Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling

Abstract

Biodegradable scaffolds seeded with bone marrow mononuclear cells (BMCs) are the earliest tissue-engineered vascular grafts (TEVGs) to be used clinically. These TEVGs transform into living blood vessels in vivo, with an endothelial cell (EC) lining invested by smooth muscle cells (SMCs); however, the process by which this occurs is unclear. To test if the seeded BMCs differentiate into the mature vascular cells of the neovessel, we implanted an immunodeficient mouse recipient with human BMC (hBMC)-seeded scaffolds. As in humans, TEVGs implanted in a mouse host as venous interposition grafts gradually transformed into living blood vessels over a 6-month time course. Seeded hBMCs, however, were no longer detectable within a few days of implantation. Instead, scaffolds were initially repopulated by mouse monocytes and subsequently repopulated by mouse SMCs and ECs. Seeded BMCs secreted significant amounts of monocyte chemoattractant protein-1 and increased early monocyte recruitment. These findings suggest TEVGs transform into functional neovessels via an inflammatory process of vascular remodeling.bone marrow | monocyte chemoattractant protein-1 | tissue engineering | neovascularization C ongenital heart disease is a leading cause of infant mortality, often requiring early surgical intervention to correct fatal cardiovascular malformations. Prosthetic vascular grafts are widely used in these reconstructive operations, but revisions are often necessary because of their inability to grow or effectively remodel within a growing child (1-3). A strategy to address this issue is the use of living tissue-engineered vascular grafts (TEVGs). Constructed from biodegradable polyester tubes seeded with autologous bone marrow mononuclear cells (BMCs), these grafts undergo extensive remodeling in animal recipients and appear to transform into living blood vessels, similar in morphology and function to the native veins into which they are interposed (4, 5). Ongoing clinical studies evaluating BMC-seeded grafts as venous conduits for congenital heart surgery report excellent safety profiles and 100% patency rates at 1-3 years of follow-up (6-8). Additionally, these grafts demonstrate growth potential, suggesting they may be more effective for the pediatric patient population than currently available vascular grafts (8,9).Although the functional efficacy and clinical utility of TEVGs are promising, little is known about how these BMC-seeded polyester tubes transform into living blood vessels in host recipients. It has been proposed that stem cells within the seeded BMC population differentiate into the endothelial cells (ECs) and smooth muscle cells (SMCs) of the developing neovessel, ultimately replacing the degrading polyester tube (10). This hypothesis, however, has not been directly examined.We recently developed a method for constructing small-diameter biodegradable synthetic scaffolds suitable for use as vascular grafts in mice (11). These tubular scaffolds are composed of the same materials and design used in clinical TEVGs...

Polymer-Based Reconstruction of the Inferior Vena Cava in Rat: Stem Cells or RGD Peptide?

“…No significant differences were found between RGD and ADSC in terms of vascular remodeling, neovessel formation, inflammatory cell response, and cytokine secretion. This result is consistent with that reported by Roh et al 17 who showed, in a murine model of infrarenal IVC replacement, that the restorative patterns observed after implantation of a human bone marrow mononuclear cell-seeded polymer could be duplicated by replacing cells with MCP-1 grafting on the scaffold. We acknowledge, however, that in the absence of covalent binding, the PDO can dissolve from the surface of the polymer with the possibility that its soluble form may, at the opposite of our objective, act as an integrin blocker preventing cell adhesion.…”

“…Another important finding from the previous work of our laboratory and others 12,[16][17][18] is that polymer-seeded cells are cleared over time, which leads to speculate that the grafted cells do not structurally integrate within the neovessel wall, but rather act as platforms releasing signalling molecules that may recruit host cells. This hypothesis provides a robust rationale for testing whether cells can, thus, be replaced by biomimetic compounds, which could duplicate their recruiting effects and promote self-healing.…”

“…Indeed, the use of different bioactive peptides as substitutes for cell therapy has been successfully tested in cardiac regeneration and other specialties. 17,[39][40][41][42] In the present study, we selected RGD, a tripeptide composed of arginine-glycine-aspartate that mimics the integrin-binding site of cells and the extracellular matrix 43 and has already been successfully tested as a biofunctionalization motif. 44 Grafting of RGD on a polymer was compared, again in a head-to-head fashion, with ADSC selected because of their ease of procurement, richness of their secretome, and potential for human applications.…”

“…First, a head-to-head comparison was performed between a PDO (taken as our reference) and two other polymers, polyhydroxyalkanoate (PHA) and polyurethane (PU), which have already been used in cardiovascular research with encouraging results in terms of endothelialization and biocompatibility. 10,11,[13][14][15] In the second step, we leveraged previous findings from our laboratory 12 and others [16][17][18] showing that cells seeded onto polymers implanted in the circulation are rapidly cleared and compared two functionalization modalities of the polymer patch based on cell seeding and peptide grafting, respectively. To this end, we selected adipose-derived stem cells (ADSCs) and the tripeptide arginine-glycine-aspartate (RGD) with the premise that this motif, which has a long-standing efficacy record in biomaterial functionalization, 19,20 might allow scaffold repopulation from the host cells.…”

Tissue engineering on matrix: future of autologous tissue replacement

“…This mechanism has, in part, been attributed to the critical role of VEGF in adult neovascularization, and prevention of neovessel regression [95][96][97]. Indeed, monocyte/macrophage infiltration associates with VEGF expression with the tissue-engineered constructs [98]. In addition to VEGF, recruited monocytes likely release multiple cytokines, which then orchestrate the proper vascular neovascularization of biodegradable implants.…”