Tissue‐engineered vascular grafts form neovessels that arise from regeneration of the adjacent blood vessel

Abstract

We developed a tissue-engineered vascular graft composed of biodegradable scaffold seeded with autologous bone marrow-derived mononuclear cells (BMMCs) that is currently in clinical trial and developed analogous mouse models to study mechanisms of neovessel formation. We previously reported that seeded human BMMCs were rapidly lost after implantation into immunodeficient mice as host macrophages invaded the graft. As a consequence, the resulting neovessel was entirely of host cell origin. Here, we investigate the source of neotissue cells in syngeneic BMMC-seeded grafts, implanted into immunocompetent mouse recipients. We again find that seeded BMMCs are lost, declining to 0.02% at 14 d, concomitant with host macrophage invasion. In addition, we demonstrate using sex-mismatched chimeric hosts that bone marrow is not a significant source of endothelial or smooth muscle cells that comprise the neovessel. Furthermore, using composite grafts formed from seeded scaffold anastomosed to sex-mismatched natural vessel segments, we demonstrate that the adjacent vessel wall is the principal source of these endothelial and smooth muscle cells, forming 93% of proximal neotissue. These findings have important implications regarding fundamental mechanisms underlying neotissue formation; in this setting, the tissue-engineered construct functions by mobilizing the body's innate healing capabilities to "regenerate" neotissue from preexisting committed tissue cells.

Hemodynamic Characterization of a Mouse Model for Investigating the Cellular and Molecular Mechanisms of Neotissue Formation in Tissue-Engineered Heart Valves

“…20,24,25 In our study, we observed fewer a-SMA-positive cells in explanted 6-month grafts compared with 3-month grafts, suggesting physiological and not pathological remodeling in our model. In tissue-engineered vascular graft constructs, our group showed that neovessel regenerates from adjacent host blood vessels and is independent of seeded cells, 26,27 a mechanism we believe may be applicable to our current findings. Alternatively, it is possible that the transplanted dPV loses viability over time; however, further work is required to delineate the origin and fate of infiltrating host cells in TEHV recipients.…”

Beyond Burst Pressure: Initial Evaluation of the Natural History of the Biaxial Mechanical Properties of Tissue-Engineered Vascular Grafts in the Venous Circulation Using a Murine Model

“…We discovered that the vascular neotissue formation is driven by migration of the host endothelial cells and smooth muscle cells (SMCs) from the neighboring blood vessel wall through an immune-mediated process orchestrated by the seeded cells using a paracrine mechanism. 9,10 So far, our studies have focused mainly on the cellular processes involved in vascular neotissue formation, less on formation of the extracellular matrix (ECM) and the associated biomechanical factors. [7][8][9][10] There is a growing literature highlighting the importance of mechanobiological principles on vascular physiology and pathophysiology.…”

“…9,10 So far, our studies have focused mainly on the cellular processes involved in vascular neotissue formation, less on formation of the extracellular matrix (ECM) and the associated biomechanical factors. [7][8][9][10] There is a growing literature highlighting the importance of mechanobiological principles on vascular physiology and pathophysiology. [11][12][13][14][15] For example, compliance mismatch between a vascular graft and the native vessel into which it is implanted has been demonstrated to be a critical factor, leading at times to the formation of neointimal hyperplasia and stenosis.…”

Differentiation and Application of Induced Pluripotent Stem Cell–Derived Vascular Smooth Muscle Cells

“…85 The iPS cell sheets containing both endothelial cells and VSMCs were seeded onto a biodegradable scaffold and implanted onto the infrarenal inferior vena cava of immunodeficient mice. Ultrasonography analysis revealed that grafts persisted after by guest on May 9, 2018 http://atvb.ahajournals.org/ Downloaded from 10 weeks; however, a significant drop in iPSC number was observed on histological examination, suggesting a decline in cell survival over time.…”