract
Transplantation of adventitial pericytes (APCs) improves recovery from tissue ischemia in preclinical animal models by still unknown mechanisms. This study investigates the role of the adipokine leptin (LEP) in the regulation of human APC biological functions. Transcriptomic analysis of APCs showed components of the LEP signalling pathway are modulated by hypoxia. Kinetic studies indicate cultured APCs release high amounts of immunoreactive LEP following exposure to hypoxia, continuing upon return to normoxia. Secreted LEP activates an autocrine/paracrine loop through binding to the LEP receptor (LEPR) and induction of STAT3 phosphorylation. Titration studies using recombinant LEP and siRNA knockdown of LEP or LEPR demonstrate the adipokine exerts important regulatory roles in APC growth, survival, migration and promotion of endothelial network formation. Heterogeneity in LEP expression and secretion may influence the reparative proficiency of APC therapy. Accordingly, the levels of LEP secretion predict the microvascular outcome of APCs transplantation in a mouse limb ischemia model. Moreover, we found that the expression of the Lepr gene is upregulated on resident vascular cells from murine ischemic muscles, thus providing a permissive milieu to transplanted LEP-expressing APCs. Results highlight a new mechanism responsible for APC adaptation to hypoxia and instrumental to vascular repair.
Highlights
Transplantation of adventitial pericytes (APCs) improves recovery from tissue ischemia in preclinical animal models by still unknown mechanisms
We show for the first time that APCs secrete abundant levels of LEP under hypoxia, by one order of magnitude higher than bone marrow (BM)-mesenchymal stem cells (MSCs)
Here we demonstrate APCs have similar morphology when cultured under normoxia or hypoxia, as assessed by contrast phase microscopy (Supplementary Figure Ia)
Summary
Transplantation of adventitial pericytes (APCs) improves recovery from tissue ischemia in preclinical animal models by still unknown mechanisms. Seminal evidence indicates components of the LEP pathway are expressed in human stem cells, but the pathophysiological implications of the LEP signalling remain unclear and controversial. Two recent studies showed that hypoxia-preconditioned murine BM-MSCs exert enhanced regenerative actions through an amplification of the LEP signalling[23, 24]. The present study investigates the expressional regulation and functional actions of LEP in human APCs. We show for the first time that APCs secrete abundant levels of LEP under hypoxia, by one order of magnitude higher than BM-MSCs. APC-derived LEP exerts autocrine promotion of APCs survival and migration as well as paracrine stimulation of endothelial cell (EC) proliferation, permeability, and network formation. The levels of secreted LEP predict the angiogenic activity of APC transplantation in a murine model of peripheral ischemia. These results revealing a novel signalling mechanism instrumental to APC functionalities may have a far-reaching and critical impact on cardiovascular regenerative medicine
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