Tissue Engineered Vascular Graft Recipient Interleukin 10 Status Is Critical for Preventing Thrombosis

Abstract

Tissue engineered vascular grafts (TEVGs) are a promising technology, but are hindered by occlusion. Seeding with bone‐marrow derived mononuclear cells (BM‐MNCs) mitigates occlusion, yet the precise mechanism remains unclear. Seeded cells disappear quickly and potentially mediate an anti‐inflammatory effect through paracrine signaling. Here, a series of reciprocal genetic TEVG implantations plus recombinant protein treatment is reported to investigate what role interleukin‐10, an anti‐inflammatory cytokine, plays from both host and seeded cells. TEVGs seeded with BM‐MNCs from wild‐type and IL‐10 KO mice, plus unseeded grafts, are implanted into wild‐type and IL‐10 KO mice. Wild‐type mice with unseeded grafts also receive recombinant IL‐10. Serial ultrasound evaluates occlusion and TEVGs are harvested at 14 d for immunohistochemical analysis. TEVGs in IL‐10 KO mice have significantly higher occlusion incidence compared to wild‐type mice attributed to acute (<3 d) thrombosis. Cell seeding rescues TEVGs in IL‐10 KO mice comparable to wild‐type patency. IL‐10 from the host and seeded cells do not significantly influence graft inflammation and macrophage phenotype, yet IL‐10 treatment shows interesting biologic effects including decreasing cell proliferation and increasing M2 macrophage polarization. IL‐10 from the host is critical for preventing TEVG thrombosis and seeded BM‐MNCs exert a significant anti‐thrombotic effect in IL‐10 KO mice.

Recombinant DTβ4-inspired porous 3D vascular graft enhanced antithrombogenicity and recruited circulating CD93 + /CD34 + cells for endothelialization

“…The highly porous, fast-degrading elastomer may recruit a sufficient number of vascular cells to assemble neoartery ( 4 ). Functionalizing bioresorbable grafts through conjugating growth factors such as vascular endothelial growth factor (VEGF) ( 5 ) or seeding bone marrow cells were expanding the success in regenerating small-caliber blood vessels in animals ( 6 ). In addition to the application of tissue engineering vascular grafts for hemodialysis access, encouraging results in Fontan operation were also reported in clinical trials ( 7 ).…”

Bioengineering and Biotechnology Approaches in Cardiovascular Regenerative Medicine, Volume II

“…Similarly, endothelial progenitor cells have been used to seed TEVG (Melchiorri et al, 2016;Muniswami et al, 2020;Tamma et al, 2020), but their high heterogeneity and rare presence could complicate the translation process (Munisso and Yamaoka, 2020). Mesenchymal stem cell (MSC), a type of progenitor cell with the potential of generating various vascular cell types (Gong and Niklason, 2008), lacks major histocompatibility complexes or other immune-stimulatory molecules while secreting anti-thrombotic and anti-inflammatory molecules, such as IL-10 (Fukunishi et al, 2018;Mirhaidari et al, 2020), and TGF-β receptor 1 . These characteristics make MSC an excellent allogeneic cell candidate for the TEVG production Afra and Matin, 2020).…”

“…Although early proposed applications focused on direct injections (Menasché et al, 2001;Laflamme et al, 2007;Sanganalmath and Bolli, 2013; and the transplantation of engineered cardiac tissues (Schaefer et al, 2017;Shadrin et al, 2017; and sheets (Ishigami et al, 2018;Bayrak and Gümüşderelioğlu, 2019;Tsuruyama et al, 2019) to resupply cardiomyocytes, lost to injuries such as myocardial infarction (MI), the uses of these cardiac surrogates have expanded to include in-vitro modeling of myocardial disease (Long et al, 2018;Giacomelli et al, 2021), drug screening (Mathur et al, 2015;Huebsch et al, 2016;Mills et al, 2017), and exosome production . A wide range of formats has been explored to fulfill the needs of each potential application including patches (Schaefer et al, 2017;Shadrin et al, 2017;, sheets (Ishigami et al, 2018;Bayrak and Gümüşderelioğlu, 2019;Tsuruyama et al, 2019), spheres (Fischer et al, 2018;Chang et al, 2020), wires (Jackman et al, 2016;, and decellularized tissues (Das et al, 2019;Alexanian et al, 2020;Hochman-Mendez et al, 2020). The utilization of these products and the needs of each use play a key role in the ideal option for each situation.…”

“…Another method to increase complexity and functionality of cardiac tissue models is to use additional cell types that more accurately recreate the myocardial environment. When cultured in a three-dimensional (3D) environment, rather than as two-dimensional monolayers, CMs coalesce into spheroids (Fischer et al, 2018;Chang et al, 2020) and tend to develop a more mature phenotype (Jha et al, 2016;Sacchetto et al, 2020;Kai-Li Wang et al, 2021). ECs and SMCs also promote CM maturation (Pinto et al, 2016;Ayoubi et al, 2017;Kwong et al, 2019) while facilitating oxygen and nutrient delivery, which improves cell survival (Garzoni et al, 2009;Zhang et al, 2021a;Pretorius et al, 2021), and CFs contribute to myocardial development both by producing components of the extracellular matrix (ECM) and by forming gap junctions with CMs to support electronic signal transduction Beauchamp et al, 2020;Giacomelli et al, 2020;Li et al, 2020;Pretorius et al, 2021).…”

Strategies to counteract adverse remodeling of vascular graft: A 3D view of current graft innovations

“…Similarly, endothelial progenitor cells have been used to seed TEVG ( Melchiorri et al, 2016 ; Muniswami et al, 2020 ; Tamma et al, 2020 ), but their high heterogeneity and rare presence could complicate the translation process ( Munisso and Yamaoka, 2020 ). Mesenchymal stem cell (MSC), a type of progenitor cell with the potential of generating various vascular cell types ( Gong and Niklason, 2008 ), lacks major histocompatibility complexes or other immune-stimulatory molecules while secreting anti-thrombotic and anti-inflammatory molecules, such as IL-10 ( Fukunishi et al, 2018 ; Mirhaidari et al, 2020 ), and TGF-β receptor 1 ( Lee et al, 2016 ). These characteristics make MSC an excellent allogeneic cell candidate for the TEVG production ( Wang et al, 2016 ; Afra and Matin, 2020 ).…”