Inspired by ultrastructural analysis of ex vivo human tissues as well as the physiological importance of structural density, we fabricated nanogrooves with 151, 153, and 155 spacing ratio (width5spacing, width 5 550 nm). In response to the nanotopographical density, the adhesion, migration, and differentiation of human mesenchymal stem cells (hMSCs) were sensitively controlled, but the proliferation showed no significant difference. In particular, the osteo-or neurogenesis of hMSCs were enhanced at the 153 spacing ratio rather than 151 or 155 spacing ratio, implying an existence of potentially optimized nanotopographical density for stem cell function. Furthermore, such cellular behaviors were positively correlated with several cell morphological indexes as well as the expression of integrin b1 or N-cadherin. Our findings propose that nanotopographical density may be a key parameter for the design and manipulation of functional scaffolds for stem cell-based tissue engineering and regenerative medicine.S tem cells are characterized by their unique ability to differentiate into various types of cells, allowing for many alternatives and opportunities in tissue engineering and regenerative medicine 1-3 . It is therefore important to develop a platform to regulate or improve stem cell functions from an integrative aspect of biology and engineering [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] . Stem cells reside within instructive and tissue-specific niches in the body, such as complex and controlled biochemical mixtures of soluble and insoluble factors 7,19 . In particular, it is widely accepted that stem cells display high sensitivity to the extracellular matrix (ECM) composed of complex and well-defined nanostructures of protein fibers such as fibrillar collagens and elastins with feature sizes (diameter and spacing) ranging from tens to several hundreds of nanometers. In conjunction with these observations, previous ex vivo and in vitro studies suggest that the use of nanotopographical cues hold great potentials to control stem cell functions [1][2][3][4][5][6][7]19 .The structure of the natural ECM in various tissues including bone, tooth, nerve, skin, muscle, and heart usually reveals highly oriented grooved structures with various length scales in nanometers (Fig. 1A) 1,5 . For example, the concentric nanoscale-thick cylinders enhance mechanical properties of cortical bone, while the aligned collagen matrix in the dermis of skin layer presents anisotropic mechanical properties 1 . Inspired by such ultrastructural observations, the utilization of nanoengineering technology to develop a nanogrooved matrix has been greatly attractive to biologists and engineers in the fields of classical stem biology and regenerative medicine 1,5,[20][21][22][23][24] . According to previous studies, the controlled polarity and subsequent mechanical tension turned out to be crucial for the cell behaviors such as spreading 25,26 , migration 27,28 , proliferation 29 , cell division 30 , tissue function 31 and tiss...

Abstract-Hypertension and elevated sympathetic drive result from consumption of a high-calorie diet and deposition of abdominal fat, but the etiology and temporal characteristics are unknown. Rabbits instrumented for telemetric recording of arterial pressure and renal sympathetic nerve activity (RSNA) were fed a high-fat diet for 3 weeks then control diet for 1 week or control diet for 4 weeks. Baroreflexes and responses to air-jet stress and hypoxia were determined weekly. After 1 week of high-fat diet, caloric intake increased by 62%, accompanied by elevated body weight, blood glucose, plasma insulin, and leptin (8%, 14%, 134%, and 252%, respectively). Mean arterial pressure, heart rate, and RSNA also increased after 1 week (6%, 11%, and 57%, respectively). Whereas mean arterial pressure and body weight continued to rise over 3 weeks of high-fat diet, heart rate and RSNA did not change further. The RSNA baroreflex was attenuated from the first week of the diet. Excitatory responses to air-jet stress diminished over 3 weeks of high-fat diet, but responses to hypoxia were invariant. Resumption of a normal diet returned glucose, insulin, leptin, and heart rate to control levels, but body weight, mean arterial pressure, and RSNA remained elevated. In conclusion, elevated sympathetic drive and impaired baroreflex function, which occur within 1 week of consumption of a high-fat, high-calorie diet, appear integral to the rapid development of obesity-related hypertension. Increased plasma leptin and insulin may contribute to the initiation of hypertension but are not required for maintenance of mean arterial pressure, which likely lies in alterations in the response of neurons in the hypothalamus. Key Words: sympathetic nervous system Ⅲ obesity Ⅲ rabbits Ⅲ blood pressure Ⅲ heart rate O besity represents a significant risk for cardiovascular disease because of the relationship between excess body fat and hypertension. It is estimated that obesity contributes to hypertension in Ͼ60% of men and women entering the Framingham study.1 The mechanisms underlying this relationship are multifactorial, and for some time there was controversy as to whether the sympathetic nervous system was activated or inhibited in obesity-related hypertension. Bray 2 proposed that obesity was a result of low thermogenic activity secondary to low sympathetic activity, and certainly data from heart rate (HR) variability studies supported this hypothesis. Young and Landsberg 3 hypothesized that sympathetic outflow is increased in obesity to facilitate energy wastage by thermogenesis and to maintain body weight homeostasis, with elevated renal sympathetic activation and hypertension the sequelae. It is now clear that norepinephrine spillover to renal and skeletal muscle beds is increased in obese humans, 4 and microneurographic data indicate that skeletal muscle sympathetic nerve activity is greater in overweight humans, 5 consistent with the observation that sympathetic vasomotor activity in skeletal muscle is elevated in established obesity. 6,7 ...

O besity is now a large-scale global epidemic that develops from a complex interaction between genotype and environment, including social, behavioral, cultural, physiological, and metabolic factors. 1 The consequences of being overweight or obese include increased incidence of hypertension, hyperlipidemia and hyperinsulinemia, insulin resistance, and diabetes mellitus.2 Clinical evidence suggests that sympathetic activation participates not only in the initial elevation in blood pressure but also in maintaining the hypertension.3 Obesity is closely linked to increased sympathetic nerve activity (SNA) to the kidneys and skeletal muscle vasculature and is linked to the accumulation of body fat. 4 Our focus has been on the mechanism underlying the increase in blood pressure and, in particular, the role of the sympathetic nervous system in the development of the hypertensive state. We have demonstrated that 3 weeks of high-fat diet (HFD) feeding leads to increased mean arterial pressure (MAP), heart rate (HR), and renal SNA (RSNA) in rabbits. 5 Importantly, we have shown that ganglion blockade completely abolishes the increase in blood pressure suggesting that this model of obesity hypertension is neurogenic. 6 We suggested that the mechanism of the hypertension involved sympathetic activation and increased responsiveness to central sympathoexcitatory effects of leptin owing to increased plasma leptin arising from visceral fat accumulation. 5,6 Leptin is an adipokine that plays an important role in regulating energy intake and energy expenditure, including appetite and metabolism, and acts as a key peripheral hormone in distinct neurons in the hypothalamus.7 Leptin is secreted primarily by adipocytes and is present in serum in direct proportion to the amount of adipose tissue.8 Chronic leptin infusion has been shown to increase HR and blood pressure in animal models 9,10 via stimulation of the sympathetic nervous system. 9,11 In addition to the rise in leptin, we also observed a marked increase in plasma insulin in rabbits fed a HFD suggesting that insulin may also contribute to the hypertension and increased RSNA in rabbits particularly early in the onset of the HFD before significant accumulation of visceral fat. 5,6 Thus, both leptin and insulin may contribute to the hypertension, and with the development of specific antagonists it is now possible to determine their relative roles. In the present study, we administered either the insulin receptor antagonist or the leptin receptor antagonist intracerebroventricularly to conscious rabbits at 1 or 3 weeks after the onset of a HFD. Materials and MethodsTwenty-seven male New Zealand White rabbits (initial body weight, 2.6-3.1 kg) were housed under controlled light (lights on 6:00 Abstract-Feeding a high-fat diet (HFD) to rabbits results in increased blood pressure and renal sympathetic nerve activity (RSNA) and marked increases in plasma leptin and insulin. We determined the contribution of insulin and leptin signaling in the central nervous system to the increased bl...