After the biotech medicine era, symbolized by the progress of genetic engineering and the developments of physiologically active substances such as proteins and cytokines as medicine, the regenerative medicine era, when cells and tissues become medicine, is going to start and getting popular in recent years in the world. In particular, regenerative medicine is highly expected as curative-therapeutic treatments that can cure patients with obstinate diseases and physically impaired function, while the conventional symptomatic treatments are unable to do so. For supporting and enhancing the progress of regenerative medicine, remarkable advancements in regenerative medical sciences, and cell and tissue engineering are desired worldwide. Furthermore, to achieve new treatments based on regenerative medicine, multidisciplinary approaches from various fields such as molecular biology, cell biology, science and engineering, and pharmaceutical and medical sciences are essential. Regenerative medicine should be recognized as a completely new interdisciplinary academic discipline, which is unable to be obtained from the extrapolations of vertically connected and conventional academic disciplines. Therefore, for realizing regenerative medicine, not only the reconstruction of conventional medical science but also the establishment of new academic field, which integrates and assimilates scientific and engineering technologies, and biotechnology, become important. For example, technology controlling the expansion and differentiations of embryonic stem (ES) cells and induced pluripotent stem (iPS) cells is essential for obtaining the sufficient numbers of the cells allowing desired medical treatments to be realized. For separating remaining small amounts of undifferentiated ES and iPS cells from the differentiated cells with a high accuracy, an interdisciplinary research project having the horizontally integration of science, engineering, medicine should be considered. Further, the developments of technologies, which can efficiently transplant somatic cells in the body, are more important than those of cell sources, and new cooperative and integrative systems having various academic disciplines including medicine, science, engineering, and pharmacy are extremely important. For example, harvested cells, which are obtained from culture dishes by treating them with enzymes including trypsin or dispase after being cultured and expanded, are damaged in their structures and functions by enzymatically cleaving their cell-membrane proteins. Upon the direct injection of suspension containing damaged cells following the enzyme treatments to the tissue or organ, approximately 95% of the cells fail to stay in the target, and only less than several percent of the cells transplanted in the organ is speculated to be effective (Hofmann et al., 2005). The unwelcome fact that possible therapeutic effects are expected with a small number of transplanted cells should be noticed seriously. Tissue engineering is extremely important in terms of the more efficient engraftment of cell transplantation and is expected to proceed further with the integration of the technology of biomaterials contacting cell directly and bio- and medical-technologies. One of the tissue engineering approaches is biodegradable polymer scaffold-based methods (Langer and Vacanti, 1993). It is important to promote research that investigates how the shape and function of cells cultured in the scaffolds are maintained after transplantation. In this special issue, the recent progress of tissue engineering approaches using biodegradable polymer scaffolds are reviewed by Rui Reis and his colleagues on periodontal tissue, Charles Vacanti and Koji Kojima on trachea, Toshiharu Shinoka and his colleagues on vasculature, Dietmar Hutmacher and his colleagues on osteochondral tissue, and Stephan Badylak and his colleagues on skeletal muscle. For maintaining cell-dense thicker tissue viability, sufficient amounts of oxygen and nutrients should be supplied into the tissue. However, scaffold-based tissue has a heavy burden to have supplies of oxygen and nutrients from the scaffold surface by diffusion, which is hampered with increasing cell density. The developments of new technologies to break through this problem would be desired. Another approach for tissue engineering is cell sheet-based methods (Yang et al., 2007). Dense monolayered cell sheets that are harvested from temperature responsive culture dishes are fully viable and almost all of the cells are engrafted and keep their function after transplantation. In this special issue, the cutting edge research using cell sheet-based tissue engineering methods are reviewed by Teruo Okano and Kazuo Ohashi on liver and islets, Tatsuya Shimizu and Katsuhisa Matsuura on cardiac tissue, Masayuki Yamato and his colleagues on periodontal tissue, and Masato Sato and his colleagues on articular cartilage. In the cornea, myocardium, periodontal ligament, esophagus, and articular cartilage, the clinical studies with this cell-sheet technology have been already initiated, and the clinical efficacies of these cell-sheet transplantations have been confirmed. Remarkable research projects investigating the preparation of three-dimensional (3-D) cell-sheet tissues by layering cell sheets have been started. Especially challenging is to make capillaries in 3-D layered cell-sheet tissue and allow them to connect with living blood vessels (Sekine et al., 2013) or the micro-channels of artificial vascular beds (Sakaguchi et al., 2013). From these successful studies, the preparations of various organs such as liver, kidney, pancreas, and so forth are expected to be accelerated.

Various stem cell types are currently under investigation. Among them, the application of tissue stem cells, also called somatic stem cells, is being developed with remarkable progress (Korbling and Estrov, 2003). Some tissue stem cells have proceeded to clinical trials and even further to general medical treatment. Hematopoietic stem cells (HSCs) are representative of such cells (Weissman and Shizuru, 2008). HSCs have been successfully administered to patients with leukemia for over 50 years (Thomas, 1983). In this special issue, Atsushi Iwama and his colleagues, Yaeko Nakajima-Takagi and Mitsujiro Osawa, review HSCs, including the methods used for identifying and expanding HSCs ex vivo, and the niche cells that control the self-renewal, differentiation, and homing of HSCs.

One special type of tissue stem cell has attracted great attention. Mesenchymal stem cells have been intensively studied for more than a decade, with new knowledge accumulating from both basic and applied studies (Kuroda et al., 2011). Importantly, more than 450 clinical studies are currently being performed throughout the world, targeting various diseases, and there are several venture capital companies focusing on mesenchymal stem cells. Mesenchymal stem cells are indeed a hot topic and a major field in basic science, clinical medicine, and medical industry. In this special issue, Yasumasa Kuroda and Mari Dezawa provide an overview of mesenchymal stem cell studies, focusing on three representative sources, bone marrow, adipose tissue, and umbilical cord, and describe the similarities and differences among them. They also describe recent advances in clinical studies and discuss perspectives of mesenchymal stem cell use. Finally, they introduce multilineage-differentiating stress enduring (Muse) cells, which are recently discovered pluripotent stem cells that make up a large percentage of mesenchymal stem cells. Muse cells have attracted attention not only because they explain the triploblastic differentiation ability of mesenchymal stem cells, but also because they are pluripotent but non-tumorigenic. Their review discusses the great potential of Muse cells for regenerative medicine.

Neural regeneration is another hot topic in regenerative medicine (Gage, 2000). While there are some candidate stem cells that relate to neural regeneration, in this special issue James St. Johns and Jenny Ekberg review olfactory ensheathing cells. Established central nervous system tissue does not possess regenerative capacity; therefore, the only way to restore damaged brain regions and spinal cord is to supply new neural cells and reconstruct neuronal circuits. Neural stem cells have attracted great attention for quite some time, but the number of available cells from fetal or adult brain is limited. Due to their regenerative capacity and feasibility of application, olfactory ensheathing cells are considered one of the strongest candidates for the treatment of spinal cord injury, and in fact, they have been already applied to patients in some countries.

For diseases of complex tissues, such as the kidney and eye, the search for tissue stem cells has not been as simple and straightforward. Motoko Yanagida and her colleague, Koji Takaori, are pioneers in the area of kidney regeneration and stem cells. Here in this special issue, they review kidney stem cells. The retina is an organ with highly sophisticated function, such as information processing ability comparable to that of the brain. In mammals, retinal stem/progenitor cells (RPCs) are suggested to be possible retinal stem cells that are quiescent and exhibit very little activity. A number of different cellular sources of RPCs have been identified in the vertebrate retina. These include RPCs at the retinal margin; pigmented cells in the ciliary body, iris, and retinal pigment epithelium; and Müller cells within the retina. Henry Yip describes the isolation and expansion of RPCs from immature and mature eyes, and their potential application to transplantation in degenerated retinal tissue.

James Trosko, the pioneer of tissue stem cells and cancer stem cells, poses questions about the reprogramming hypothesis of iPS cells. His review proposes novel insights into the relation between iPS cells and cancer stem cells.

A survey of the stem cell world reveals that tissue stem cells are diverse and complex, just as our bodies are composed of complex sophisticated systems. Our bodies are able to maintain tissue homeostasis perhaps because of the evolutionary development of tissue stem cells to acquire a variety of functions. We hope that this special issue will stimulate development of additional tissue engineering and tissue stem cell studies.


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