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outcome of this thesis

The ability to restore vascular perfusion at sites of ischemic damage is essential for tissue regeneration [362]. However, current therapies aimed to restore vascular perfusion are only successful when the large-diameter blood vessels (internal diameter (ID) > 6 mm) are affected [66;363]. Hence, novel therapies such as tissue engineering of ‘designer’ blood vessels and (stem) cell therapy for therapeutic neovascularization are warranted. In this thesis we have investigated the cellular plasticity of endothelial progenitor cells (EPC) and explored its applicability for vascular regenerative medicine. In part I, we have found that human EPC contain the intrinsic capacity to differentiate into both mature and functional endothelial cells (EC) and smooth muscle cells (SMC) on degradable biomaterials. These EC and SMC can be employed to tissue engineer bioartificial autologous small-diameter blood vessels (Figure 1A). Furthermore, in part II, we have identified a paracrine function of EPC during (therapeutic) neovascularization by the secretion of pro-angiogenic growth factors and cytokines (Figure 1B).

Thus, the EPC offers enormous potential for tissue engineering of ‘designer’ blood vessels as well as in (stem) cell therapy. Hence, in future perspective, EPC-based therapies will enable true tissue regeneration therapies and pose great possibilities for autologous therapies. In this chapter we will discuss the cellular plasticity of EPC and how that can be used to alleviate the pitfalls of current (cardio)vascular therapies. Also, we discuss future challenges for vascular regenerative medicine that originate from this thesis.

current (cardio)Vascular therapies

Ischemic cardiovascular diseases are the main cause of death globally (www.who.org). In 2005, an estimated 44 000 people died of ischemic cardiovascular diseases in the Netherlands alone, representing approximately 32% of all annual deaths [1]. Although current treatments focus on the restoration of vascular perfusion of the large-diameter blood vessels, e.g. by bypass surgery or angioplasty, these treatments cannot be used to restore perfusion by the small-diameter blood vessels and microvasculature. Clinically used synthetic replacement vessels, such as pFTE, are thrombogenic and cause blood clotting in the low-flow conditions of the small-diameter blood vessels [364;365]. Considerable research efforts are being made to develop synthetic graft materials with favorable blood compatibility, however, at present no true anti-thrombogenic material has been produced [364].

If the microvasculature is affected, vascular perfusion can be induced by different therapies. Ischemic episodes, resulting from decreased perfusion in the myocardial or peripheral tissues, evoke the formation of neovessels from the preexisting vascular branches by a process termed angiogenesis [4]. Yet, in adults suffering from vascular disease, the natural processes of neovascularization may be dysfunctional and insufficient to restore tissue vascularization. Animal studies and clinical trials are focused on the in vivo induction of human EPC-mediated microvessel formation through the delivery of pro-angiogenic factors like VEGFa, bFGF or HGF. Administration of these factors occurs either through bolus injection, from drug-release platforms or by gene

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therapy [366]. Although such pro-angiogenic therapies have shown promising results, bolus administration of pro-angiogenic factors is hampered by its temporal nature, while sustained-release of single factors is insufficient to support both the formation and sustainability of the microvessels. Hence, the in vivo administration of the cells that augment microvessel formation, i.e. the autologous EPC, may prove a better therapeutic option.

Thus, there is a great clinical need for therapies that result in the generation of, on the one hand anti-thrombogenic replacement vessels for bypass surgery based on autologous progenitor cells, and on the other hand progenitor cell therapies that aid the natural processes of microvessel formation in ischemic tissues; such therapies concern the tissue engineering of ‘designer blood vessels’ (part I) and therapeutic neovascularization through (stem) cell therapy (part II).

part i: engineering ‘designer’ Blood Vessels

Vascular tissue engineering utilizes a multidisciplinary approach to generate autologous bioartificial small-diameter replacement vessel for the restoration of vascular perfusion. Principally, a tissue engineered blood vessel resembles its native counterpart and must be able to withstand physiological pressure changes. Hence, degradable biomaterials are under study as temporal scaffold that provides the tissue engineered conduit with initial mechanical strength, and favors the attachment of cells. In theory, after implantation, (seeded) cells start to produce their native extracellular matrix (ECM) while degrading the biomaterial. Thus, the bioartificial vessel is remodeled in vivo into a fully functional native vessel over time.

EPC hold great promise for vascular tissue engineering. EPC are immature cells present in the bone marrow and peripheral blood that can differentiate into mature and functional endothelial cells (EC) for tissue engineering purposes [46]. In this thesis, we have shown that human EPC can be easily obtained from peripheral blood and in vitro differentiated into mature and functional EC by use of several pro-angiogenic factors, i.e. bFGF, VEGFa, HGF and IGF-1. Moreover, EPC differentiation into functional EC can be achieved on various degradable biomaterials (chapter 2), thus providing proof-of-principle for autologous vascular tissue engineering.

Since EC have intrinsic anti-thrombogenic properties [364], endothelializing biomaterials may prevent thrombus formation on the biomaterial upon blood contact. However, in current vascular tissue engineering approaches, the limited lifespan of these mature EC, causes cell death and detachment of the EC resulting contact between the thrombogenic material and the blood which subsequently forms blood clots [367]. In this thesis we have shown that human EPC exert longevity and self-renewal potency (chapter 5). An EPC-based tissue engineered small-diameter vessel may thus self-repair when damaged and may alleviate current challenges in EC retention.

A small-diameter blood vessel not only comprises a structural component and anti-thrombogenic EC, but also needs smooth muscle cells (SMC) providing mechanical strength and extracellular matrix (ECM) -forming ability. Since the EC and SMC share a common origin during embryogenesis [159], we have hypothesized that EPC retain the cellular plasticity to transdifferentiate into functional SMC through endothelial-

1. CVD Patient

2. Isolation of Circulating EPC

3a. Culture of Endothelial Outgrowth Cells

4a. Differentiation of EC and SMC

5a. Cell Seeding on Degradable Biomaterial

6a. Restoration of Vascular Perfusion by Implantation as Bypass Graft

4b. Induction of Sprouting Angiogenesis through Paracrine Signaling

5b. Relief of Tissue Ischemia by Improved Microvascular Density

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Myocardial infarction

Neovascularization in vivo

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Figure 1. Endothelial cell plasticity in vascular regenerative medicine. Circulating EPC have the plasticity to differentiate into EC and SMC. These specialized cells are seeded onto a degradable tubular biomaterial in order to generate a tissue engineered bypass graft (A). Another feature of EPC plasticity is the secretion of pro-angiogenic factors. In response to tissue ischemia, human EPC start to produce and secrete pro-angiogenic cytokines and growth factors which induce sprouting angiogenesis by the surrounding endothelium, relieving the ischemia.

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and may even aid in the induction of new microvessel formation. Hence, cell therapy for neovascularization poses a highly interesting treatment option for diseases wherein the microvasculature is affected [46].

However, discrepancy between improved vascular perfusion (induction of microvessel formation) and actual engraftment of human EPC into the neovasculature has raised controversy on the mechanisms of action of these EPC after implantation [65;274]. We and others therefore hypothesized that EPC contain an additional level of plasticity, that is the secretion of pro-angiogenic factors that favor spouting angiogenesis by the surrounding endothelium (chapter 8)[263;368].

The human peripheral blood contains two distinct types of EPC, which can be discriminated based on expression of either CD14 or CD34 [62]. In this thesis, we have investigated the relative capacity of these two EPC-types to EC differentiation in vitro (chapter 7) and on in vivo neovascularization (chapter 8). In vitro, the CD34+ EPC produces high amounts of the pro-angiogenic growth factors VEGFa, bFGF and HGF. These factors subsequently induced EC differentiation of CD14+ EPC in a paracrine fashion.

We contemplated that the interaction between CD34+ and CD14+ EPC would thus lead to increased neovascularization in vivo and incorporation of the CD14+ EPC into the neovessels. Although we were able to show that combined administration of CD34+ and CD14+ EPC indeed amplifies the paracrine signaling events, we did not find engraftment of human EPC into the neovessels in nude mice (chapter 8). Therefore, we concluded that neovascularization was solely derived from mouse EC lining the vessels, initiated by pro-angiogenic signals secreted by administered human EPC. Hence, clinical administration of these factors, i.e. IL-8, MCP-1, bFGF, HGF and VEGFa, from slow-release depots may replace human EPC administration and holds promise in the treatment of ischemic diseases by the induction of microvessel formation.

On the other hand, it may be possible that engraftment of human EPC into the neovasculature depends not on the functional capacity of EPC, but rather by the stimulus provided. In this respect, Popa et al. have described that the efficacy of EPC-induced neovascularization is not generally warranted, but dependable on the molecular microenvironment [169]. Their data indicate that in a pro-angiogenic and hypoxic environment EPC engraft into the neovasculature, while in a pro-inflammatory environment no engraftment was observed. Controversially, sprouting angiogenesis was present in both models to a similar extent. Thus, human EPC react to their molecular environment and change it accordingly. In a ‘friendly’ pro-arteriogenic microenvironment (e.g. limb ischemia) EPC are actively involved in neovessels formation, while in a ‘hostile’ inflammatory environment EPC secrete pro-angiogenic factors in order to change the environment and induce neovascularization. Hence, human EPC engraftment can be found in animal models for arteriogenesis [61], while it is absent in models for angiogenesis [274].

Taken together, in this thesis we have shown that human EPC have the ability for sense their ischemic environment and secrete pro-angiogenic factors, i.e. IL-8, MCP-1, bFGF, HGF and VEGFa, which induce the formation microvessels and result in diminishment of ischemia (Figure 1B). Hence, the clinical administration of pro-angiogenic factors from slow-release depots may pose an interesting treatment option that aids the body to regenerate itself.

to-mesenchymal transdifferentiation (EnMT). Indeed, in chapters 4 and 5 we showed that SMC can be derived from circulating human EPC. EnMT by these EPC could be evoked in degradable biomaterials and thus used for future small-diameter vascular tissue engineering. Hence, we have generated a new tissue engineering paradigm that utilizes a single human progenitor cell type for the generation of both EC and SMC (chapter 6).

Although the differentiation of EC and SMC from a single human progenitor cell type on degradable biomaterials is a huge step towards the generation of a viable long-lasting blood vessel replacement, it is merely one step in vascular tissue engineering.

One of the challenges that need to be addressed in an interdisciplinary approach is the biofunctionalization of the degradable biomaterials. Since, the differentiation of EC and SMC from EPC is guided by external factors, such as ECM components and growth factors, these molecular clues need to be incorporated into biomaterials such that differentiation is dictated by these materials and maintained in vivo. Although biomaterials research has focused on the incorporation of some of these molecular clues, a biomaterial capable of presenting multiple clues simultaneously still needs to be developed (chapter 6). Hence, future research should focus more on the integration of the biological principles described in this thesis into the biomaterials sciences.

A second challenge is to determine the influence of flow on the behavior and plasticity of human EPC. Physiologically, EPC need to function under site-specific fluid shear- and tensile stress exerted by the blood on the vessel wall. At present, most EPC differentiation and functional studies are performed in static cell cultures. While these cultures do provide insight into the molecular mechanisms behind EPC differentiation into EC and SMC, they do not mimic the physiological circumstances under which these cells need to function in vivo.

A third challenge will be to modulate the delicate balance between biomaterial degradation and the build-up of the cells natural ECM. Ideally, in vivo degradation of a biomaterial occurs at a similar rate as ECM deposition by the seeded and surrounding cells. Desynchronizing these processes would lead to changes in mechanical strength and possibly malfunction of the tissue engineered vascular construct.

Taken together, this thesis has added to the feasibility of small-diameter vascular tissue engineering by revealing that human EPC contain the cellular plasticity to form both EC and SMC on degradable biomaterials (Figure 1A). Hence the cellular components for tissue engineered ‘designer blood vessels’ can be derived out of one human progenitor cell type. Future challenges lie in the integration of these molecular clues into smart biomaterials and in exploring the behavior of engineered bioartificial small-diameter blood vessel in an in vivo environment. Only if the progenitor cell-based tissue engineered vessel can be fully remodeled into a native vessel in vivo, vascular tissue engineering can be utilized as true regeneration therapy.

part ii: therapeutic neoVasculariZation

Therapeutic neovascularization utilizes the endogenous angiogenic capacity of human EPC for the treatment of tissue ischemia. In theory, administration of the vessel-forming EPC improves the body’s capacity to repair the injured microvessels

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concluding remarks

In this thesis we showed that human EPC have the intrinsic capacity to differentiate into EC and SMC and are long-lived. This finding suggests that human autologous EPC may be used in vascular tissue engineering as source for both EC and SMC with inherent self-regenerating capacity (chapters 2, 4-6). Furthermore, we have shown that administered human EPC can sense their ischemic environment and induce microvessel formation by the secretion of pro-angiogenic factors that induce sprouting angiogenesis (chapters 7-9). The plasticity of human EPC, therefore, renders them a valuable tool for vascular regenerative medicine.

However, for future autologous application, the plasticity of patient-derived EPC needs to be addressed. In this thesis we have shown that patients with increased risk for cardiovascular disease also have numerical and functional impaired EPC (chapter 3). These limitations challenge the use of autologous EPC for vascular regenerative medicine. Hence, in future research it would be interesting to determine the molecular basis of EPC dysfunction in patients with vascular diseases.

appendices

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