Adiponectin Stimulates Exosome Release to Enhance Mesenchymal Stem-Cell-Driven Therapy of Heart Failure in Mice

Abstract

Mesenchymal stem/stromal cells (MSCs) are cultured adult stem cells that originally reside in virtually all tissues, and the gain of MSCs by transplantation has become the leading form of cell therapy in various diseases. However, there is limited knowledge on the alteration of its efficacy by factors in recipients. Here, we report that the cardioprotective properties of intravenously injected MSCs in a mouse model of pressure-overload heart failure largely depend on circulating adiponectin, an adipocyte-secreted factor. The injected MSCs exert their function through exosomes, extracellular vesicles of endosome origin. Adiponectin stimulated exosome biogenesis and secretion through binding to T-cadherin, a unique glycosylphosphatidylinositol-anchored cadherin, on MSCs. A pharmacological or adenovirus-mediated genetic increase in plasma adiponectin enhanced the therapeutic efficacy of MSCs. Our findings provide novel insights into the importance of adiponectin in mesenchymal-progenitor-mediated organ protections.

Identification and Clinical Associations of 3 Forms of Circulating T-cadherin in Human Serum

“…1A ). Western blots of each immunoprecipitate of human mesenchymal stem cell lysate, which expresses human T-cad ( 20 ), using the respective monoclonal antibodies are shown in Fig. 1B .…”

“…Native APN stimulated exosome biogenesis and secretion by binding to T-cad ( 17 ). Recently, we found that mesenchymal stem/stromal cells (MSCs) expressed T-cad and produced many exosomes in response to APN ( 20 ). Heart protection by transplanted MSCs in a heart failure mouse model requires circulating APN and T-cad expression in MSCs to produce exosomes ( 20 ).…”

Extracellular Vesicles from Human Adipose-Derived Mesenchymal Stem Cells: A Review of Common Cargos

“…Human AT-MSC-EVs transport different types of proteins [12,52,[57][58][59][60][61][62][63][64][65], RNAs [11,12,53,54,59,[64][65][66][67][68][69][70][71][72][73][74] and lipids [58]. Due to this variety of cargo molecules, AT-MSC-EVs are involved in a wide range of biological functions including migration, immune regulation, cell proliferation, angiogenesis, osteocyte metabolism and nerve regeneration (for a comprehensive review see ref.…”

Extracellular vesicle-derived miRNA as a novel regulatory system for bi-directional communication in gut-brain-microbiota axis

“…The biogenesis of EV is regulated by a variety of intracellular proteins, enzymes and signaling pathways including: (1) RNA-binding proteins such as hnRNPA2B1 and Argonaute-2; (2) membranous proteins such as Caveolin-1 and Neural Sphingomyelinases; (3) Rab GTPases, ARRDC1, and ESCRT complexes; (4) lipid rafts or membrane lipid microdomains; (5) cytosolic proteins (syntenin) and endosomal enzymes (Heparanase); and, 6) Intracellular calcium-signaling pathways [ 82 – 89 ]. Biogenesic processes can also be modulated by different extracellular stimuli including: (1) viral infection; (2) oncogenic transformation or stresses; (3) hypoxia; (4) alcohol exposure; (5) irradiation; (6) impaired autophagy; and, (7) circulating hormones, which all have important implications in elucidating the pathophysiological mechanisms for development of novel therapeutic targets [ 90 – 95 ].…”