Elsevier

New Biotechnology

Volume 32, Issue 1, 25 January 2015, Pages 191-198
New Biotechnology

Research paper
Applications of nuclear reprogramming and directed differentiation in vascular regenerative medicine

https://doi.org/10.1016/j.nbt.2014.07.005Get rights and content

As vertebrates proceed through embryonic development the growing organism cannot survive on diffusion of oxygen and nutrients alone and establishment of vascular system is fundamental for embryonic development to proceed. Dysfunction of the vascular system in adults is at the heart of many disease states such as hypertension and atherosclerosis. In this review we will focus on attempts to generate the key cells of the vascular system, the endothelial and smooth muscle cells, using human embryonic stem cells (hESCs) and human induced pluripotent stem cells (iPSCs). Regardless of their origin, be it embryonic or via somatic cell reprogramming, pluripotent stem cells provide limitlessly self-renewing populations of material suitable for the generation of multi-lineage isogenic vascular cells-types that can be used as tools to study normal cell and tissue biology, model disease states and also as tools for drug screening and future cell therapies.

Introduction

The vascular system permeates every organ and tissue of the human body. Acting as the conduit delivering oxygen and nutrients around the body, it is also necessary to allow the translocation of various factors, signals and by-products. Blood vessels consist of endothelial cell (EC) networks, which are often associated with mural cells including smooth muscle cells (SMCs) and pericytes.

The vascular system is divided into arterial and venous portions, in which the vessel architecture and function are distinct. The arterial system carries oxygenated blood to target tissues. It has higher blood pressures and has a higher component of smooth muscle cells underlying the endothelium. The venous system, whose goal is to deliver the deoxygenated blood back to the heart, has developed valves to deal with pressure changes and veins tend to have a larger luminal area in cross section compared to arteries. In addition, the vascular branch has macro- and micro-vascular components, from large vessels such as the aorta to capillary networks in the peripheral regions.

Section snippets

Normal function and pathological aberrations of ECs

Endothelial cells line the innermost surface of blood and lymphatic vessels. Under normal conditions they form a mono-layered structure that provides a semi-selective yet dynamic barrier function between the lumen of the vessel and the surrounding tissues [1]. This permits the controlled passage of factors and cells, such as those of the immune system, from the blood or lymph into the tissue the vessel passes through. It is also responsible for regulating blood flow, vascular tone and vascular

The future: building vessels

In addition to the considerations raised earlier regarding the translation of pluripotent stem cell derived vascular cells to the clinic and for improved disease modelling and drug screening, we must also consider how we can use these cells to generate functional blood vessels for potential transplantation therapies. To do this we would firstly have to consider the heterogenicity of the vascular system to be sure of using the right combination of cell-types, and so it is clear that more work is

Conclusion

Both endothelial and smooth muscle cell dysfunction can lead to a variety of vascular pathologies but the limited renewal capacity of cell lines producing these cell types has impeded research in this area. The availability of pluripotent cell lines and the subsequent establishment of directed differentiation protocols into endothelial and smooth muscle populations have overcome the limitations caused by a finite source of experimental material. Both endothelial and VSMC populations are

Acknowledgements

The work was funded by British Heart Foundation and British Heart Foundation Centre for Regenerative Medicine, Fight for Sight, Robert McApline Foundation and Dinosaur Trust and supported by the Foundation Le Ducq and Cambridge NIHR Biomedical Research Centre.

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