E-Selectin-Overexpressing Mesenchymal Stem Cell Therapy Confers Improved Reperfusion, Repair, and Regeneration in a Murine Critical Limb Ischemia Model.

AIMS: Novel cell-based therapeutic angiogenic treatments for patients with critical limb ischemia may afford limb salvage. Mesenchymal stem cells (MSCs) do not overexpress E-selectin; however, we have previously demonstrated the cell-adhesion molecule's vital role in angiogenesis and wound healing. Thus, we created a viral vector to overexpress E-selectin on MSCs to increase their therapeutic profile. METHODS AND RESULTS: Femoral artery ligation induced hind limb ischemia in mice and intramuscular injections were administered of vehicle or syngeneic donor MSCs, transduced ex vivo with an adeno-associated viral vector to express either GFP+ (MSCGFP) or E-selectin-GFP+ (MSCE-selectin-GFP). Laser Doppler Imaging demonstrated significantly restored reperfusion in MSCE-selectin-GFP-treated mice vs. controls. After 3 weeks, the ischemic limbs in mice treated with MSCE-selectin-GFP had increased footpad blood vessel density, hematoxylin and eosin stain (H&E) ischemic calf muscle sections revealed mitigated muscular atrophy with restored muscle fiber size, and mice were able to run further before exhaustion. PCR array-based gene profiling analysis identified nine upregulated pro-angiogenic/pro-repair genes and downregulated Tumor necrosis factor (TNF) gene in MSCE-selectin-GFP-treated limb tissues, indicating that the therapeutic effect is likely achieved via upregulation of pro-angiogenic cytokines and downregulation of inflammation. CONCLUSION: This innovative cell therapy confers increased limb reperfusion, neovascularization, improved functional recovery, decreased muscle atrophy, and thus offers a potential therapeutic method for future clinical studies.

Utility of routine intraoperative cholangiogram during cholecystectomy in children: A nationwide analysis of outcomes and readmissions.

PURPOSE: This study aims to determine postoperative outcomes and readmissions in pediatric cholecystectomy with routine intraoperative cholangiogram (IOC) utilization. METHODS: The Nationwide Readmissions Database 2010-2014 was queried for all pediatric cholecystectomies. A propensity score-matched analysis (PSMA) with over 30 covariates was performed between cholecystectomy alone (CCY) versus those with routine IOC (CCY + IOC, no biliary obstruction, dilatation, or pancreatitis). χ2 analysis or Mann-Whitney U were used for statistical analysis with p < 0.05 set as significant. RESULTS: 34,390 cholecystectomies were performed: 92% were laparoscopic, most were teenage females (75%, 15 years [13-17]) and did not undergo IOC (75%). Postoperative mortality rate was 0.1%. The PSMA cohort comprised of 1412 CCY and 1453 CCY + IOC. Patients with CCY alone had higher rates of 30-day (7% vs 5%), 1-year readmissions (13% vs 11%) and had higher rates of overall complications (22% vs 12%) compared with CCY + IOC, all p < 0.05. Although uncommon, bile duct injuries were more prevalent in CCY (2% vs 0%, p < 0.001), while there was no difference in readmissions for retained stones. Resource utilization was increased in CCY patients, likely due to increased complication rates. CONCLUSION: This nationwide PSMA suggests pediatric CCY with routine IOC is associated with decreased readmissions, overall resource utilization, complications, and bile duct injuries. TYPE OF STUDY: Retrospective Comparative Study. LEVEL OF EVIDENCE: Level III.

Increasing the Therapeutic Potential of Stem Cell Therapies for Critical Limb Ischemia.

Peripheral Arterial Disease (PAD) is a progressive, atherosclerotic disease that at its end stage, Critical Limb Ischemia (CLI), results in severely diminished limb perfusion and causes leg pain at rest, non-healing ulcers, and tissue gangrene. Many patients with CLI fail current medical and surgical therapies and thus are deemed "no option" and require limb amputation. Novel therapies to attempt limb salvage in these "no option" patients are needed. Stem cell therapy is one therapeutic angiogenic avenue that has been tested over the last 20 years. To date, clinical trials have shown promise but with only modest improvement and none demonstrated a significant decrease in amputation rates in those treated with stem cell therapy. Thus, recent investigations into improving stem cell therapy have been the focus of our laboratory and many others. This review aims to describe recent advances in increasing the therapeutic potential of stem cell therapies for CLI.