Image-Guided Transarterial Directed Delivery of Human Mesenchymal Stem Cells for Targeted Gastrointestinal Therapies in a Swine Model.

PURPOSE: To evaluate the feasibility of catheter-directed intra-arterial stem cell delivery of human mesenchymal stem cells (MSCs) to the small bowel in a porcine model. MATERIALS AND METHODS: The cranial mesenteric artery of 6 Yucatan minipigs was selectively catheterized under fluoroscopic guidance following cut-down and carotid artery access. A proximal jejunal branch artery was selectively catheterized for directed delivery of embolic microspheres (100-300 µm) or MSCs (0.1-10 million cells). The pigs were euthanized after 4 hours and specimens collected from the proximal duodenum and the targeted segment of the jejunum. The Chiu/Park system for scoring intestinal ischemia was used to compare hematoxylin and eosin-stained sections of jejunum and duodenum. RESULTS: Successful delivery of microspheres or MSCs in a proximal jejunal branch artery of the cranial mesenteric artery was achieved in all subjects. Radiopaque microspheres and post-delivery angiographic evidence of stasis in the targeted vessels were observed on fluoroscopy after delivery of embolics. Preserved blood flow was observed after MSC delivery in the targeted vessel. The Chiu/Park score for intestinal ischemia in the targeted proximal jejunal segments were similar for microspheres (4, 4; n = 2) and MSCs (4, 4, 4, 3; n = 4), indicating moderate ischemic effects that were greater than for control duodenal tissue (3, 1; 0, 0, 3, 3). CONCLUSIONS: Selective arteriographic deployment of MSCs in swine is feasible for study of directed intestinal stem cell delivery. In this study, directed therapy resulted in intestinal ischemia.

Effects of High-protein and High-fiber Diets on Weight and Glucose Regulation in Spiny Mice (Acomys cahirinus).

Despite the long-term contributions of the spiny mouse (Acomys cahirinus) to research, basic knowledge of appropriate nutrition is lacking for this species. In the wild, spiny mice eat a high-fiber, high-protein food source. In the research setting, spiny mice are prone to obesity that can lead to diabetes mellitus. Common dietary modifications for weight control in humans with diabetes mellitus consist of increased fiber and protein. We hypothesized that increasing the dietary protein or fiber of spiny mice would reduce weight gain and improve their glycemic control, whereas the combination of protein and fiber in the diet would achieve optimal weight management and glycemic control without diet-related pathologic changes. We randomly assigned cages of young adult spiny mice (n = 34) to one of 4 diets: high protein (HP), high fiber (HF), a combination of both high protein and high fiber (HPF), or the base (control) diet (BD). Over the 8-wk study, spiny mice given HF diets maintained baseline weights despite the elevated dietary protein. None of the diets altered blood glucose levels; all diet groups maintained mean blood glucose levels within normal ranges. Spiny mice seem particularly sensitive to changes within their environment, as seen by increased food waste and transient elevated blood glucose levels when the spiny mice were transitioned to novel diets. The short-term elevations in protein and fiber that we tested were well tolerated by spiny mice. Although HF was effective in controlling weight, the ideal percentage of fiber still needs to be determined. The combination diet (HPF) maintained weight and body condition scores and showed a nonsignificant elevation of blood glucose that warrants a longer diet trial before our recommending this specific combination.

Lentiviral Vector Induced Modeling of High-Grade Spinal Cord Glioma in Minipigs.

BACKGROUND: Prior studies have applied driver mutations targeting the RTK/RAS/PI3K and p53 pathways to induce the formation of high-grade gliomas in rodent models. In the present study, we report the production of a high-grade spinal cord glioma model in pigs using lentiviral gene transfer. METHODS: Six Gottingen Minipigs received thoracolumbar (T14-L1) lateral white matter injections of a combination of lentiviral vectors, expressing platelet-derived growth factor beta (PDGF-B), constitutive HRAS, and shRNA-p53 respectively. All animals received injection of control vectors into the contralateral cord. Animals underwent baseline and endpoint magnetic resonance imaging (MRI) and were evaluated daily for clinical deficits. Hematoxylin and eosin (H&E) and immunohistochemical analysis was conducted. Data are presented using descriptive statistics including relative frequencies, mean, standard deviation, and range. RESULTS: 100% of animals (n = 6/6) developed clinical motor deficits ipsilateral to the oncogenic lentiviral injections by a three-week endpoint. MRI scans at endpoint demonstrated contrast enhancing mass lesions at the site of oncogenic lentiviral injection and not at the site of control injections. Immunohistochemistry demonstrated positive staining for GFAP, Olig2, and a high Ki-67 proliferative index. Histopathologic features demonstrate consistent and reproducible growth of a high-grade glioma in all animals. CONCLUSIONS: Lentiviral gene transfer represents a feasible pathway to glioma modeling in higher order species. The present model is the first lentiviral vector induced pig model of high-grade spinal cord glioma and may potentially be used in preclinical therapeutic development programs.