Abstract
Objective: Mesenchymal Stem Cells (MSCs) are adult multipotent cells that possess regenerative and immunosuppressant properties. Homing of MSCs to target organs remains a major challenge as intravenous delivery results in intravascular entrapment of most MSCs in vascularized organs. Intra-Arterial (IA) administration of MSCs to arteries feeding a specific organ improved the delivery of cells to these organs but often resulted in vessels obstruction. To improve targeting of MSCs into a transplant we designed a novel method for IA delivery of MSCs during the transplantation procedure. This study was aimed at evaluating the safety and efficacy of this method. Methods: A syngeneic groin free flap between Lewis rats was performed in all experiment groups. Treatment groups included 3 groups (n ≥ 7) in which 1 × 106, 0.5 × 106 or 0.05 × 106 adipose derived MSCs (ASCs) were administered via a femoral artery branch prior to the final reperfusion of the flap. In vivo real time fluorescence imaging and intravital microscopy were used to define ASCs IA movement after transplantation. Results: High concentrations of ASCs per injection resulted in poor flap survival rates (14.3%) due to flap necrosis. At 0.05 × 106 ASCs, increased long-term flap viability rates (85%) were observed. Whole-body imaging of fluorescently labeled ASCs demonstrated significant targeting of cells into the flap even at such a low cell quantity. ASCs were detected in proximity to small blood vessels within the viable flap. Conclusions: Local IA administration of ASCs into a vascularized transplant/flap is feasible and allows high local cell concentrations with minimal cell dosing.
Highlights
Mesenchymal Stem Cells (MSCs) are multipotent, as evidenced upon culture by their ability to undergo differentiation into adipogenic, osteogenic and chondrogenic fates [1]
High concentrations of adipose derived MSCs (ASCs) per injection resulted in poor flap survival rates (14.3%) due to flap necrosis
In the treatment groups each rat received a volume of 200 μl saline with decreasing concentration of ASCs (ASCs characterization is shown in supplementary Figure 1)
Summary
Mesenchymal Stem Cells (MSCs) are multipotent, as evidenced upon culture by their ability to undergo differentiation into adipogenic, osteogenic and chondrogenic fates [1]. Systemic introduction of mesenchymal stem cells to prevent VCA rejection is a promising alternative evident in in vivo systemic application of adipose derived MSCs (ASCs) to a VCA swine or rat models [3,6,7,8]. Despite their proven ability to actively target inflamed and ischemic tissues [9] the vast majority of systemically intravenous (IV) administrated MSCs are found entrapped in vascularized organs such as the lungs and liver with very limited localization of the cells to the target organs [10,11,12,13]. Developing novel modalities for enhanced targeting of MSCs allowing improved treatments with substantially reduced cell quantities, treatment cost and cell culturing time remains a major challenge in MSCs based cell therapy
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