Heart failure is one of the most important cardiovascular health problems throughout the world and has high mortality, and there is a need to develop more effective therapeutic strategies to replace such specialized treatment as mechanical circulatory support and cardiac transplantation. Mesenchymal stem cells (MSC) are multipotent plastic-adherent cells obtained from bone marrow, adipose tissue, and other tissues and can be easily expanded in culture. MSC exert their role in cardiac regeneration not only by differentiating into specific cell types such as cardiomyocytes and vascular endothelial cells but also through paracrine effects via secretion of angiogenic and antiapoptotic factors. On the basis of information obtained from basic and translational research, several clinical trials have recently been started to evaluate the safety and efficacy of autologous MSC for heart failure.

There are the methods made various regenerative tissue from embryonic stem cell and tissue stem cell for regenerative medicine. We have performed the basic studies to product the regenerative bone and cartilage with mesenchymal stem cell included in bone marrow. Based on the results, we have cultured patient's bone marrow in cell processing center after approval of our ethic committee and placed the regenerative bone and cartilage on scaffolds and total prostheses. These materials were replaced on lesions of bone and joint diseases by cartilaginous damage, osteoarthritis, bone tumor and congenital anomaly. The follow-up periods are not so long, because they were started from 2001. The good results of them without rejection and infection have been obtained for the present.

The cornea is the avascular, transparent, and main optical element of the eye consisting primarily of 3 layers: the corneal epithelium, stroma, and endothelium. It is believed that corneal epithelial stem cells exist in the basal cell layer of the limbal region. In cases of corneal epithelial stem cell deficiency, corneal epithelial replacement using a tissue engineering technique holds great promise for ocular surface reconstruction. Autologous cultivated corneal epithelial sheets are the safest and most reliable treatment, however, they are not useful for treating bilaterally affected ocular surface disorders. In order to treat these bilateral cases, we must choose either an allogeneic cultivated corneal epithelial sheet or an autologous cultivated oral mucosal epithelial sheet.

A goal of periodontal therapy is to regenerate periodontal tissue, which had been destroyed by periodontal diseases. Transplantation of bone marrow-derived mesenchymal stem cells (MSCs) into periodontal defects would be a useful option for periodontal tissue regeneration. We have developed a novel method for periodontal therapy using MSCs. Human bone marrow cells are obtained from the iliac crest and MSCs are isolated and expanded in vitro at Cell and Tissue Engineering Center in Hiroshima University Hospital. MSCs are mixed with 2% Atelocollagen at final concentration of 2 x10(7) cells/mL. These MSCs in Atelocollagen are transplanted into periodontal osseous defects at the periodontal surgery.

Functional recovery in acute renal failure is well known, and the adult kidney is generally recognized to have the capacity to regenerate and repair. Several groups have reported the contribution of bone marrow-derived cells in this process, and others have confirmed the existence of adult stem cells in the kidney, including label retaining cells, slow-cycling cells, side population cells, and rKS506 cells. However, recent data demonstrated that in vivo differentiation of bone marrow-derived cells into renal tubular cells may not occur at all, or is at most a minor component of the repair process. Moreover, it is now generally accepted that stem cells and multipotent cells contribute to the regenerative process by producing protective and regenerative factors rather than by directly differentiating to replace damaged cells. This review will focus on current understanding of kidney regeneration.

Pancreatic beta-cells possess a well-regulated insulin secretory property that maintains systemic glucose homeostasis. Although it has long been thought that differentiated beta-cells are nearly static, recent studies have shown that beta-cell mass dynamically changes throughout the lifetime. The beta-cell mass could be maintained by several mechanisms, including self-replication of pre-existing beta-cells, neogenesis from unidentified stem/progenitor cells, and transdifferentiation from differentiated duct or acinar cells. Recent studies have suggested that self-replication of pre-existing beta-cells is a major source for maintenance of beta-cell mass in adult pancreas. However, regeneration of beta-cells from non-beta-cells does occur under certain conditions, especially in vitro culture systems. In this article, recent progress of regenerative medicine of the pancreas is reviewed.

Recent progress of stem cell biology gives us the hope for neural repair. We have established methods to specifically induce functional Schwann cells and neurons from bone marrow stromal cells (MSCs). The effectiveness of these induced cells was evaluated by grafting them either into peripheral nerve injury, spinal cord injury, or Parkinson' s disease animal models. MSCs-derived Schwann cells supported axonal regeneration and re-constructed myelin to facilitate the functional recovery in peripheral and spinal cord injury. MSCs-derived dopaminergic neurons integrated into host striatum and contributed to behavioral repair. In this review, we introduce the differentiation potential of MSCs and finally discuss about their benefits and drawbacks of these induction systems for cell-based therapy in neuro-traumatic and neuro-degenerative diseases.

Although adult neurogenesis is limited in regions, accumulating evidence indicates the existence of neural regeneration even in non-neurogenic regions. In the adult retina, Müller glias generate new neurons in response to injury. Although the naively regenerated neurons were a very few in number, it could be increased by Wnt treatment. Retinal cell transplantation is another strategy for retinal regeneration. The cell source for transplantation will be prepared, for example from ES cells. There are some ways to enhance the integration of grafted cells into the host retina. We need to understand the mechanisms for integration of newly generated cells or grafted cells into existing neural networks, and to determine functional recovery in animal models of the retinal diseases.

The availability of enough cardiomyocytes to transplant as a cardiac tissue is able to read the achievement of regenerative cardiac medicine. Tissue derived stem cells, embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are all potential cell sources. Several types of cardiac tissue stem cells have already been reported, and we describe about the characteristics and multipotency of these tissue stem cells with an accurate comparison. ES cells and iPS cells are highly proliferative and suitable for mass production, and efficient protocols for selective cardiomyocyte induction using ES cells and iPS cells are also significant. On the other hand, these cells still have several issues about purification and safety as well as ethical problems.

Tissue regeneration by using stem/progenitor cells has been recognized as a maintenance or recovery system of many organs in adult. The isolation of endothelial progenitor cells (EPCs) derived from the peripheral blood (PB) was one of the amazing discovery for the recognition of "neovessel formation" in adult occurring as physiological and pathological responses. These findings that EPCs home to sites of neovascularization and differentiate into endothelial cells (ECs) in situ is consistent with "vasculogenesis", a critical paradigm well described for embryonic neovascularization, but proposed recently in adults in whom a reservoir of stem or progenitor cells contributes to vascular organogenesis. On the basis of the regenerative potency, these stem/progenitor cells are expected as a key factor of therapeutic applications for the ischemic diseases.

Hair growth cycle is coordinated with complex processes that are dependent on the interactions of follicular stem cells and dermal papilla cells (DPCs). For the past 10 years, the developmental mechanism of hair follicles has been extensively studied, and spatial and temporal expressions of many molecules are required for the hair morphogenesis. These molecules are also required for hair cycle progression. Androgen receptor, which is a ligand dependent transcription factor, plays an important role in human hair cycle. Frontal scalp DPCs from androgenetic alopecia (AGA) are the target cells of androgen action. Minoxidil and Finasteride were recently introduced for the treatment of AGA, and cell therapy using DPCs is a next strategy for the innovative treatment.

For successful regeneration therapy of tissues and organs, it is important and indispensable to develop the technology and methodology of tissue engineering with biomaterials for molecular design and creation of a local environment which enables stem cells to enhance the proliferation and differentiation, inducing cell-based tissue regeneration. Various scaffolds of biomaterials have been investigated to demonstrate the feasibility in the basic researches of stem cell biology and the applications of their results to regenerative therapy. This paper introduces several examples of regenerative medical therapy based on tissue engineering technologies to emphasize the scientifically and clinically significant contribution of cell scaffolds not only to the regenerative medicine of basic stem cell researches, but also to their therapeutic applications of regenerative medicine.

Mesenchymal stem cells (MSCs) are a potential cellular source for stem cell-based therapy, since they have the ability to proliferate and differentiate into mesodermal tissues. Human MSCs have been used clinically to treat patients with graft versus host disease and osteogenesis imperfecta. We previously showed that murine and human marrow-derived MSCs can differentiate into cardiomyocytes, skeletal myocytes, osteoblasts, chondroblasts, adipocytes, and neuron. We here show that sources of MSCs with multipotency includes placenta, endometrium, menstrual blood, umbilical cord, cartilage and so on. Differentiation potentials of MSCs depend on cell source, implying that MSCs obtained from each source have differential default state ex vivo.

Human embryonic stem(ES) cells are very promising resources that will be highly likely applied to the clinic directly and/or indirectly in the near future. For example, some kinds of ES cell-derivatives may be applied to the cell transplantation therapy, or ES cell-derived hepatic cells may be utilized in the field of pharmacology. Thus, the development of technology relating to ES cells is very important and many scientists around the world are currently working intensively in this field. Here we describe what is possible at the moment and what should be developed in the future in relation to ES cell technology.

By retroviral transduction of four or three transcription factors, mouse and human somatic cells have been reprogrammed to an undifferentiated state similar to embryonic stem (ES) cells, and these cells have been termed induced pluripotent stem (iPS) cells. This technology has opened the avenue to generate patient- and disease-specific pluripotent stem cells, which are useful for not only customized cell transplantation therapy without rejection but also for understanding disease mechanisms, drug screening and toxicology. In this review, we discuss the overview of the advance of iPS cells.

A medical system is anticipated, where high-quality medical services are accessible without anxieties whenever we are ill or injured. The innovative regenerative medical products have enabled us to overcome some life threatening diseases, however, challenges still remain for others. The Ministry of Health, Labour and Welfare has implemented "The guideline for clinical research using human stem cells" and has launched on Sept 1, 2006. The major goal of the guideline is to reinforce and ensure safe on investigational new regenerative medical products. In this paper, I will give an overview of the guideline for clinical research using human stem cells, which intends to satisfy unmet medical needs in the field of regenerative medicine as well as to keep medical advances in Japan.

Regenerative medicine using stem cells is one of the most important topics today. Embryonic stem cells (ES cells) are useful in the studies of the differentiation of various cells or tissues for transplantation therapy, because of their pluripotency to differentiate into almost all types of cells in the body. However, it is controversial to use human ES cells, because it is necessary to sacrifice the life of human embryos for the establishment of these cells. Induced pluripotent stem cells (iPS cells) generated from somatic cells of patients are one of the alternative sources of human pluripotent stem cells while avoiding ethical problems. Epigenetic studies using iPS cells may be valuable to find the way to control cell differentiation more effectively.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of midbrain dopaminergic (DA) neurons and a subsequent reduction in striatal dopamine. As a treatment for advanced Parkinson's disease, deep brain stimulation (DBS) of the thalamus was introduced in 1987 to treat tremor, and was applied in 1993 to the subthalamic nucleus. Now high-frequency stimulation of the subthalamic nucleus has become a surgical therapy of choice. Another surgical treatment is a cell replacement therapy. Transplantation of fetal dopaminergic (DA) neurons can produce symptomatic relief, however, the technical and ethical difficulties in obtaining sufficient and appropriate donor fetal brain tissue have limited the application of this therapy. Then, neural precursor cells and embryonic stem (ES) cells are expected to be candidates of potential donor cells for transplantation. We induced DA neurons from monkey ES cells, and analyzed the effect of transplantation of the DA neurons into MPTP-treated monkeys as a primate model of Parkinson's disease. Behavioral studies and functional imaging revealed that the transplanted cells functioned as DA neurons, attenuating the MPTP-induced neurological symptoms. DA neurons have also been generated from several human ES cell lines. Furthermore, functional recovery of rat PD models after transplantation was observed. One of the major problems in ES cell transplantation is tumor formation, which is caused by a small fraction of undifferentiated ES cells in the graft. So, it is essential for undifferentiated ES cells to be eliminated from the graft in order for transplantation to be feasible. These efforts will lead to clinical application of ES cell transplantation to the patients with PD.