Vascular Regenerative Surgery: Promised Land for Tissue Engineers?

Cardiovascular cell therapy

Cardiovascular Cell Therapy is a promising new field for the development of treatments for cardiovascular diseases, which remain a major cause of mortality around the world. In this review, we highlight the options currently available for the development of specific cell therapy approaches applied to regeneration of cardiac and vascular tissues. Different cell types have attracted a lot of attention and extensive investigations for the treatment of vascular diseases, including embryonic stem cells, mesenchymal stem cells, induced pluripotent stem cells, and endothelial progenitors. The combination of human cells and increasingly safe and physiologically compliant biomaterials is currently offering an unprecedented opportunity to develop effective cell therapy for either major blood vessels or the microvasculature. Efficacy and safety of cell therapy are the challenges for the new generation of regenerative medicine scientists determined to develop new remedies for cardiovascular diseases. Here we present the state of the art in this biomedical field and the options in terms of cell types and biomaterials currently available for cardiovascular cell therapy.

Tissue engineering

The tissue engineering field has exponentially grown over the last decade and has progressively moved from being exclusively a lab-bench discipline to an emerging part of today’s medical care. It has largely evolved from the pre-existing field of biomaterials and consists of the de novo engineering of tissues and organs by combining scaffolds, cells and biological molecules, often drawing cues from the most up-to-date knowledge in developmental biology. Although this field is focused mainly on replacing damaged or lost tissues, it is often somewhat misnamed with the term “regenerative medicine”, which has a broader meaning. The latter encompasses research on self-healing – where the emphasis is rather placed on inducing the healing of a target tissue by potentiating the body’s own ability to regenerate, through the delivery of biologically active agents, such as nucleic acids or proteins. In addition, tissue engineering has revolutionized the study of human diseases and drug toxicity by supporting the development of three-dimensional in vitro models that can mimic far more realistically tissue-and organ-level structures and functions that are at the root of disease. While our complex immune system performs remarkably well at keeping us safe from disease, its inherent ability to protect us from any foreign agent is also the main reason why the replacement of body tissues and organs is so challenging. Although surgical techniques for transplanting organs have improved tremendously, it is simply not possible to cope with the overwhelming demand for tissues and organs by retrieving them from volunteer donors. Moreover, even in cases where a suitable donor is found and an organ is successfully transplanted, the therapeutic efficacy is only partial and temporary. The most important limitation is that the immune response against the implanted organ requires permanent immunosuppression and thus ensures a lifelong struggle against immune rejection. Hence, tissue engineering aims at overcoming these hurdles by creating new tissues or organs from the cells of the same patient who receives the treatment. This would eliminate the necessity of either finding a compatible donor or using immunosuppressant drugs. There are four important factors that need to be considered in order to successfully engineer a tissue in vitro: an appropriate cell population, a scaffold that can support the cells, the right biomolecules (such as growth factors), and physical and mechanical stimuli to influence the proper development of the construct into the target tissue. Engineering such tissue surrogates at a scale that is clinically relevant bring about a major challenge: the diffusion of oxygen, nutrients, and waste products. In the human body, most cells are found within 100-200μm from the nearest capillary, which allows for that exchange to happen, and in the lab, this can be simulated - or at least compensated for - through the use of perfusion bioreactors. Without its own vascular network, any areas of a construct that are beyond this diffusional limit will not be sufficiently oxygenated, resulting in cell death and, most likely, overall scaffold failure soon after implantation. Therefore, the engineering of artificial blood vessels and capillary networks is not only a major area of interest within the field, but it is also one on which the future success of the whole tissue engineering endeavor depends.

Cell Sources for Vascular Tissue Engineering

The basic strategy for cell-based vascular tissue engineering is described in Figure 1 and consists of 3 fundamental steps: cell isolation, in vitro amplification and implantation. Each tissue engineering strategy faces its own specific challenges and considerations with regards to the choice of cells, but a number of these are common to all, independent of the target tissue. Firstly, it must be feasible to either directly obtain the required number of cells or devise a method of inducing the proliferation of the starting population to expand these to the necessary numbers, either in vitro or in situ. Next, these cells should be as easy to isolate as possible. In this context, applications based on cells originating from peripheral blood or from relatively non-vital superficial tissues (e.g. skin or adipose tissue) are more likely to be translated to the clinic than those created with cells that require more complicated surgical interventions (e.g. bone marrow or vascular tissue). Cells also need to possess the correct phenotype, or be able to permanently differentiate into it, in order to perform the desired cellular functions such as ECM deposition, cytokine release, etc. Other requirements may include the ability of these cells to integrate in a seamless manner with native cells and tissue, as well as to connect with the existent neural and/or vascular networks. Lastly, cells should be amenable to the chosen delivery method. For example, endothelial cells (ECs) must be delivered using a material that is permissive to their adhesion via surface integrins as their survival is known to be intimately linked to this process. Depending on the nature of the approach and its specifications, a number of different sources of cells can be used for the engineering of vascular tissues. Most patients with vascular disorders are elderly, thus mature vascular cells from these patients are not suitable for tissue engineering. As an example, smooth muscle cells (SMCs) isolated from the walls of blood vessels have been shown to suffer from aging-associated cellular changes, such as decreased proliferation and collagen synthesis.

Embryonic stem cells

Embryonic stem cells are derived from the inner cell mass of the pre-implantation blastocyst and are capable of differentiation into all mature cell types. In addition to their pluripotency, ESCs can also replicate indefinitely while in their undifferentiated state, mainly due to their high telomerase activity. Originally, ES cell lines were derived by co-culture on growth arrested mouse embryonic fibroblasts, but more recently they have also been derived under Good Manufacturing Practice (GMP) conditions using human fibroblasts or amnion epithelial cells while avoiding the use of animal products in the culture medium, reducing the risk of animal-borne disease transmission and improving their clinical applicability. Several groups have managed to differentiate human ECSs into ECs, with various degrees of success, and demonstrate their ability to form capillary networks in vivo using murine ischemic hindlimb models. The differentiation of ESCs has also been guided towards an SMC phenotype, which could be valuable for the in vitro generation of arterial vessels. Although ESCs constitute a suitable cell source for in vitro disease and drug toxicity modeling and also provide useful insights into the de novo formation of blood vessels (i.e. vasculogenesis), their clinical use is severally hampered by ethical issues that arise from the necessary destruction of human embryos. In addition, another major hurdle has been the potential for teratoma formation as a result of administering patients with pluripotent cells. However, in recent reports of long-term patients, no adverse effects of this nature were shown, despite the immunosuppressant regimen that they were on. Crucially, just like with transplanted organs, ESCs need to be matched to individual patients to avoid immune rejection, thus their future application in the engineering of organs and tissues is dependent on the creation of vast stem cell banks.

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