tsa inhibitor Conflicts of interest br Introduction The

Conflicts of interest
Introduction The goal of islet transplantation is to use the donor β-cells to restore the insulin production and glycemic regulation in patients with type 1 diabetes to avoid serious complications (Barton et al., 2012; Goland and Egli, 2014). For long-term graft survival, neurovascular regeneration in the new islet microenvironment is essential for the engraftment process (Jansson and Carlsson, 2002; Persson-Sjogren et al., 2000; Reimer et al., 2003). The graft–host integration through the neurovascular networks is important for grafts to receive nutrients and stimulations from the circulation and nerves to maintain survival and respond to physiological cues. Thus, identification of the mechanisms and cellular players that participate in islet neurovascular regeneration holds the key to improving the outcome of transplantation. In the pancreas, the endocrine islets receive rich neurovascular supplies, which consist of not only the nerves (sympathetic, parasympathetic, and sensory nerves; Ahren, 2012; Borden et al., 2013; Tang et al., 2014) and blood vessels, but also the Schwann tsa inhibitor (the glial cells of the peripheral nervous system) and pericytes residing at the exterior and interior boundaries of the islet, facing the exocrine pancreas and endothelium, respectively (Donev, 1984; Hayden et al., 2008; Richards et al., 2010; Sunami et al., 2001). Morphologically, the islet Schwann cell network resides in the islet mantle, forming a mesh-like sheath (with apparent openings) surrounding the islet. The Schwann cells also release neurotrophic factors such as the nerve growth factor and glial cell line-derived neurotrophic factor (GDNF) to the islet microenvironment to support the “neuroendocrine” tissue (Mwangi et al., 2008; Teitelman et al., 1998). The pericytes, also known as the mural cells, reside on the abluminal side of the blood vessels, guarding the vascular network. The pericyte and endothelium interactions are important for the angiogenesis and survival of endothelial cells (Armulik et al., 2005; Lindahl et al., 1997; von Tell et al., 2006). Particularly in angiogenesis, the release of platelet-derived growth factor from the endothelial cells recruits pericytes to establish their physical contact for paracrine signaling to stabilize the vascular system. While sheathing the islets and blood vessels, in the pancreas the Schwann cells and pericytes also react to the islet injury and lesion formation in experimental diabetes (Tang et al., 2013; Teitelman et al., 1998; Yantha et al., 2010). For example, in the rodent model of islet injury induced by the streptozotocin injection, both Schwann cells and pericytes become reactive in response to the islet microstructural and vascular damages (Tang et al., 2013; Teitelman et al., 1998). In the non-obese diabetic (NOD) mouse model, the islet lesion induced by lymphocytic infiltration leads to peri-lesional and perivascular Schwann cell activation occurring at the front of lymphocytic infiltration in insulitis (Tang et al., 2013). Regarding the pericytes, their cellular responses were also found in the islet injuries induced by streptozotocin injection and lymphocytic infiltration with global (streptozotocin injection) and localized (NOD mice) changes of pericyte density (Tang et al., 2013). Importantly, the plasticity of Schwann cells and pericytes in response to islet injury suggests their potential reactivity in islet transplantation, in which the injuries occur both to the donor islets and at the transplantation site of the recipient. To elucidate the ability of Schwann cells and pericytes in the participation of islet graft neurovascular regeneration, in this research we transplanted the mouse islets under the kidney capsule and prepared transparent graft specimens by tissue clearing (or optical clearing, use of an immersion solution of high refractive index to reduce scattering in optical microscopy; Chiu et al., 2012; Fu et al., 2009; Fu and Tang, 2010; Liu et al., 2015) to characterize the 3-dimensional (3-D) features of the Schwann cell and vascular networks, which otherwise cannot be easily portrayed by the standard microtome-based histology. We also transplanted the labeled islets with the nestin (the marker of neurovascular stem/progenitor cells; Dore-Duffy et al., 2006; Mignone et al., 2004; Treutelaar et al., 2003) promoter-driven green fluorescence protein (GFP) expression in the Schwann cells and pericytes (Alliot et al., 1999; Clarke et al., 1994; Frisen et al., 1995) to trace their locations and activities in the recipient.