For biological synapses, high sensitivity is crucial for transmitting information quickly and accurately. Compared to biological synapses, memristive ones show a much lower sensitivity to electrical stimuli since much higher voltages are needed to induce synaptic plasticity. Yet, little attention has been paid to enhancing the sensitivity of synaptic devices. Here, electrochemical metallization memory cells based on lightly oxidized ZnS films are found to show highly controllable memristive switching with an ultralow SET voltage of several millivolts, which likely originates from a two-layer structure of ZnS films, i.e., the lightly oxidized and unoxidized layers, where the filament rupture/rejuvenation is confined to the two-layer interface region several nanometers in thickness due to different ion transport rates in these two layers. Based on such devices, an ultrasensitive memristive synapse is realized where the synaptic functions of both short-term plasticity and long-term potentiation are emulated by applying electrical stimuli several millivolts in amplitude, whose sensitivity greatly surpasses that of biological synapses. The dynamic processes of memorizing and forgetting are mimicked through a 5 × 5 memristive synapse array. In addition, the ultralow operating voltage provides another effective solution to the relatively high energy consumption of synaptic devices besides reducing the operating current and pulse width.

Rationale: Mesenchymal stromal cell–based therapy is promising against ischemic heart failure. However, its efficacy is limited due to low cell retention and poor paracrine function. A transmembrane protein capable of enhancing cell-cell adhesion, N-cadherin garnered attention in the field of stem cell biology only recently. Objective: The current study investigates whether and how N-cadherin may regulate mesenchymal stromal cells retention and cardioprotective capability against ischemic heart failure. Methods and Results: Adult mice–derived adipose tissue–derived mesenchymal stromal cells (ADSC) were transfected with adenovirus harboring N-cadherin, T-cadherin, or control adenovirus. CM-DiI-labeled ADSC were intramyocardially injected into the infarct border zone at 3 sites immediately after myocardial infarction (MI) or myocardial ischemia/reperfusion. ADSC retention/survival, cardiomyocyte apoptosis/proliferation, capillary density, cardiac fibrosis, and cardiac function were determined. Discovery-driven/cause-effect analysis was used to determine the molecular mechanisms. Compared with ADSC transfected with adenovirus-control, N-cadherin overexpression (but not T-cadherin) markedly increased engrafted ADSC survival/retention up to 7 days post-MI. Histological analysis revealed that ADSC transfected with adenovirus-N-cadherin significantly preserved capillary density and increased cardiomyocyte proliferation and moderately reduced cardiomyocyte apoptosis 3 days post-MI. More importantly, ADSC transfected with adenovirus-N-cadherin (but not ADSC transfected with adenovirus-T-cadherin) significantly increased left ventricular ejection fraction and reduced fibrosis in both MI and myocardial ischemia/reperfusion mice. In vitro experiments demonstrated that N-cadherin overexpression promoted ADSC-cardiomyocyte adhesion and ADSC migration, enhancing their capability to increase angiogenesis and cardiomyocyte proliferation. MMP (matrix metallopeptidases)-10/13 and HGF (hepatocyte growth factor) upregulation is responsible for N-cadherin’s effect upon ADSC migration and paracrine angiogenesis. N-cadherin overexpression promotes cardiomyocyte proliferation by HGF release. Mechanistically, N-cadherin overexpression significantly increased N-cadherin/β-catenin complex formation and active β-catenin levels in the nucleus. β-catenin knockdown abolished N-cadherin overexpression–induced MMP-10, MMP-13, and HGF expression and blocked the cellular actions and cardioprotective effects of ADSC overexpressing N-cadherin. Conclusions: We demonstrate for the first time that N-cadherin overexpression enhances mesenchymal stromal cells–protective effects against ischemic heart failure via β-catenin-mediated MMP-10/MMP-13/HGF expression and production, promoting ADSC/cardiomyocyte adhesion and ADSC retention.

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