Muscular dystrophy is defined as "a group of hereditary disorders with the major symptom of progressive muscle weakness due to muscle fiber degeneration and necrosis". After the discovery of the dystrophin gene and the gene product for Duchenne muscular dystrophy in 1986, there has been remarkable progress in the differential diagnosis and in understanding the pathogenetic mechanism of muscle fiber necrosis. With discoveries of genes responsible for many other disorders, the classification of muscular dystrophy has become more complicated; for instance, there are at least 15 diseases in the limb-girdle muscular dystrophy (LGMD) group, including the autosomal dominant forms, LGMD1A-1E and the recessive forms, LGMD2A-2I. Among them, gene defects in the sarcoglycan complex (sarcoglycanopathy) have been added to LGMD2C-2F. Sarcoglycanopathy seems to be rare in Japan since only 6-7% of LGMD patients had this defect. There are two major possible strategies in treating these patients. One is gene therapy, which is recently being investigated in the mdx mouse by using adenovirus-associated virus (AAV) vector inserted with a microdystrophin gene. Dr Takeda has reported favorable results in mdx mouse muscle with this method. Another is regeneration therapy using stem cells. There are many barriers to overcome to treat patients with stem cells isolated from bone marrow. The most difficult problem to solve is how to culture the stem cells to increase their numbers for application and how to introduce the normal dystrophin gene into these cells.

Cerebral ischemia often results in neuronal loss, leading to the neurological deficits in stroke patients. To obtain the functional recovery after stroke, cell transplantation and enhancement of endogenous neurogenesis may have potential application. Recent evidence has demonstrated that neural stem cells exist in the adult mammalian brain. After cerebral ischemia, newly born neurons were found not only in hippocampal dentate and olfactory bulb but also in hippocampal CA1 and striatum, where neurons were lost after ischemia. Administration of neurotrophic factors or genes encoding them into the lateral venticule could enhance endogenous neurogenesis in experimental ischemia model. Furthermore, we have recently developed non-invasive gene transfer into macrophages infiltrating an infarct to stimulate proliferation of neural stem cells in cerebral infarction. Several strategies including gene therapy and pharmacological approach will be tried in stroke patients in near future. However, it remains unclear whether the number of new-born neurons from endogenous neural stem cells is sufficient for replacement of damaged neurons. Cell transplantation will have the advantage of preparing the large amount of transplanted cells. Human neural stem cells, embryonic stem cells and bone marrow-derived cells will be donor cells in stroke patients. Surprisingly, neuron-like cells derived from human teratoma cell line were already applied in stroke patients. However, ethical aspect will have to be discussed carefully before cells from other individuals are used as donor cells in stroke patients.

We report the case of 13-year-old boy who had been diagnosed as having anaplastic large cell lymphoma (ALCL) when he was 11 years old. He suffered a relapse despite the chemotherapy regimens he had been subjected to. Since anaplastic lymphoma kinase (ALK), one of the important prognostic factors of ALCL, was not expressed in the tumor cells, allogeneic peripheral blood stem cell transplantation (PBSCT) from his HLA-matched elder brother was performed. Eleven months after PBSCT, the patient developed nephrotic syndrome as a consequence of chronic graft-versus-host disease (GVHD). He was diagnosed as having membranous nephropathy (MN) based on the results of histological examinations. Soluble interleukin-2 receptor and anti-nuclear antibody closely reflected the clinical course of MN, therefore some immune mechanisms closely related to chronic GVHD seemed to contribute to the occurrence of MN after PBSCT.

Articular cartilage has a limited capacity for repair. Repair of articular cartilage has been an important theme for orthopaedic surgeons. With the progress of tissue engineering in the treatment of articular cartilage injury, we can obtain good results, to some extent, by cell transplantations. This review summarized the present status of the treatment of articular cartilage injuries by cell transplantations.

Injury to the articular cartilage occurs under various pathological conditions such as trauma, inflammation and aging and is followed by osteoarthritic changes of the affected joints. Recently, some studies have revealed that enough chondrogenic proliferation was required using some factors such as TGF-beta and BMPs. We, also, have reported that synovial tissues include multipotent mesenchymal stem cells, which can differentiate into chondrocytes. These results suggest that not only are synovial cells a good therapeutic target of inflammatory joint diseases, but also can be utilized for tissue engineering of cartilage.

Cartilage plays multiple roles in vertebrate animals. In an embryonic stage and early postnatal life, cartilage is important not only as a structural support of early embryo but also as a template of endochondral bone. In a later postnatal life, cartilage provides smooth joint movement and tissue elasticity. A number of critical signaling molecules that regulate cartilage formation and chondrocytes maturation in endochondral bone formation have been identified to date. The interplay of those important molecules is also actively studied. However, several fundamental questions still remain unsolved. What signal initiates mesenchymal cell condensation? Does condensation enough to make cells competent for BMP-induced chondrogenesis? Is there chondrocyte stem cell in cartilage? Likewise, it is not known which factor triggers chondrocytes maturation. In this review article, we summarized the action of several key factors including BMP, hedgehog, PTHrP, and Wnt in condensation, chondrogenenic differentiation and maturation of chondrocytes. Towards further understanding of above fundamental questions, this review article also tried to propose future direction of cartilage biology research.

Tooth is a composite of the three different biological mineralized tissues (dentin, enamel, and cementum) that acquired supreme mechanical properties and function necessary for the mechanical digestion of the food throughout life. The underlining mechanisms of mineralization of each of these three components are unique and different from each other. Here the focus was placed on the mineralization process of dentin and enamel of the teeth of vertebrates.

Bone morphogenetic proteins (BMP) are cytokines that promote differentiation of mesenchymal stem cells into differentiated osteoblasts and bone formation. Recently, HMG-CoA reductase inhibitors (statins) emerged as a candidate for the treatment of osteoporosis, because they stimulate BMP-2 expression and bone formation. Inhibition of Rho/Rho-kinase pathway may be involved in statin effect on bone formation.

PPARgamma is a ligand-dependent nuclear receptor and regulates adipogenesis and associates with diabetes, obesity. Recently, relationship between PPARgamma and bone metabolism was investigated. Here, we report the molecular mechanism of PPARgamma transcriptional activity and the suppression of PPARgamma activity by cytokines in bone marrow-derived mesenchymal stem cells.

A 51-year-old woman was admitted to our hospital with tonsillar swelling. After tonsillectomy was performed, she was diagnosed as having CD56-positive T-cell lymphoma, mainly composed of small and medium-sized atypical cells. An immunohistochemical study showed that the malignant lymphocytes were positive for CD3, CD8, CD56, TIA-1 and granzyme B, while negative for CD20, CD5 and CD10. Flowcytometry demonstrated the lymphocytes were positive for CD56. Southern blot analysis revealed a rearrangement of the T-cell receptor gamma chain. The disease stage by Ann Arbor staging classification was II B. We provided MCEC therapy followed by autologous peripheral blood stem cell transplantation, and complete remission (CR) was achieved. Two months after CR, however, the patient relapsed with peritonitis due to perforation of an ileal tumor, and died of sepsis. It is rare for CD56-positive T-cell lymphoma to occur primarily in the tonsils. Because small bowel ulcers were revealed during the course of induction chemotherapy, we report a valuable case in which suspected CD56-positive enteropathy-type T-cell lymphoma (ETL) occurred primarily in the tonsils.

A 42-year-old woman presented with pericardial and pleural effusion, ascites and para-aortic lymphadenopathy of unknown etiology. Six months later she was admitted with fever, pain and motor disturbance of lower limbs, and exacerbation of the effusion, ascites and edema. Physical examination showed hepatosplenomegaly, skin pigmentation and hypertrichosis. Immunoelectophoresis revealed monoclonal IgA-lambda protein in the serum and Bence-Jones protein-lambda in the urine. Bone marrow aspiration showed a mild increase of atypical plasma cells. Vascular endothelial growth factor (VEGF) had markedly increased to 10,900 pg/ml. Electromyography showed changes suggestive of demyelination. These clinical features were consistent with the diagnosis of POEMS syndrome. VAD chemotherapy was not effective for the effusion and neuropathic deterioration. After control of the massive pleural effusion by chest tube drainage, peripheral blood stem cell (PBSC) collection was performed with cyclophosphamide and G-CSF. The patient received melphalan 100 mg/m2 on 2 consecutive days and the PBSC were infused 2 days later. The bone marrow recovered rapidly and the pericardial and pleural effusion disappeared completely. Her performance status markedly improved from a bedridden state. High-dose melphalan with auto-PBSCT should be investigated further as a recommended therapy for POEMS syndrome.

It has been well established that the liver can regenerate after resection. Liver regeneration is a fundamental mechanism by which the liver responds to injury. This review article discusses molecular and cellular mechanism of liver regeneration, including growth factors and cytokines in the initiation and regulation of liver regeneration, the importance of the liver extracellular matrix and its dynamic effect on hepatocyte growth, and finally, stem cell biology in liver regeneration.

Despite the promising outcomes of unrelated cord blood transplantations (UCBT) in pediatric recipients, the major limitation in the widespread use of cord blood (CB) as a source of hematopoietic stem cells (HSC), particularly in adults, is the physiological small number of cells. To overcome this limitation, we developed an ex vivo expansion system for HSC, in which CB CD34+ cells are cultured on feeder cells (HESS-5 cells) in the presence of cytokines (TPO, SCF and Flt3 ligand). A phase I/II clinical trial, approved by our institutional review board, has been started to assess the safety and effectiveness of this system. A 52-year-old woman with metastatic breast cancer and myelodysplastic syndrome (MDS) received a non-myeloablative preparative regimen followed by UCBT. On day 0, 75% of the whole CB and a fraction of CD34 negative cells were transplanted. The remaining 25% of the CB was CD34-selected and expanded on HESS-5 in a non-serum media in the presence of TPO, SCF, and Flt3-L. On day 5, the ex vivo-expanded, CD34+ cells were transplanted. The patient received 1.83 x 10(7)/kg of total nucleated cells and 7.7 X 10(4)/kg of CD34+ cells (expanded and unexpanded). No acute adverse effects were observed after the infusion of the cultured cells. She suffered from pneumonia on day 37, a cerebral hemorrhage on day 48, and died on day 50. Further studies are required to assess the effectiveness of this protocol.

A 51-year-old female with acute myeloid leukemia was admitted to our hospital in December 2001. Though she had undergone two courses of induction chemotherapy (idarubicin hydrochloride + cytarabine), she failed to achieve a complete remission. In April 2002, while in non-complete remission, she subsequently underwent total body irradiation (TBI) and treatment with cyclophosphamide (CY) and etoposide (VP-16) before receiving an allogeneic peripheral blood stem cell transplant from her HLA-identical brother. For graft-versus-host disease (GVHD) prophylaxis, she was given tacrolimus and methotrexate. The infused CD34 positive cells provided 8.1 x 10(6) cells per kg. Engraftment was obtained on post-transplant day 14, and there was no evidence of clinical acute GVHD. The use of tacrolimus was discontinued on post-transplant day 60. As there was no occurrence of clinical acute GVHD, the patient received a donor lymphocyte infusion (CD3 cells 0.57 X 10(7) cells per kg) on post-transplant day 105. On day 132, however, she complained of coughing and fever, and on day 135, she was admitted to our hospital again for dyspnea. A CT scan demonstrated ground-glass opacity in the right pulmonary lobe. After considering her clinical course, symptoms, blood gas, CT scans, etc., we suspected interstitial pneumonia. The dyspnea progressively worsened, however, and despite the use of mechanical ventilation from day 143, the patient died on day 149. From the day she was admitted till the day she was intubated, she was unable to produce sputum. Autopsy findings revealed yellow-white tracheal pseudomembranes, as well as Aspergillus hyphae in the trachea, bronchus, and bilateral lungs. These findings are characteristic of Aspergillus tracheobronchitis. The clinical course of Aspergillus tracheobronchitis in allogeneic stem cell transplant recipients is, however, different from that of the usual invasive Aspergillus infection, and although Aspergillus tracheobronchitis is a very rare disease, attention should be paid to the possibility of its occurrence.