Macrophages, osteoclasts and dendritic cells are derived from hematopoietic stem cells through monocyte/macrophage lineage common precursor cells. Macrophages are induced in the presence of M-CSF alone whereas osteoclasts are induced by M-CSF and RANKL. The cooperation of transcription factors, c-Fos and NFATc1 is essential for osteoclast differentiation. GM-CSF is an inducer of dendritic cells, and in contrast to osteoclast differentiation, M-CSF and c-Fos are inhibitors of dendritic cell differentiation. On the other hand, mesenchymal stem cells(MSCs) give rise to osteoblasts. In embryonic stage, MSCs in perichondrium are marked by ALCAM. Recently, osteoblasts are reported to provide 'Niche' for hematopoietic stem cells in bone marrow. Here we review the differentiation and functions of monocyte/macrophage lineage cells and osteoblasts.

Chronic periodontitis is a destructive disease that affects the supporting structures of the teeth including periodontal ligament, cementum, and alveolar bone. If left untreated, patients may lose multiple teeth and extensive prosthetic treatment will be required. In order to re-engineer lost tooth-supporting tissues, various therapeutic modalities have been used clinically. Periodontal regeneration procedures including guided tissue regeneration have achieved substantial effects. However, there are several issues to be solved. They are highly technique-sensitive, applicable to limited cases which are susceptible to treatment, and supposed to have relatively low predictability. Therefore, it is necessary to develop new approaches to improve the predictability and effectiveness of regenerative therapies for periodontal tissues. Recently, the concept of tissue engineering has been introduced to restore lost tissues more effectively where the biological process of healing is mimicked. To achieve this, integration of three key elements is required: progenitor/stem cells, growth factors and the extracellular matrix scaffold. Although it has been shown that implantation of bone marrow-derived mesenchymal stem cells into periodontal osseous defects induced regeneration of cementum, periodontal ligament and alveolar bone in dogs, further extensive preclinical studies are required. On the other hand, application of growth factors, particularly basic fibroblast growth factor in the treatment of human periodontitis, is promising and is now in clinical trial. Furthermore, the rate of release of growth factor from the scaffold also can profoundly affect the results of tissue engineering strategies and the development of new materials is expected. In addition, as tissue regenerative potential is negatively regulated by aging, the effects of aging have to be clarified to gain complete regeneration.

Appropriate dental implants are known to improve the quality of life in totally and partially edentulous patients, as well as to prevent future tooth loss, and so prosthetic treatment modalities have drastically changed recently with reconstruction therapy. However, dental implant therapy did not win the confidence of the dental community in the early developmental stage, until osseointegration between titanium and surrounding bone tissue was discovered and the modality utilizing osseointegration became reliable and produced durable treatment outcomes for long-term function. On the other hand, the biological mechanism of osseointegration has not been clarified yet and the time required for osseointegration is still long, e.g. three to four months. As well, when the implant is applied in the upper posterior region, the acquisition of osseointegration and the long-term survival of the implant are still not clinically adequate. Therefore, to reduce the time required for osseointegration and to regenerate enough alveolar bone mass in the target implantation site, the oral implant modality must be made more useful and potent as one of the treatment options for partial and total edentulism. With this background, we have studied biological strategies for reducing the time required for osseointegration and for regenerating enough alveolar bone mass, e.g., investigation of the specific genes for osseointegration between titanium and bone, nano-level surface modification of the titanium, biodegradable apatite foam for alveolar bone regeneration, application of bone formation-related growth factors with biological scaffold, and autologous cell transplantation of bone marrow derived mesenchymal stem cells. In this article, we review the current status of regenerative medicine being applied in prosthodontics and discuss our future research direction.

Duodeno-gastro-esophageal reflux has been thought to induce Barrett's esophagus. Recently, we designed a new duodenal reflux model using rats, and studied sequential morphological changes of esophageal mucosa leading to Barrett's esophagus. A specialized columnar epithelium (SCE) developed 20 weeks after operation. Barrett's epithelium originated from pyloric-foveolar metaplasia of stem cells in the basal layer of the esophageal squamous epithelium. The pyloric-foveolar metaplasia was then followed by the appearance of goblet cells, becoming a typical SCE. The expression of homeobox gene Cdx2 was seen in this process, thereby suggesting a role of Cdx2 in intestinal differentiation of Barrett's esophagus. We noticed the pyloric-foveolar metaplasia followed by the appearance of goblet cells is common to entire gut in regenerative process, and proposed a concept of GRCL (gut regenerative cell lineage), and an implication of GRCL in digestive tract carcinogenesis was discussed.

Cells, which are the basic unit of life, are the most intelligent particles on earth. Recent advances in life science research encourage the development of cell therapy utilizing specialized functions of highly differentiated cells, the self-renewal and differentiation abilities of stem cells, and signal networks among various types of cells. Although cell therapy including ex vivo gene therapy, cellular immunotherapy, and regenerative therapy is expected to become the next generation of medical care for intractable disorders, the establishment of technology to prepare cells as medical supplies, namely, cytomedicine, is essential for the assurance of efficacy and safety in cell therapy. This review introduces our approach to the design and creation of cytomedicine for application to cell therapy against diabetes mellitus and cancer.

The neurosciences to understand the pathophysiology of psychiatric disorders such as depression and schizophrenia were started from the analysis of neurotransmitter function change, and proceed to the cellular signaling change in the brains. In the next step, it developed to the studies of neuroplasticity change through expressions various cytokines and transcriptional factor regulations. Recently, the existence of neural stem cells and lineage of stem cells to neurons are identified in the adult mammalian brains. In addition, since the brain structural changes in depression and schizophrenia have well defined by the development of neuroimaging analysis, many researchers have been suggested the relationship between the pathophysiology of these disorders and the dysfunction of neurogenesis which strongly affects the maintenance and repair of brain neuronal network. In this report, we describe the new strategy and approach to the investigation of the treatment of psychiatric illness, and introduce our present study of the way to refine the neural network through promoted actions on stem cell functions such as differentiation to neurons.

A major goal of periodontal therapy is to reconstruct healthy periodontium destroyed by periodontal diseases. Basic studies have revealed that transplantation of mesenchymal stem cells (MSC) into periodontal defects promotes regeneration of periodontal tissue. We have developed a novel method for periodontal therapy using MSC. Human bone marrow cells are obtained from the iliac crest and expanded in vitro at Cell and Tissue Engineering Center in Hiroshima University Hospital. MSC are, then, isolated and mixed with Atelocollagen at final concentrations of 2 x 10(7) cells/mL. These MSC in Atelocollagen are transplanted into periodontal osseous defects at the periodontal surgery. The results in all seven patients who received the own MSC transplantation have shown good clinical course. Further basic studies and the continuous clinical trial are needed to prove the effectiveness of the clinical application.

Blood cell production is maintained throughout the lifetime of an individual by hematopoietic stem cells (HSCs). Interaction of HSCs with their particular microenvironments, known as stem cell niches, is critical for maintaining the stem cell properties, including self-renewal capacity and the ability of differentiation into single or multiple lineages. Recently, it was clarified that a osteoblast is a critical component of the niche for HSCs. HSCs keep balance between quiescence and cell division/proliferation in the osteoblastic niche. The HSC specific properties are dynamically controlled by the signalings of receptors/ligands and cell adhesion molecules produced by osteoblasts.