Bone marrow mononuclear cells stimulate angiogenesis when transplanted into surgically induced fibrocollagenous tunnels: Results from a canine ischemic hindlimb model

Abstract

Progenitor cell transplantation has been considered as a potential angiogenesis therapy for the ischemic hindlimb. In this work we performed an ischemic hindlimb model in dogs. We ligated the middle sacra and the external right iliac arteries. After 7 days, the femoral artery was ligated and removed, and three Silastic tubes were inserted into the gracilis muscle to create fibrocollagenous tunnels. After Silastic implantation, we administered saline or granulocyte colony stimulating factor (G-CSF) subcutaneously daily during 5 days. Fourteen days after device positioning we transplanted bone marrow mononuclear cells (BMMC) into the tunnels previously formed by Silastic tube reaction. Twenty-eight days later, contrasted angiographies were performed and angiographic scores were calculated. Also, vessels and endothelial cells and proliferating cells were identified by immunochemistry of muscle sections. Results demonstrated that BMMC transplantation enriched by G-CSF administration significantly stimulates angiogenesis in the ischemic hindlimb, and more than BMMC transplantation alone. Transplantation of progenitor cells in an appropriate extracellular matrix is a potential therapy for hindlimb ischemia.

Long-term effect of autologous progenitor cell therapy to induce neo angiogenesis in patients with critical limb ischemia transplantated via intramuscular vs combined intramuscular and distal retrograde intra venous

“…Using a rat ischemic limb model we previously demonstrated the induction of effective neo-vascularization after bone marrow mononuclear cell (CD 34+ and CD 133+ ) transplantation into surgically induced fibrocollagenous tunnels used as scaffolds to enhance cell survival and differentiation [24]. In a second experimental study, our group used dogs as an ischemic limb model confirming that transplantation of mobilized BM-MNC to peripheral blood through the use of Granulocyte Colony-Stimulating Factor (G-CSF) statistically significant increased angiogenesis as compared with cell transplant without G-CSF treatment [25]. Based on the evidence of neo-angiogenesis as a result of mobilized BM-MNC autologous transplantation on these experimental models, we obtained the ethical and research institution committee approval to start a clinical trial in humans for the progenitor cell therapy of CLI patients.…”

Models for the Study of Angiogenesis

“…The term angiogenesis refers to the formation of capillaries from preexisting vessels in embryos and adult organisms. It begins with endothelial cell activation and an increase in vascular permeability, followed by disruption of the basement membrane [1]. Subsequent endothelial cell migration, extracellular matrix invasion into interstitial spaces, cell proliferation, formation of the basement membrane, and capillary lumen formation complete the process of angiogenesis.…”

“…Despite progress in revascularization procedures, a substantial number of patients are not candidates for these procedures [1]. Stimulation of angiogenesis by exogenous growth factor administration or gene transfer has emerged as an alternative strategy to salvage ischemic cardiac and skeletal muscles [2,3].…”

Deciphering the in vivo Dynamic Proteomics of Mesenchymal Stem Cells in Critical Limb Ischemia

“…Cell-based therapies were regarded as an innovative way to improve blood flow recovery in order to prevent necrosis and amputation and limb-threatening complications ( Tongers et al, 2014 ; Cho et al, 2015 ; Hou et al, 2016 ). Various stem and progenitor cells have been applied, including whole bone marrow cells, bone marrow mononuclear cells, hematopoietic stem cells, endothelial progenitor cells, and hemangiocytes ( Padilla et al, 2007 ; Zhang et al, 2008 ; Kwon et al, 2011 ; Agudelo et al, 2012 ; Lee et al, 2013 ). Amid them, mesenchymal stem cells (MSCs) have been regarded as the most potential and promising cell types at both preclinical and clinical levels ( Zhang et al, 2018 ; Jaillard et al, 2020 ; Yan et al, 2020 ; Yao et al, 2020 ).…”