Future Perspectives on the Role of Stem Cells and Extracellular Vesicles in Vascular Tissue Regeneration

Abstract

Vascular tissue engineering is an area of regenerative medicine that attempts to create functional replacement tissue for defective segments of the vascular network. One approach to vascular tissue engineering utilizes seeding of biodegradable tubular scaffolds with stem (and/or progenitor) cells wherein the seeded cells initiate scaffold remodeling and prevent thrombosis through paracrine signaling to endogenous cells. Stem cells have received an abundance of attention in recent literature regarding the mechanism of their paracrine therapeutic effect. However, very little of this mechanistic research has been performed under the aegis of vascular tissue engineering. Therefore, the scope of this review includes the current state of TEVGs generated using the incorporation of stem cells in biodegradable scaffolds and potential cell-free directions for TEVGs based on stem cell secreted products. The current generation of stem cell-seeded vascular scaffolds are based on the premise that cells should be obtained from an autologous source. However, the reduced regenerative capacity of stem cells from certain patient groups limits the therapeutic potential of an autologous approach. This limitation prompts the need to investigate allogeneic stem cells or stem cell secreted products as therapeutic bases for TEVGs. The role of stem cell derived products, particularly extracellular vesicles (EVs), in vascular tissue engineering is exciting due to their potential use as a cell-free therapeutic base. EVs offer many benefits as a therapeutic base for functionalizing vascular scaffolds such as cell specific targeting, physiological delivery of cargo to target cells, reduced immunogenicity, and stability under physiological conditions. However, a number of points must be addressed prior to the effective translation of TEVG technologies that incorporate stem cell derived EVs such as standardizing stem cell culture conditions, EV isolation, scaffold functionalization with EVs, and establishing the therapeutic benefit of this combination treatment.

Advances in Analysis of Biodistribution of Exosomes by Molecular Imaging

“…Especially, exosomes are widely accepted as next generation therapeutics due to the extensive investigation of potential applications [28,29]. As mentioned, the size ranges of exosomes and microvesicles overlap and it is difficult to differentially isolate these EVs according to their size [30][31][32]. Recently, an alternative term, small extracellular vesicles (sEVs), was proposed to refer to EVs with diameters smaller than 200 nm [21].…”

“…The absence of these proteins on the exosomal surface suggests no immune rejection can be expected for allogeneic therapeutics [32][33][34][35]. Exosomes derived from stem cells are actively being developed as a cell-free therapy because they recapitulate the functions of stem cells such as repair, regeneration, anti-inflation, and immune modulation without the limitations and risks of stem cells themselves [30,31,36,37]. As an example, exosomes derived from MSCs have therapeutic effects on various diseases including myocardial infarction [6,38], CCl4-induced liver injury [39], graft-versus-host disease (GvHD) [20], acute and chronic kidney injury [40], and atopic dermatitis [34,41].…”

Mesenchymal Stem Cells Reduce Corneal Fibrosis and Inflammation via Extracellular Vesicle-Mediated Delivery of miRNA

“…EVs fuse with remote cells delivering a cargo of protein and RNA that can modify the phenotype of the target cells [14,[20][21][22]. Involvement of EVs has been implicated in regenerative effects of MSCs in a wide variety of tissues including skin, muscle, neural tissues, lung, vascular tissue, bone, and cartilage [21,[23][24][25][26][27][28][29]. MicroRNA (miRNA) has been frequently cited as an important mediator of the biological effects of MSCsecreted EVs [1,23,24,30,31].…”

Exosomes From 3d Culture of Marrow Stem Cells Enhances Endothelial Cell Proliferation, Migration, and Angiogenesis via Activation of the Hmgb1/akt Pathway

“…Increasing evidence demonstrates that the therapeutic effect of BMSCs is not attributed to multi-lineage function but secreted exosomes, through which proteins, miRNAs and other molecular could be transferred to recipient cells (15,33,34).The 3D scaffolds have been proved to be a key material that modulates the paracrine function of cells (15). Haraszti et al have reported that 3D-exos show higher yield and improved activity than 2D-exos (35).…”