Frontiers in Stem Cell and Regenerative Medicine Research

Tissue engineering is a major breakthrough in cardiovascular medicine that holds amazing promise for the future of reconstructive surgical procedures. The three main components used in creating a tissue engineered construct are: 1) a scaffold: used to mimic the extracellular matrix, 2) a cell type: seeded to the scaffold to help with biocompatibility and regeneration, and 3) cell signaling: communication between the cells via biochemical, physio-chemical signaling. Our goal in this chapter is to review the short history of organ and tissue regeneration, the advances in the regeneration field, and the current state of vascular tissue engineering.

Endothelial cells (ECs) and smooth muscle cells (SMCs) play pivotal roles in maintaining vascular homeostasis. Their dysregulations are critical in the pathogenesis of various disease processes such as atherosclerosis which leads to severe cardiovascular diseases such as coronary heart disease and stroke. Vascular regeneration serves as an effective therapeutic strategy for these diseases. The therapeutic prospect of stem cell-based therapy, given the capacity of stem cells to replicate, to differentiate and to directly form new blood vessels, represents the ideal approach for vascular regeneration. The identification of adult stem/progenitor cells in both circulating blood and on the vessel wall indicates that endogenous stem cells have the capacity to repair injured endothelium and restore vascular homeostasis. On the other hand, pluripotent stem cells (PSCs), which have eminent capacity for selfrenewal, represent the ideal candidates in regenerative medicine. There are enormous excitements surrounding the prospect of generating functional vascular cells through activating vascular lineage differentiation of PSCs (such as embryonic stem cells (ESCs) and induced PSCs (iPSCs)) for clinical cell therapy. Recent advances in induced lineage conversion from fibroblasts to ECs and SMCs present another exciting strategy in vascular regeneration. Progresses in vascular tissue engineering have further complemented the vascular differentiation and grafting of reprogrammed vascular lineage cells onto the sites of vessel injury, through scaffolds made with native matrices, synthetic polymers or decellularised tissues. Finally, the progresses made in generating more origin-specific vascular cells from patient-derived iPSCs have enabled researchers in uncovering new insights on the molecular mechanisms underlying various vascular diseases, as well as for drug discovery, drug screening, toxicity testing and personalised medicine delivery. In this chapter, we will describe different strategies and highlight the recent efforts in generating functional vascular cells from various populations of stem and progenitor cells, their underlying molecular mechanisms, and their roles in therapeutic vascular regeneration. With the field of regenerative medicine moving in an accelerating pace, the prospect of using stem and progenitor cells clinically for vascular regeneration in treating vascular and ischemic diseases is on the horizon.

Studies on neural cell replacement therapy appear in the literature as far back as the 19th century. While FDA-approved clinical trials have been ongoing since the 1980s, pre-clinical and clinical outcomes have been variable, and the field is still widely considered to be in its infancy today. Stem cells have properties that are suited for repair of the injured central nervous system (CNS), but a primary question is how these cells can best be grafted to produce long term functional benefit to the host environment. Among the challenges in neural cell transplantation is controlling the ultimate characteristics of grafted cells, pertaining to their survival, phenotypes and performance. This chapter will discuss phenotypic fates and functional integration of neural tissue grafted in animal models of CNS disease, with focus on researchers’ current ability to anticipate graft behavior. Topics will encompass conventional and novel procedures used to treat CNS disorders with neural tissue. We will give attention to neural stem and precursor cells derived from adult, fetal and embryonic sources, as well as induced pluripotent sources, and finally the differentiated progeny of these cells.

Three-dimensional scaffolds are known to directly influence proliferation and differentiation of mesenchymal stem cells into bone tissue due to their properties such as stiffness and topography. While conventional methods for chemical induction of differentiation processes are based on incorporation of growth factors and/or cytokines via blending or adhesion onto the scaffold surfaces, novel approaches use template-mediated biomineralization to mimic the stimuli stem cells receive in their natural niche. This chapter summarizes recent progresses in guided bone tissue engineering with particular focus on design and functionality of three dimensional scaffolds, chemical templates and promising approaches for the corresponding cellbased approaches for future therapies.

Regenerative medicine in ocular diseases has shown major advances over the last few years. The most critical progress has been achieved for diseases of the cornea and retina, for which the transplantation of local and differentiated stem cells (SC) is being studied. The treatment of the cornea is aimed at restoring corneal clarity after severe injuries and diseases. Corneal blindness is the fourth leading cause of visual impairment worldwide, and access to corneal transplantation surgery, the main treatment for corneal blindness, is difficult given the shortage of tissue donors. For this reason, the development of alternative therapies using SC is of special interest. The corneal endothelium (CE) is the innermost layer of the cornea, and it is in contact with the aqueous humor. It consists of a monolayer of polygonal cells which maintains an optimal hydration state and clarity in the cornea through an active ATP-Na/K pump. This tissue possesses limited mitotic ability. Therefore, when major injury occurs, it can only be treated with a corneal graft. Recent advances have shown potential in harvesting corneal endothelial cells (CECs) in order to obtain enough quantities to perform a transplant. However, these strategies are still limited by the need for tissue donors, as well as by the long time lapses required to proliferate the CECs. SC isolated from different sources, including adipose tissue and dental pulp, are being investigated in regenerative medicine given their potential to differentiate into other cell lines. For use in CE restoration, a broad analysis must be performed, taking into account CE embryological pathways, current reports in SC differentiation into ocular tissues, and recently available bioinformatic tools, which can be used for differentiation assays. This review encompasses the present knowledge of CE development and embryological molecular signaling, recent reports in SC differentiation into CE, and the available bioinformatic tools used to direct in vitro SC differentiation.

Despite the significant advances in the management of hepatocellular carcinoma (HCC), the results are still far from satisfactory. One of the reasons for this is the need to identify the mechanisms involved in the molecular pathogenesis of HCC, so as to be able to provide patient-targeted therapies. The difficulty in this endeavor lies in the multitude of pathways involved and the challenge of finding out how each one of them fits into the larger picture.

As is the case in several different organs, stem cells appear to have a critical role in the evolution of the liver and its neoplasms, as well as in key aspects of hepatic regeneration and response to various injury mechanisms. The goal of this chapter is to present basic principles of stem cells and identify pathways involved in the development of stem cells, which can at the same time affect the evolution and diagnosis of HCC. Finally, therapeutic strategies involving stem cells will be presented, in an effort to identify future challenges.