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Chronic cocaine use triggers inflammatory and oxidative processes in the central nervous system, resulting in impaired microglia. Mesenchymal stem cells, known for their immunomodulatory properties, have shown promise in reducing inflammation and enhancing neuronal survival. The study employed the cocaine self-administration model, focusing on ionized calcium-binding adaptor protein 1 (Iba-1) and cell morphology as markers for microglial impairment and PLX-PAD cells as a treatment for attenuating cocaine craving. The results revealed an addiction-stage and region-specific impairment in microglia following chronic cocaine exposure, with deficits observed in the Nucleus Accumbens (NAc) during the maintenance stage and in both the NAc and Dentate Gyrus (DG) during the extinction and reinstatement stages. Furthermore, PLX-PAD cell therapy demonstrated a significant reduction in cocaine craving and seeking behavior, interestingly accompanied by the prevention of Iba-1 level decrease and restoration of microglial activity in the NAc and DG. These findings highlight the unique role of microglia in modulating cocaine addiction behaviors through their influence on synaptic plasticity and neuronal remodeling associated with memory formation. They also suggest that PLX-PAD therapy may mitigate the detrimental effects of chronic cocaine exposure on microglia, underscoring the importance of incorporating microglia in comprehensive addiction rehabilitation strategies. [ABSTRACT FROM AUTHOR]

Background In peripheral artery disease (PAD), blockage of the blood supply to the limbs, most frequently the legs, leads to impaired blood flow and tissue ischemia. Pluristem's PLX-PAD cells are placenta-derived mesenchymal stromal-like cells currently in clinical trials for the treatment of peripheral artery diseases. Methods In this work, the hind limb ischemia (HLI) mouse model was utilized to study the efficacy and mechanism of action of PLX-PAD cells. ELISA assays were performed to characterize and quantitate PLX-PAD secretions in vitro. Results PLX-PAD cells administered intramuscularly rescued blood flow to the lower limb after HLI induction in a dose-dependent manner. While rescue of blood flow was site-dependent, numerous administration regimes enabled rescue of blood flow, indicating a systemic effect mediated by PLX-PAD secretions. Live PLX-PAD cells were more efficacious than cell lysate in rescuing blood flow, indicating the importance of prolonged cytokine secretion for maximal blood flow recovery. In vitro studies showed a multifactorial secretion profile including numerous pro-angiogenic proteins; these are likely involved in the PLX-PAD mechanism of action. Discussion Live PLX-PAD cells were efficacious in rescuing blood flow after the induction of HLI in the mouse model in a dose- and site-dependent manner. The fact that various administration routes of PLX-PAD rescued blood flow indicates that the mechanism of action likely involves one of systemic secretions which promote angiogenesis. Taken together, the data support the further clinical testing of PLX-PAD cells for PAD indications. [ABSTRACT FROM AUTHOR]

The administration of mesenchymal stromal cells (MSCs) provides an exciting emerging therapeutic modality for the treatment of peripheral arterial disease, a condition that is associated with critical limb ischemia as its end stage. Placental-derived MSCs, termed PLX-PAD cells, are stable adhesive stromal cells isolated from full-term human placentae, cultured on carriers, and expanded in a bioreactor called the PluriX. These cells can be expanded in vitro without phenotypic or karyotypic changes. We studied the safety and biodistribution properties of PLX-PAD cells following intramuscular administration in NOD/SCID mice. No significant clinical signs, hematological and biochemical parameters, or major pathological changes were found in PLX-PAD-treated animals in comparison to vehicle controls. Several animals in the control and PLX-PAD-treated groups developed thymic malignant lymphoma, first seen after one month, as expected in this mouse strain. In addition, both groups developed spontaneous mesenteric vessel inflammation. Real-time quantitative polymerase chain reaction (RT-qPCR) demonstrated that distribution of PLX-PAD cells was confined to the injection site. Placental-derived MSCs remained in this site with gradual decrease in concentration during a three-month period. In view of these data, we conclude that the administration of PLX-PAD cells is not associated with any adverse effects in NOD/SCID mice. [ABSTRACT FROM PUBLISHER]

Background aims Mesenchymal stromal cells (MSC) are spindle-shaped plastic-adherent cells isolated from bone marrow (BM), adipose tissue and other organs, including the placenta. Autologous BM-derived MSC have been studied in animals with experimentally induced critical limb ischemia (CLI) as a model of end-stage peripheral vascular disease. While demonstrating therapeutic benefit, the use of these cells is limited by the need to surgically extract BM and the fear of thrombosis secondary to the use of granulocyte-colony-stimulating factor (G-CSF) to mobilize the cells. Methods We studied the use of placental-derived adherent stromal cells (ASC) in a standard limb ischemia model of male Balb/c mice. These placental-derived cells, termed PLX-PAD, share the adherence and marker expression of BM-derived MSC but lack their differentiation potential. PLX-PAD are isolated from human placenta following a Caesarean section and cultured in a bioreactor, termed the PluriX™ System. The PluriX™ System provides a three-dimensional (3-D) microenvironment that enables the large-scale growth of these cells. PLX-PAD are stable adhesive cells that can be expanded in vitro without the loss of phenotype and without showing signs of karyotypic changes. Results The intramuscular (i.m.) administration of PLX-PAD in our model significantly improved blood flow (BF) (P=0.0008), increased capillary density (P=0.021), reduced oxidative stress (P=0.034) and reduced endothelial damage (P=0.004), while increasing limb function versus the administration of a phosphate-buffered saline (PBS) control vehicle in the affected limb. Conclusions Allogeneic placental-derived ASC may provide an off-the-shelf supply of therapeutic cells that would need no histocompatible tissue matching and be potentially less expensive and considerably more convenient than BM or adipose-derived MSC. [ABSTRACT FROM AUTHOR]