First Evidence That Bone Marrow Cells Contribute to the Construction of Tissue-Engineered Vascular Autografts In Vivo

Abstract

Background-Materials commonly used to repair complex cardiac defects lack growth potential and have other unwanted side effects. We designed and tested a bone marrow cell (BMC)-seeded biodegradable scaffold that avoids these problems. Methods and Results-To demonstrate the contribution of the BMCs to histogenesis, we labeled them with green fluorescence, seeded them onto scaffolds, and implanted them in the inferior vena cava of dogs. The implanted grafts were analyzed immunohistochemically at 3 hours and subsequently at 2, 4, and 8 weeks after implantation using antibodies against endothelial cell lineage markers, endothelium, and smooth muscle cells. There was no stenosis or obstruction caused by the tissue-engineered vascular autografts (TEVAs) implanted into the dogs. Immunohistochemically, the seeded BMCs expressing endothelial cell lineage markers, such as CD34, CD31, Flk-1, and Tie-2, adhered to the scaffold. This was followed by proliferation and differentiation, resulting in expression of endothelial cells markers, such as CD146, factor VIII, and CD31, and smooth muscle cell markers, such as ␣-smooth muscle cell actin, SMemb, SM1, and SM2. Vascular endothelial growth factor and angiopoietin-1 were also produced by cells in TEVAs. Conclusions-These results provide direct evidence that the use of BMCs enables the establishment of TEVAs. These TEVAs are useful for cardiovascular surgery in humans and especially in children, who require biocompatible materials with growth potential, which might reduce the instance of complications caused by incompatible materials and lead to a reduced likelihood of further surgery.

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

“…Early reports of transdifferentiation may be attributable to misinterpretations of cell fusion (26)(27)(28)(29). It is possible that cell fusion may also explain results of prior TEVG studies, which used fluorescent membrane labeling techniques to track seeded BMCs (10). As determined in this study, monocytes/macrophages are the predominant cellular infiltrate in TEVGs, and they are very adept at phagocytosis and cell fusion.…”

“…Additionally, our chimeric hBMC-SCID/bg mouse model enabled us to validate our immunohistochemical findings further with species-specific quantitative RT-PCR (Fig. 2I), a method that could not be used in prior studies, which employed autologous BMC sources (4,9,10).…”

“…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.…”

Response of mesenchymal stem cells to shear stress in tissue-engineered vascular grafts

“…Sutherland et al [6] successfully constructed heart valves using mesenchymal stem cells (MSCs) and biodegradable scaffolds. Among the stem cells used in cardiovascular tissue engineering, MSCs seem to be an ideal cell source because they can differentiate into SMCs and ECs in vitro [7,8] and in vivo [6,9] and can be expanded by several million-fold in culture. MSCs harvested from patients' bone marrow do not have the problem of immune rejection, unlike embryonic stem cells.…”

Tissue Engineering, Stem Cells, and Cloning

“…However, these materials typically lack growth potential and may place the recipient at risk for complications such as stenosis, thromboembolization, or infection (120).…”