Spinal cord injury (SCI) is one of the most challenging clinical issues. It is characterized by the disruption of neural circuitry and connectivity, resulting in neurological disability. Adipose-derived stem cells (ADSCs) serve as a promising source of therapeutic cells for SCI treatment. However, the therapeutic outcomes of direct ADSCs transplantation are limited in the presence of an inflammatory microenvironment. Herein, a cell-adaptable neurogenic (CaNeu) hydrogel was developed as a delivery vehicle for ADSCs to promote neuronal regeneration after SCI. The dynamic network of CaNeu hydrogel loaded with ADSCs provides a cell-infiltratable matrix that enhances axonal growth and eventually leads to improved motor evoked potential, hindlimb strength, and coordination of complete spinal cord transection in rats. Furthermore, the CaNeu hydrogel also establishes an anti-inflammatory microenvironment by inducing a shift in the polarization of the recruited macrophages toward the pro-regeneration (M2) phenotype. Our study showed that the CaNeu-hydrogel‒mediated ADSCs delivery resulted in significantly suppressed neuroinflammation and apoptosis, and that this phenomenon involved the PI3K/Akt signaling pathway. Our findings indicate that the CaNeu hydrogel is a valuable delivery vehicle to assist stem cell therapy for SCI, providing a promising strategy for central nervous system diseases.

Diabetic retinopathy is the most common complication in diabetic patients relates to high expression of VEGF and microaneurysms. Scutellarin (Scu) turned out to be effective against diabetes related vascular endothelial cell dysfunction. However, its clinical applications have been limited by its low bioavailability. In this study, we formulated and characterized a novel intestinal target nanoparticle carrier based on amphiphilic chitosan derivatives (Chit-DC-VB12) loaded with scutellarin to enhance its bioavailability and then evaluated its therapeutic effect in experimental diabetic retinopathy model. Chit-DC-VB12 nanoparticles showed low toxicity toward the human colon adenocarcinoma (Caco-2) cells and zebra fish within concentration of 250 μg/ml, owing to good biocompatibility of chitosan. The scutellarin-loaded Chit-DC-VB12 nanoparticles (Chit-DC-VB12-Scu) were then prepared by self-assembly in aqueous solution. Scanning electron microscopy and dynamic light scattering analysis indicated that the Chit-DC-VB12-Scu nanoparticles were spherical particles in the sizes ranging from 150 to 250 nm. The Chit-DC-VB12-Scu nanoparticles exhibited high permeation in Caco-2 cell, indicated it could be beneficial to be absorbed in humans. We also found that Chit-DC-VB12 nanoparticles had a high cellular uptake. Bioavailability studies were performed in Sprague–Dawley rats, which present the area under the curve of scutellarin of Chit-DC-VB12-Scu was two to threefolds greater than that of free scutellarin alone. Further to assess the therapeutic efficacy of diabetic retinopathy, we showed Chit-DC-VB12-Scu down-regulated central retinal artery resistivity index and the expression of angiogenesis proteins (VEGF, VEGFR2, and vWF) of retinas in type II diabetic rats. Chit-DC-VB12 nanoparticles loaded with scutellarin have better bioavailability and cellular uptake efficiency than Scu, while Chit-DC-VB12-Scu nanoparticles alleviated the structural disorder of intraretinal neovessels in the retina induced by diabetes, and it also inhibited the retinal neovascularization via down-regulated the expression of angiogenesis proteins. In conclusion, the Chit-DC-VB12 nanoparticles enhanced scutellarin oral delivery efficacy and exhibited potential as small intestinal target promising nano-carriers for treatment of type II diabetes induced-retinopathy.

Journal of Experimental and Clinical Cancer Research is ranked in the first quartile of oncology journals in Journal Citation Reports and is the official ...

Excellent biocompatibility and bioactivity are necessary requirements for a scaffold for nerve repair and regeneration. Natural plant protein zein was chosen as the primary material and poly(L-lysine), which is composed of common amino acids in the human body, was used to modify it. Poly(L-lysine) modified zein (ZPLL) with different PLL contents of 1.46%, 3.57%, and 6.18% was synthesized and nanofibrous membranes were prepared by electrospinning. The hydrophilicity of the membranes improved with an increase of PLL content. The biodegradability of the membranes was proved by in vitro experiments. Compared with pure zein membranes, ZPLL membranes can efficiently improve cell viability, adhesion, proliferation, and differentiation of neural stem cells (NSCs) and the effect of PLL content was further investigated. The results show that when the PLL content was 3.57%, cell adhesion and proliferation proved to be the best and most differentiated toward mature neurons with extensive neurite formation and astrocytes rather than oligodendrocytes. The ZPLL was made into nerve conduits for future study and they may be a promising biomaterial for nerve repair and regeneration.

Bone marrow stem cells (BMSCs) have been shown to improve neurological function recovery in cerebral ischemia. Hypoxia-inducible factor-1 (HIF-1) α-AA is a more stable mutant form of HIF-1α, which is a crucial oxygen-sensitive regulator. To investigate the protective effects of HIF-1α-AA-modified BMSCs on neuron survival in cerebral ischemia models, we co-cultured HIF-1α-AA-modified BMSCs with neuron-like cells (PC12 cells) and observed a significant increase in the release of vascular endothelial growth factor (VEGF) from BMSCs, the decreased PC12 cell apoptosis, and the upregulation of Survivin expression reduced by hypoxia in PC12 cells compared to enhanced green fluorescent protein (EGFP) BMSCs. In addition, to explore whether VEGF secreted by HIF-1α-AA-modified BMSCs plays an important role in preventing hypoxia-induced apoptosis and the possible mechanism involved, exogenous VEGF were applied and the similar protective effects on PC12 cells were observed in vitro. Furthermore, hypoxia reduced the expression of phosphorylated Akt and phosphorylated FoxO1, whereas the administration of VEGF reversed these changes. Transfection of FoxO1 H215R, a DNA-binding mutant, abrogated the inhibitory ability on Survivin promoter activity, whereas FoxO1 AAA, the active form of FoxO1, presented further repression on Survivin promoter, indicating that FoxO1 directly binds on Survivin promoter as a transcriptional repressor and that phosphorylation status of FoxO1 affects its inhibition on the Survivin promoter. Transplantation of HIF-1α-AA-modified BMSCs after cerebral ischemia in vivo sufficiently reduced neurons apoptosis, decreased cerebral infarction volume, and induced a significant improvement on the modified neurological severity score compared to the EGFP BMSCs group. In conclusion, HIF-1α-AA-modified MSCs showed an obvious protective effect on neuron-like cells or neuron after ischemia in vitro and in vivo, at least in part, through the VEGF/PI3K/Akt/FoxO1 pathway.