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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]

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]