Placenta-derived PLX-PAD mesenchymal-like stromal cells are efficacious in rescuing blood flow in hind limb ischemia mouse model by a dose- and site-dependent mechanism of action

• Published in: Cytotherapy (Oxford, England) Vol. 19; no. 12; pp. 1438 - 1446
• Main Authors: Zahavi-Goldstein, Efrat, Blumenfeld, Michal, Fuchs-Telem, Dana, Pinzur, Lena, Rubin, Shy, Aberman, Zami, Sher, Noa, Ofir, Racheli
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.12.2017
• Subjects: Animals; Cytokines - metabolism; Disease Models, Animal; Female; hind limb ischemia; Hindlimb - blood supply; Ischemia - physiopathology; Ischemia - therapy; Male; mesenchymal stromal cells; Mesenchymal Stromal Cells - cytology; Mice, Inbred C57BL; Peripheral Arterial Disease - therapy; placenta; Placenta - cytology; PLX-PAD; Pregnancy; Regional Blood Flow; Stromal Cells - transplantation; placenta; PLX-PAD; mesenchymal stromal cells; hind limb ischemia
• ISSN: 1465-3249; 1477-2566
• DOI: 10.1016/j.jcyt.2017.09.010

•PLX-PAD rescues blood flow in hind limb ischemia in a dose- and site-dependent manner.•Live PLX-PAD cells are more efficacious than cell lysate.•PLX-PAD secrete numerous pro-angiogenic factors.•The proposed PLX-PAD mechanism of action involves multifactorial endocrine secretion. 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. 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. 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. 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.