Molecular Therapy
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.
Keywords
Adiponectin is an atypical factor that is present abundantly in the peripheral circulation and is exclusively secreted by adipocytes as a trimer, hexamer, and high-molecular-weight (HMW) multimer. Adiponectin circulates at the highest plasma concentrations known among adipocytokines/adipokines.1,2 Cross-sectional research in humans has demonstrated an inverse correlation between plasma adiponectin concentrations and body weight or body mass index (BMI).3,4 Functionally, adiponectin had been thought to play various metabolically important roles via adipoRs2 and dead cell opsonization through calreticulin.5 Clinical analyses have confirmed that HMW multimer (≥6 mers) adiponectin is the active form and that it possesses pleiotropic effects.6, 7, 8, 9 HMW multimer adiponectin is abundantly present in various tissues such as the heart, vascular endothelium, and skeletal muscles by binding with T-cadherin,10,11 a unique glycosylphosphatidylinositol (GPI)-anchored cadherin. We recently reported that native adiponectin binds to the cells expressing T-cadherin but not other proposed binding partners of adiponectin, such as adipoRs and calreticulin.12 The presence of HMW adiponectin (HMW-APN) in large amounts in these tissues is revealed as essential for adiponectin-mediated cardiovascular protection13, 14, 15 and skeletal muscle regeneration.16
Mesenchymal stem/stromal cells (MSCs) are cultured progenitor cells that originally reside in virtually all tissues and are thought to play a role in tissue homeostasis.17,18 A gain in MSCs is beneficial in a variety of diseases, including graft-versus-host disease,19 heart disease,20 type 1 diabetes,21 and type 2 diabetes.22 According to the public clinical trials database,23 more than 893 clinical trials have, so far, used MSCs in the treatment of diverse diseases. However, there is limited knowledge on the alteration of its efficacy by factors in recipients.
Exosomes are secreted small vesicles (50–150 nm) delimited by a lipid bi-layer generated by inward budding of the limiting membrane during endosome maturation into multivesicular bodies (MVBs) in the endocytic pathway. The exosomal release serves as a disposal pathway alternative to the lysosome.24 In addition to this, exosomes are thought to functionally mediate cell-to-cell communication under normal and pathological conditions by transferring active proteins, lipids, mRNAs, and small non-coding RNAs stably in various biofluids25,26 and play important roles in metabolic regulation pathways.27 Especially stem-cell-secreted exosomes are considered to be organ protective by modulating the immune function of the recipient cells28 or by stimulating the repair of recipient cells.29, 30, 31 A recent proteomics study indicated that T-cadherin is one of the most abundantly expressed proteins on the cell surface of MSCs.32
In our previous studies, we developed a new one-step purification method of the clinically important multimer adiponectin from serum11 and demonstrated that the use of adiponectin obtained through this procedure enhances exosome biogenesis and secretion.27,33 Furthermore, the systemic levels of exosome in the peripheral blood decreased by genetic loss of adiponectin and increased by overexpression of adiponectin in vivo.27,33 Adiponectin increased exosome biogenesis. It required the presence of T-cadherin but not AdipoRs.16,27,33 Adiponectin-induced stimulation of exosomes was also observed in muscle cells and correlated with improved muscle regeneration by adiponectin.16,27
The present study was designed to determine the role of adiponectin in the beneficial effects of human adipose tissue-derived mesenchymal stem cells (hMSCs) in heart failure. Systemic injection of hMSCs in the load-induced ventricular hypertrophy mouse model improved left ventricular cardiac function. This therapeutic effect of hMSCs largely depended on circulating adiponectin in recipient mice, T-cadherin expression in hMSCs, and ESCRT (endosomal sorting complex required for transport)-mediated exosome production by hMSCs. The use of peroxisome-proliferator-activated receptor γ (PPARγ) agonist or adenoviral overexpression of adiponectin increased plasma adiponectin levels and thereby enhanced MSC-induced cardioprotection, whereas no such protection was noted in adiponectin knockout (AKO) mice.