Mesenchymal stem cells, derived from human-induced pluripotent stem cells (iPSC), are valuable for generating smooth muscle cells (SMCs) for vascular tissue engineering applications. In this study, we synthesized biodegradable α-amino acid-substituted poly(organophosphazene) polymers and electrospun nano-fibrous scaffolds (~200 nm diameter) to evaluate their suitability as a matrix for differentiation of iPSC-derived mesenchymal stem cells (iMSC) into mature contractile SMCs. Both the polymer synthesis approach and the electrospinning parameters were optimized. Three types of cells, namely iMSC, bone marrow derived mesenchymal stem cells (BM-MSC), and primary human coronary artery SMC, attached and spread on the materials. Although L-ascorbic acid (AA) and transforming growth factor-beta 1 (TGF-β1) were able to differentiate iMSC along the smooth muscle lineage, we showed that the electrospun fibrous mats provided material cues for the enhanced differentiation of iMSCs. Differentiation of iMSC to SMC was characterized by increased transcriptional levels of early to late-stage smooth muscle marker proteins on electrospun fibrous mats. Our findings provide a feasible strategy for engineering functional vascular tissues.

Despite the efforts devoted to drug discovery and development, the number of new drug approvals have been decreasing. Specifically, cardiovascular developments have been showing amongst the lowest levels of approvals. In addition, concerns over the adverse effects of drugs to the cardiovascular system have been increasing and resulting in failure at the preclinical level as well as withdrawal of drugs post-marketing. Besides factors such as the increased cost of clinical trials and increases in the requirements and the complexity of the regulatory processes, there is also a gap between the currently existing pre-clinical screening methods and the clinical studies in humans. This gap is mainly caused by the lack of complexity in the currently used 2D cell culture-based screening systems, which do not accurately reflect human physiological conditions. Cell-based drug screening is widely accepted and extensively used and can provide an initial indication of the drugs' therapeutic efficacy and potential cytotoxicity. However, in vitro cell-based evaluation could in many instances provide contradictory findings to the in vivo testing in animal models and clinical trials. This drawback is related to the failure of these 2D cell culture systems to recapitulate the human physiological microenvironment in which the cells reside. In the body, cells reside within a complex physiological setting, where they interact with and respond to neighboring cells, extracellular matrix, mechanical stress, blood shear stress, and many other factors. These factors in sum affect the cellular response and the specific pathways that regulate variable vital functions such as proliferation, apoptosis, and differentiation. Although pre-clinical in vivo animal models provide this level of complexity, cross species differences can also cause contradictory results from that seen when the drug enters clinical trials. Thus, there is a need to better mimic human physiological conditions in pre-clinical studies to improve the efficiency of drug screening. A novel approach is to develop 3D tissue engineered miniaturized constructs in vitro that are based on human cells. In this review, we discuss the factors that should be considered to produce a successful vascular construct that is derived from human cells and is both reliable and reproducible.

• TEVGs
• biodegradable
• polycaprolactone
• sheep carotid bypass model
• small diameter artery
• tissue engineered vascular grafts

• Bioreactor
• Cardiovascular
• Grafts
• Small diameter
• Tissue engineering
• Veins

• Animals
• Bioreactors
• Blood Vessel Prosthesis
• Humans
• Myocytes, Smooth Muscle/physiology
• Perfusion
• Publications
• Tissue Engineering/methods
• Tissue Engineering/trends

• Adipose derived stromal cells
• Co-culture
• Monocytes
• Paracrine-signalling
• Vascular smooth muscle cells

• Adipose Tissue/cytology
• Biomarkers/metabolism
• Calcium-Binding Proteins/metabolism
• Cells, Cultured
• Cytokines/metabolism
• Cytoskeletal Proteins/metabolism
• DNA/metabolism
• Extracellular Matrix/metabolism
• Humans
• Inflammation Mediators/metabolism
• Insulin-Like Growth Factor I/metabolism
• Interleukin-6/metabolism
• Microfilament Proteins/metabolism
• Monocytes/cytology
• Muscle Contraction
• Muscle Proteins/metabolism
• Muscle, Smooth, Vascular/cytology
• Myocytes, Smooth Muscle/cytology
• Paracrine Communication
• Phenotype
• Signal Transduction
• Stromal Cells
• Time Factors
• Transforming Growth Factor beta1/metabolism
• Calponins

• 230762 CIHR

Obesity is an independent risk factor for cardiovascular disease. Adipose tissue was initially thought to be involved in metabolism through paracrine. Recent researches discovered mesenchymal stem cells inside adipose tissue which could differentiate into vascular lineages in vitro and in vivo, participating vascular remodeling. However, there were few researches focusing on distinct characteristics and functions of adipose-derived stem cells (ADSCs) from different regions. This is the first comprehensive review demonstrating the variances of ADSCs from the perspective of their origins.

• adipose-derived stem cells
• endothelial cell
• smooth muscle cell
• vascular remodeling

• Alginates/chemistry
• Blood Vessels/cytology
• Blood Vessels/drug effects
• Blood Vessels/physiology
• Cell Line
• Coculture Techniques
• Collagen/chemistry
• Drug Combinations
• Endothelin-1/pharmacology
• Endothelium, Vascular/cytology
• Endothelium, Vascular/drug effects
• Endothelium, Vascular/physiology
• Extracellular Matrix/chemistry
• Human Umbilical Vein Endothelial Cells/cytology
• Human Umbilical Vein Endothelial Cells/drug effects
• Human Umbilical Vein Endothelial Cells/physiology
• Humans
• Hydrogels/chemistry
• Laminin/chemistry
• Microfluidic Analytical Techniques
• Models, Cardiovascular
• Myocytes, Smooth Muscle/cytology
• Myocytes, Smooth Muscle/drug effects
• Myocytes, Smooth Muscle/physiology
• Proteoglycans/chemistry
• Tissue Engineering/methods
• Tissue Scaffolds
• Vasoconstriction/drug effects
• Vasoconstrictor Agents/pharmacology

• Fondation Lefoulon Delalande
• Agence Nationale de la Recherche
• INSERM

To evaluate the angiogenic effect of platelet-rich plasma (PRP)-preconditioned adipose-derived stem cells (ADSCs) both in vitro and in a mouse ischemic hindlimb model.

ADSCs were divided based on culture medium: 2.5% PRP, 5% PRP, 7.5% PRP, and 10% PRP. Cell proliferation rate was analyzed using the MTS assay. The gene expression of CD31, vascular endothelial growth factor, hypoxia-inducible factors, and endothelial cell nitric oxide synthase was analyzed using reverse transcription polymerase chain reaction. Cell markers and structural changes were assessed through immunofluorescence staining and the tube formation assay. Subsequently, we studied the in vivo angiogenic capabilities of ADSCs by a mouse ischemic hindlimb model.

The proliferation rate of ADSCs was higher in the 2.5%, 5%, and 7.5% PRP groups. The expression of hypoxia-inducible factor, CD31, vascular endothelial growth factor, and endothelial cell nitric oxide synthase in the 5% and 7.5% PRP groups increased. The 5%, 7.5%, and 10% PRP groups showed higher abilities to promote both CD31 and vascular endothelial growth factor production and tubular structure formation in ADSCs. According to laser Doppler perfusion scan, the perfusion ratios of ischemic limb to normal limb were significantly higher in 5% PRP, 7.5% PRP, and human umbilical vein endothelial cells groups compared with the negative control and fetal bovine serum (FBS) groups (0.88 ± 0.08, 0.85 ± 0.07 and 0.81 ± 0.06 for 5%, 7.5% PRP and human umbilical vein endothelial cells compared with 0.42 ± 0.17 and 0.54 ± 0.14 for the negative control and FBS, P < 0.01).

PRP-preconditioned ADSCs presented endothelial cell characteristics in vitro and significantly improved neovascularization in ischemic hindlimbs. The optimal angiogenic effect occurred in 5% PRP- and 7.5% PRP-preconditioned ADSCs.

• Platelet-rich plasma
• Adipose-derived stem cells
• Mesenchymal stem cell
• Angiogenesis
• Endothelial differentiation
• Mouse ischemic hindlimb model

• biomaterials
• gene/cell therapy
• regenerative medicine
• tissue engineering

• Adipose Tissue/cytology
• Animals
• Clinical Trials as Topic
• Humans
• Regenerative Medicine
• Stem Cells/cytology
• Tissue Engineering
• Translational Research, Biomedical

• FFABRMARTINO-2018 Ministero dell'Istruzione, dell'Università e della Ricerca

• blood-contacting surfaces
• endothelialization
• surface modification
• vascular engineering
• vascular grafts

• Animals
• Blood Vessel Prosthesis
• Blood Vessel Prosthesis Implantation
• Collagen/chemistry
• Humans
• Swine
• Tissue Engineering/methods
• Tissue Scaffolds/chemistry

• R15 CA202656 NCI NIH HHS
• R15 HL115521 NHLBI NIH HHS

Tissue engineering has emerged as a promising alternative for small-diameter vascular grafts. The aim of this study was to determine the feasibility of using decellularized aortae of fetal pigs (DAFPs) to construct tissue-engineered, small-diameter vascular grafts and to test the performance and application of DAFPs as vascular tissue-engineered scaffolds in the canine arterial system.

DAFPs were prepared by continuous enzymatic digestion. Canine vascular endothelial cells (ECs) were seeded onto DAFPs in vitro and then the vascular grafts were cultured in a custom-designed vascular bioreactor system for 7 days of dynamic culture following 3 days of static culture. The grafts were then transplanted into the common carotid artery of the same seven dogs from which ECs had been derived (two grafts were prepared for each dog with one as a backup; therefore, a total of 14 tissue-engineered blood vessels were prepared). At 1, 3, and 6 months post-transplantation, ultrasonography and contrast-enhanced computed tomography (CT) were used to check the patency of the grafts. Additionally, vascular grafts were sampled for histological and electron microscopic examination.

Tissue-engineered, small-diameter vascular grafts can be successfully constructed using DAFPs and canine vascular ECs. Ultrasonographic and CT test results confirmed that implanted vascular grafts displayed good patency with no obvious thrombi. Six months after implantation, the grafts had been remodeled and exhibited a similar structure to normal arteries. Immunohistochemical staining showed that cells had evenly infiltrated the tunica media and were identified as muscular fibroblasts. Scanning electron microscopy showed that the graft possessed a complete cell layer, and the internal cells of the graft were confirmed to be ECs by transmission electron microscopy.

Tissue-engineered, small-diameter vascular grafts constructed using DAFPs and canine vascular ECs can be successfully transplanted to replace the canine common carotid artery. This investigation potentially paves the way for solving a problem of considerable clinical need, i.e., the requirement for small-diameter vascular grafts.

• Decellularized aortae of fetal pigs
• Scaffold
• Tissue-engineered small-diameter vascular grafts
• Vascular endothelial cells

• Biomaterial scaffolds
• Cellular microenvironment
• Differentiation
• Mesenchymal stromal cells
• Signalling mechanisms
• Vascular smooth muscle cells