Frontiers in Stem Cell and Regenerative Medicine Research

Tooth loss due to periodontitis, traumatic injury, or deep caries can cause facial aesthetic problems and difficulties with mastication. The ultimate goal of dental prosthetic treatment is to generate fully functioning organs to replace dental tissue that has been lost or damaged due to disease, injury or aging. Tissue engineering is a rapidly expanding field of applied biology and biomedical sciences, which aims to replace defective tissues with newly-generated tissue by combining cells, scaffolds, and biologically active molecules. Stem cells hold great promise for tissue engineering owing to their multipotency and self-renewal ability. In this article, we will present the current progress in stem cell-based dental tissue regeneration and elaborate on the potential of dental stem cells for clinical application.

Epidermal stem cells in the skin are located in distinct stem cell niches, such as the interfollicular epidermis (IFE), hair follicle (HF) and sebaceous glands (SB), where they are known to produce several distinct lineages of cells. The IFE keratinocyte stem cells populate the basal layers of the epidermis and their progeny differentiate and migrate through the layers of the epidermis to be shed as part of the natural turnover of skin. The contribution of keratinocyte stem cells to the homeostatic maintenance of the epidermis is essential for the barrier function of skin.

After severe injuries to the skin, such as those sustained in severe burns or scalds, functioning epithelium is lost, and restoration of this barrier is essential to patient survival. Cultured keratinocytes have been used as an adjunct therapy in the treatment of such injuries for the past 30 years. For such cell therapies to be successful, the cell isolation and culture method must ensure that highly regenerative stem cells are preferentially expanded while differentiating cells are excluded, as these do not contribute to tissue regeneration. Significant advances in the culturing and manufacturing processes employed in the preparation of epithelial cell therapies have been made since the conception of this treatment method. An improved understanding of the biology of epithelial stem cells has further elucidated the tissue regenerative potential, which these cells harbour. In addition, novel strategies to improve cell expansion and delivery hold promising potential to improve healing. Although the regeneration of skin appendages, such as hair follicles and sebaceous glands, is not possible after severe cutaneous injury at present, advances in tissue engineering strategies have begun to tackle these complex structures.

Novel stem cell therapies for epithelial regeneration hold the potential to significantly improve wound healing in patients and positively influence clinical outcomes. Advances in epithelial stem cell research both in vitro and in vivo are reviewed here and their potential impact highlighted specifically in the context of clinical application for patients with severe cutaneous injuries.

Cancer stem cells (CSCs) are a subset of cells within a tumor having selfrenewal and differentiation capacity. Due to their “stem cell”-like properties, CSCs are thought to be responsible for cancer initiation, progression, metastasis, recurrence and drug resistance. Thus, therapeutic strategies that focus on targeting CSCs and their microenvironmental niche address the ineffectiveness of traditional cancer therapies to eradicate the CSCs that otherwise result in therapy resistance. Over the past years, a great effort has been invested in the development of new compounds and repositioning of already approved drugs that selectively target CSCs, some of which have been evaluated in preclinical and clinical studies.

Over the past few years, stem cell-based therapeutics has emerged as a promising strategy for many severe human diseases. The recent studies on stem cells in heart regeneration have stimulated discoveries directed towards potential clinical applications. A series of recent advances in signaling pathway and experimental models provide a new opportunity for the treatment of cardiac diseases. This section will cover the progress made towards the mechanisms underlying the stem cell development and heart regeneration.

The following chapter outlines the current research status of studies exploring the generation of two essential ovarian cell types from stem cells: meiotic female germ cells from primordial germ cells to oocytes; and supporting somatic granulosa cells that are necessary for correct germ cell development and sex hormone production. Recent studies have reported the generation of both cell types in vitro and in vivo from a variety of sources, including somatic stem cells, induced pluripotent stem cells, and embryonic stem cells. While significant progress has been demonstrated, there are many areas that require further investigation. This review also discusses current research limitations and future prospects of this field within the context of regenerative medicine.

Since their discovery in 2006, induced pluripotent stem cells (iPSCs) have generated much excitement as a potential source of therapeutic cells. Diverse applications, including for diabetes, neurological and ocular disorders, and heart failure are currently being investigated, and new therapies could enter into a growing regenerative medicine market. Despite this, there are significant challenges in the development of iPSC therapeutics and their ultimate translation to clinical use. Heterogeneity in iPSC products can be introduced throughout the complex process of iPSC generation and selection. Challenges with, and current approaches to, developing scalable, consistent methods for reprogramming of somatic cells, and selection, validation and characterization of iPSCs are, therefore, discussed in the context of good manufacturing guidelines and quality assurance. Further, we discuss issues and considerations with immuno-compatibility and the possible need for immune suppression. The final barrier to the development of iPSC therapeutics discussed is intellectual property.

The core cell cycle machinery and its associated signaling pathways play critical roles in regulation of stem cell properties. Cell cycle length and rate is a determining factor for stem cells to maintain pluripotency or undergo differentiation. Manipulating the cell cycle has functional consequences for tissue differentiation as well as somatic cell reprogramming. In addition, accumulating evidence indicates that cell cycle regulators may control pluripotency and differentiation by direct interaction with the pluripotency network and other essential signal pathways without altering the cell cycle per se. In this chapter, we summarize the current understanding of the role of the cell cycle and cell cycle regulators in the process of development, pluripotency, differentiation, and reprogramming.

Previous studies have demonstrated that nerve damage results in rapid disruption of nerve function. Neural stem cells (NSCs) from spinal cord have been shown to promote peripheral nerve regeneration. However, the stem cell therapy still shows low efficiency in vivo and some miscommunications after nerve recovery. Our studies found that chemotactic factor stromal-cell derived factor 1α and hypoxia may improve the survival of the transplanted NSCs and their function. Here we discuss the effects of microenvironment on neural stem cell therapy for peripheral nerve injury and recent progresses in this research field.

Neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of longterm neurological disability in children, being responsible for at least 14% of the cases of cerebral palsy. Despite the moderate protection provided by therapeutic hypothermia, a significant number of infants would still benefit from an adjuvant therapy. Since the first report showing the beneficial effect of umbilical cord blood cells (UCBCs) transplantation in a rat model of HIE in 2006, a growing number of studies have improved our understanding of the mechanisms underlying the neuroprotective action of transplanted cells in animal models of HIE, intrauterine hypoxia and neonatal stroke. The aim of this book chapter is to summarize these findings and to discuss recent data from several clinical trials and case reports that have evaluated the safety and feasibility of UCBCs therapy in newborns with HIE and in children with cerebral palsy.

Articular cartilage is prone to damage from sports injuries/aging, which often progresses to osteoarthritis, an inflammatory and degenerative joint disease characterized by degradation of the entire joint, leading to pain and disability. Current pharmaceutical and surgical interventions relieve pain and improve joint function, but the long-term results are not satisfactory. More recently, stem cell-based strategies that include direct intraarticular injection of mesenchymal stem cells and implantation of tissue-engineered cartilage grafts have been developed. This chapter will first review the cartilage structure, composition, and pathology, and then summarize the most recent advances in applying mesenchymal stem cells for treatment of cartilage defects and osteoarthritis.