Multiple myeloma (MM) is a systemic malignancy of pathologic plasma cells that is treatable with various chemotherapeutic agents and irradiation, but rarely curable. The mean age of affected patients is mid-60s. Recent clinical studies have confirmed that high-dose chemotherapy with stem cell transplantation is the standard therapy for MM. Furthermore, novel therapeutic agents, such as thalidomide and other immunomodulatory agents have been extensively investigated. Recent advances in the diagnosis and treatment were reviewed and summarized.

Myelodysplastic syndrome (MDS) is a heterogenous syndrome which has features of refractory anemia and preleukemic state due to the ineffective hematopoiesis of bone marrow cells. MDS is classified by the FAB classification and/or WHO classification, and has an International Prognostic Scoring System (IPSS) for evaluation of the prognosis. Available therapies consist of a variety of modalities from supportive therapy to hematopoietic stem cell transplantation, and are selected according to the condition of each patient.

Tissue engineering applies the principles of biology and engineering to the development of functional substitutes,for example 1) cells, 2) scaffolds, 3) some cytokines, for lost tissues. The meaning of this bone regeneration is that it decreases the needed tissues and burden of patients. In this time, we applied to mesenchymal stem cells (MSCs) from the own bone marrow as cell sources. MSCs are thought to be multipotent cells that can replicate. And we also used a beta-tricalcium phosphate (beta-TCP) as a scaffold and fibrin glue as materials to regenerate a injectable bone and we injected into the subcutaneous space on the dorsum of the rat. After 8 weeks of implantation, it could be confirmed newly formed bone and fibrin glue functioned as a injectable materials without loosing the cell activity and the proliferation of MSCs. Next we applied Platelet Rich Plasma (PRP) to improve the ability of osteogenesis. PRP contains some cytokines and are expected to promote the increase of osteogenesis. The merit is not immunity rejection from autologous blood collected in the immediate preoperative period. The admixtures of PRP or fibrin glue have fluidity and gel-like consistency as the thrombin mixing. They can be injected with a syringe in tissues. We named this "Injectable Bone". According to the histological observations, the MSCs with PRP were well formed mature bone and neovascularization compared with control (defect only) after 8 weeks implantation. These results demonstrated that the mixture of MSCs and PRP were useful as injectable bone substitute and its ability of bone regeneration is almost equal to autogenous particulate cancellous bone and marrow (PCBM).

In the embryonic development of skeletal elements, cartilage appears to form through the cellular condensation at a particular region within mesenchymal tissues. During this process, cartilage stem cells (or chondroprogenitor cells) pass through several distinct cellular stages, which are regulated by a variety of growth and differentiation factors. In contrast to embryos, chondrogenesis rarely occurs in vivo after birth, except in the process of fracture healing or, to a limited extent, repair of articular cartilage. Full-thickness defects that penetrate articular cartilage are filled with fibrous tissue, fibrocartilage, or rarely with hyaline cartilage. Here we discuss ongoing attempts to induce chondrogenesis for the future therapeutic applications.

Bone marrow mesenchymal stem cells have been considered to differentiate into cells in bone, cartilage, tendon, muscle, and fat. Further analyses revealed that these cell also give rise to myocardial cells, oval cells and nerve cells, indicating high plasticity of these cells. Recent researches have been focused to utilize these cells to regenerate not only bone but also the life-maintaining major organs. As a cell source for the future regeneration of multiple organs, regeneration of the bone marrow is critical and thus studies on the process of bone marrow regeneration will benefit not only bone physiology field alone but also that of many other organs.

Growth factors have been reported to show important roles in fracture healing process. Many studies of experimental animal models demonstrated that some growth factors could enhance bone formation. Clinical applications using the growth factors have been reported, however, effective strategies have not been established. Here, we report a mini review of the growth factors and our new technology, which utilizes growth factors and marrow mesenchymal stem cells.

Gene therapy for advanced breast cancer is expected to be useful therapeutic approach. Strategies in ongoing clinical protocols can be divided into four: (1) suppression of oncogenes or transduction of tumor suppressor genes; (2) enhancement of immunological response; (3) transduction of suicide genes; (4) protection of bone marrow using drug resistance gene. We have started clinical study of multidrug resistance (mdr1) gene therapy. Advanced breast cancer patients received high dose chemotherapy and autologous peripheral blood stem cell transplantation (PBSCT) with mdr1-transduced hematopoietic cells, and then were treated with docetaxel. 2 patients have been treated so far, and in vivo enrichment of mdr1-transduced cells with docetaxel treatment was seen. Both patients are in complete remission and have no apparent adverse effect from mdr1 gene transduction.

Atherosclerosis is responsible for more than half of all deaths in western countries. Numerous studies have reported that exuberant accumulation of smooth muscle cells plays a principal role in the pathogenesis of vascular diseases. It has been assumed that smooth muscle cells derived from the adjacent medial layer migrate, proliferate and synthesize extracellular matrix. Although much effort has been devoted, targeting migration and proliferation of medial smooth muscle cells, no effective therapy to prevent occlusive vascular remodeling has been established. Recently, we reported that bone marrow cells substantially contribute to the pathogenesis of vascular diseases, in models of post-angioplasty restenosis, graft vasculopathy and hyperlipidemia-induced atherosclerosis. It was suggested that bone marrow cells may have the potential to give rise to vascular progenitor cells that home in the damaged vessels and differentiate into smooth muscle cells or endothelial cells, thereby contributing to vascular repair, remodeling, and lesion formation. This article overviews recent findings on circulating vascular precursors and describes potential therapeutic strategies for vascular diseases, targeting mobilization, homing, differentiation and proliferation of circulating progenitor cells.

Despite of plethora of reports on stem cell transplantation leading to neovascularization in infarct models, whether sustaining clinical benefit in post-myocardial infarction patients is manifested by myocyte repair remains unclear. Cardiac muscle regeneration in adult heart is thought to occur through the mobilization and differentiation of mesenchymal stem cells in bone marrow origin, however, recent studies have suggested that substantial cardiac stem cells may exist in the heart itself, repopulating the damaged cardiac muscle during injury or aging processes. The implications of cardiac stem cells-based myocyte plasticity have recently begun to define in human heart, neither arisen from bone marrow nor circulating precursors. Introduction of cardiac stem cells may improve myocardial function, but several hurdles exist and should be coaxed far beyond the clinical application of cardiac regenerative therapies. On-going investigations may lead to the discovery of mediators of cardiac stem cells migration, proliferation and differentiation that, in turn, might result in the mending of the broken heart after injury.

We report a 6-year-old boy who was diagnosed as having neuron-specific enolase (NSE)-positive pro-T cell type lymphoblastic lymphoma preceded with a variety of symptoms such as skin rash, giant splenomegaly, and hyper-gamma globulinemia. He first showed cervical lymphadenopathy in June 1999, followed by a fever of unknown origin with atypical erythema, hepatosplenomegaly, and a few lymphoblastoid cells present in the bone marrow in September. However, no specific treatments were started at this point because a cervical lymph node biopsy failed to show malignancy and the patient's signs and symptoms resolved spontaneously. Two months later, oral prednisolone therapy was started due to recurrence of the fever and erythema, but resulted in exacerbation of the skin lesions and generalized lymphadenopathy. A biopsy of the right inguinal lymph node performed in January 2000 revealed proliferation of lymphoblastic cells positive for CD3, CD5 and NSE with a rearrangement of T cell receptor gene Jdelta, leading to the diagnosis of lymphoblastic lymphoma. After intensified chemotherapy, he received an autologous peripheral blood stem cell transplantation and has been in complete remission for 4 years.

Monoclonal antibodies (mAbs) therapies have been introduced to the many kinds of malignancies. Rituximab (Rituxan), a chimeric anti-CD20 monoclonal antibody, has improved clinical outcome in the patients with B cell non-Hodgkin's lymphoma (NHL) as a single agent as well as combination with chemotherapies including CHOP and stem cell transplantation. The efficacy has been reported in the patients with follicular lymphoma as well as aggressive NHL. The expression of CD20 should be confirmed by immunopathological staining or flow cytometry before the treatment. Gemtuzumab ozogamicin (Mylotarg), calicheamicin conjugates of anti-CD33 mAb, has been introduced in the treatment of AML. CD33 is not expressed by immature pluripotent stem cells even though expressed on myeloid progenitor cells. Mylotarg is internalized via CD33, however, detouched calicheamicin might be pumped out by multi-drug resistant related p glycoprotains (p-gp). The expression of CD33 and p-gp should be analyzed by flow cytometry before the treatment. We should give another caution to tumor-lysis syndrome and veno-occlusive disease.

Regenerative medicine, which takes advantage of the unique capacity of stem cells, is a novel medical strategy to cure irreversible organ failure. There are three important elements in regenerative medicine: cells, scaffolds and signals. Although substantial progress regarding each element has been made in the past few years, it still falls short of clinical applications. In the geriatric field, osteoporosis, osteoarthritis and periodontitis are the major targets of regenerative medicine. They are usually not life-threatening, but often severely affect QOL of elderly patients. Since elderly people have already reduced number of stem cells in bone and cartilage, we need to know the sufficient conditions for osteogenesis and chondrogenesis by comprehensively screening various conditions. We developed a marker gene system expressing green fluorescence protein (GFP) under the control of osteoblast- and chondrocyte-specific promoters. This system helps us monitor osteoblast and chondrocyte differentiation easily, precisely and non-invasively. Using this system, we are now trying to find the sufficient conditions for osteogenesis and chondrogenesis, and to discover osteogenic and chondrogenic small compounds.

Drug therapy, gene therapy, and cell therapy may be effective to degenerative muscular diseases caused by genetic mutations including muscular dystrophy. Stem cells including embryonic stem (ES) cells and adult stem cells (tissue stem cells) are generally believed to be applicable to cell therapy. However, both types of cells have several problems to be solved for the cell therapy. We have shown that the expression of SV40 large T antigen in terminally differentiated mouse C2 skeletal muscle myotubes induce mitosis and dedifferentiation. This finding has exploded the concept that terminally differentiated cells never proliferate. It remains to be determined, however, whether mature myofibers in vivo are capable of dedifferentiation and proliferation. Here we present the data showing that mouse myofibers dedifferentiate and proliferate to form many mononucleated cells. Eventually, these dedifferentiated cells redifferentiate and regenerate myofibers. The isolated dedifferentiated cells show stem cell-like phenotype. These cells are expected to be applied to the cell therapy for degenerative muscular diseases.

An approach for symptomatic Parkinson's disease (PD) therapy is fetal dopamine neuron transplantation. This approach remains the technical and ethical difficulties in obtaining sufficient and appropriate donor fetal brain tissue. In developments of stem cell biology, neural stem cells exist in the adult brain as well as embryo and have the capacity to regenerate and to give rise to the three cell lineages in the nervous system. Embryonic stem cells (ES cells) and multipotent adult progenitor cells (MAPCs) are pluripotent cells, which give rise to all cells in the organism. Current findings suggest that stem cells but not fetal brain tissues may be suitable for cell replacement therapies in the treatment of neurodegenerative disorders. We will briefly review the current state of cell therapy, and will critically discuss the potential of stem cells for the treatment of PD.