To develop a new cell based therapy for chronic obstructive pulmonary disease (COPD), we need to understand 1) the role of tissue-specific and bone marrow-derived stem cells, 2) extracellular matrix, and 3) growth factors. Recently, bronchioalveolar stem cells were identified in murine distal lungs. Impairment of these stem cells may cause improper lung repair after inflammation, resulting in pulmonary emphysema. Bone marrow-derived cells are necessary to repair injured lungs. However, the long term role of these cells is not understood yet. Although we need more careful analysis and additional experiments, growth factors, such as hepatocyte growth factor, are good candidates for the new cell based therapy for COPD. Lung was believed as a non-regenerative organ. Based on these recent reports about lung regeneration and stem cells, however, new strategies to treat COPD and a new point of view to understand the pathophysiology of COPD are rising.

Age-related macular degeneration (AMD) is a leading cause of legal blindness in developed countries. Even with the recent advent of several treatment options, treatment of exudative AMD, characterized by choroidal neovascularization (CNV), remains difficult. Thus, in this review article, we report on the investigation of novel approaches for the management of AMD, antiangiogenic therapy for CNV, and retinal regenerative therapy. Polyion complex(PIC) micelles have a range in size of several tens of nanometers formed through an electrostatic interaction, and accumulate in solid tumors through an enhanced permeability and retention(EPR) effect. In this study, we examined the distribution of the PIC micelles which encapsulate fluorescein isothiocyanate-labeled poly-L-lysine{FITC-P(Lys)} in experimental CNV in rats, to investigate whether PIC micelles can be used for the treatment of CNV. We demonstrated that PIC micelles accumulate in the CNV lesions and are retained in the lesions for as long as 168 hours after intravenous administration. These results raise the possibility that PIC micelles can be used for achieving an effective drug delivery system against CNV. Although photodynamic therapy (PDT) is a very promising treatment for AMD, most patients require repeated treatments. For effective PDT against AMD, the selective delivery of a photosensitizer to the CNV lesions and an effective photochemical reaction at the CNV site are necessary. The characteristic dendritic structure of the photosensitizer prevents aggregation of its core sensitizer, thereby inducing a highly effective photochemical reaction. We present an effective PDT for AMD employing a supramolecular nanomedical device, i.e., a novel dendritic photosensitizer encapsulated in a polymeric micelle formulation. With its highly selective accumulation in CNV lesions, this treatment resulted in a remarkably efficacious CNV occlusion with minimal unfavorable phototoxicity. Our results will provide a basis for an effective approach to PDT for AMD. Spatial control of gene transfection in the body is a core issue in the gene therapy for ocular diseases including AMD. Photochemical internalization (PCI) is a technology that effects light-induced delivery of DNA directly inside cells. PCI usually requires that a photosensitizer be added to the drug-delivery system to photochemically destabilize the endosomal membrane. We have developed a ternary complex composed of a core containing DNA packaged with cationic peptides and enveloped in the anionic dendrimer, phthalocyanine, which provides the photosensitizing action. Subconjunctival injection of the ternary complex followed by laser irradiation resulted in transgene expression only in the laser-irradiated site in rats. This PCI-mediated gene delivery system is potentially useful in gene therapy for ophthalmic diseases. Accumulation of lipofuscin is related to an increased risk of AMD. We report that a major lipofuscin component, A2E(N-retinyledin-N-retinylethanolamin), activates the retinoic acid receptor (RAR). In vivo experiments suggest that A2E accumulation results in the pro-angiogenic conversion of retinal pigment epithelial(RPE) cell phenotype. This physiological consequence of A2E accumulation may be related to a novel potential therapeutic target for CNV. To recover visual function damaged by AMD, retinal regenerative therapy is essential. We investigated whether subretinal transplantation of bone marrow mesenchymal stem cells(MSCs) promotes photoreceptor survival in a rat model of retinal degeneration. Morphological and functional studies in vivo, including histological analysis and electrophysiological studies, indicate that the subretinal transplantation of MSCs delays retinal degeneration and preserves retinal function. These results suggest that MSC is a useful cell source for cell-transplantation therapy for retinal degeneration. In order to elucidate the molecular mechanisms of development of the fovea, which is composed mainly of cone photoreceptors and is susceptible to injury from AMD, we performed a comparative gene expression analysis between the central and peripheral regions of the monkey retina using monkey (rhesus macaque) genome microarray chips. We then selected the clones which were expressed at significantly higher levels in the central region and confirmed their expression in the monkey retina by section in situ hybridization. This study sheds light on the mechanisms of foveal development and may lead to the development of regenerative medicine for cone photoreceptors.

Oxidative stress due to free radicals is related to the pathogenesis of many chronic disorders including cancer, inflammation, and neurological diseases. Oxidative stress such as aging and light exposure is also considered to be associated with age-related macular degeneration and cataract. The ocular surface is chronically exposed to oxidative stress including ultraviolet light, the oxygen in air, and changes in oxygen pressure due to blinking. We demonstrated that a rat dry eye model with a jogging board showed corneal epithelial disoders and elevated levels of oxidative stress, suggesting that the pathogenesis of epithelial disorders in dry eye with low frequency of blinking is related to oxidative stress. Next, using a model of laser-induced choroidal neovascularization (CNV), we showed that angiotensin receptormediated inflammation is required for the development of CNV. We also demonstrated that mice deficient in superoxide dismutase (SOD) showed typical clinical features of AMD. Finally, we proposed our thoughts about regenerative medicine, that is, to maintain quiescent stem cells, we have to regulate the aging of stem cells.

Pediatric hematopoietic stem cell transplantation (SCT) has been well established. Recent advances in the transplantation conditioning regimens and in the stem cell sources allow us to increase the candidates for transplantation, but the actual number of pediatric SCTs has been decreased because of the decline in the pediatric population and the progress of various chemotherapies and molecular targeted therapies. Pediatric SCT has become rather sophisticated. Cord blood (CB) stem cell transplantation has the problem of rejection and high relapse rate in the advanced malignant diseases. To overcome the rejection and relapse, it is important to select CB with a large number of the cells and the HLA-mismatched CB. Reduced intensity preparative regimens are increasingly adopted to reduce the early and late transplantation-related complications. In the pediatric setting, reduced intensity transplantation is still under investigation. Late complications for pediatric SCT, growth failure and secondary malignancies should be considered for the increasing number of long-term survivors.

Clinically, fatty marrow, accumulation of adipocytes in bone marrow, is often observed in the patients who manifest bone diseases such as osteoporosis. Since adipocytes and osteoblasts are differentiated from mesenchymal stem cells, it would be clinically and biologically important to understand regulatory mechanisms of the balance between adipogenesis and osteoblastogenesis. Recently, experimental findings indicated the involvement of adipokines including leptin and adiponectin in bone metabolisms. Thus, adipocytes appear to play a role in regulation of bone metabolisms.

Skeletal muscles become atrophied by muscular disorders such as muscular dystrophy, wasting and even aging. In addition to muscle atrophy, progressive muscle damage, inflammation and replacement of muscle fibers with fibrous and fatty tissues are observed in muscular dystrophy. Neuronal innervation is required for skeletal muscle, and muscles become atrophic when motor neurons are affected by neurodegenerative disorders such as amyotrophic lateral sclerosis. Restoring muscle mass and function lost by diseases such as muscular dystrophy and neurodegenerative disorders is important. There are three rational therapies for muscular dystrophy and related diseases: gene therapy, cell therapy and drug therapy. Gene therapies to replace the defective genes have been tried with various degrees of effectiveness. Multiple myogenic stem cells including satellite cells, bone marrow cells, muscle side population cells, muscle-derived stem cells and mesoangioblast have been characterized. Cell therapies using these stem cells are one of the promising therapies for neuromuscular diseases causing muscle atrophy. As pharmacological drug therapies, increasing skeletal muscle mass by myostatin inhibition is quite promising and will be applied clinically in the near future.

Mediastinal germ cell tumor (MGCT) is histologically similar to, but is different from that in gonad glands. As to therapy, mature teratoma can be cured by resection alone. But cisplatin-based chemotherapy, often together with resection and radiation, has been playing a primary role in managing malignant MGCT consisting of seminoma and non-seminomatous MGCT. Consequently, comparably high cure rate in MGCT has been achieved. Treatment decisions should be based on the available evidence mainly obtained by retrospective studies because of the rarity of the entity. In this article, we reviewed the current strategy for MGCT, and described the outcome of 30 cases of malignant MGCT in our institution, in addition to presenting a case of nonseminomatous MGCT. Seventeen of 18 patients with malignant MGCT survived after surgery with cisplatin-based chemotherapy, while only 3 of 12 survived before cisplatin was introduced. In non-seminomatous MGCT, we now adopt cisplatin-based chemotherapy followed by surgery, including high-dose chemotherapy with peripheral blood stem cell transplantation to obtain the normalization of tumor markers. Additional chemotherapy is considered, if viable cells are found in resected specimen.

Researchers have demonstrated the feasibility of transplanting human cultured corneal endothelial cells (HCEC) in various animal models. This review provides an overview of recent advances in our understanding of cultured corneal endothelial cell transplantation. We propose HCEC transplantation with a collagen sheet as the substitute carrier of HCEC. We also propose a novel strategy for corneal endothelial cell deficiency with the injection of adult human corneal endothelial precursors (HCEP). Using white rabbits or nude rats as keratopathy models, cultured HCEC were seeded on a collagen sheet. Descemetorhexis was performed on rabbit eyes. The HCEC collagen sheet was brought into the anterior chamber and fixed to the posterior stroma (HCEC group). Rabbit corneas with collagen sheet transplantation after descemetorhexis(collagen group) and with only descemetorhexis(no transplantation group) were the controls, respectively. As for HCEP transplantation, HCEP, isolated from rabbit corneal endothelial cells by sphere-forming assay, were injected into the anterior chamber and a face-down position was maintained for 24 hours in the rabbits (HCEP group). Pump function parameters of the HCEC sheets were 76-95% of those of human donor corneas. Mean corneal thickness in the HCEC group was significantly less than in the collagen and no transplantation groups 1, 3, 7, 14, 21, and 28 days (p< 0.05) after surgery. Cells were spread over the rear corneal surface in the HCEC group. In HE staining, marked stromal edema was present in the collagen and in the no transplantation groups, but not in the HCEC group with collagen sheets bearing monolayer cells. In the HCEP group, injected spheres were spread over the rear surface of the cornea and corneal edema was markedly suppressed. Our findings indicate that transplantation of cultured HCEC from adult human donor cornea by means of a collagen sheet can maintain the function of corneal dehydration. This suggests the feasibility of transplantation using cultured HCEC with a collagen sheet for corneal endothelial cell dysfunction. Additionally, adult precursor injection therapy can be also an effective strategy for corneal endothelial cell deficiency in place of conventional full-thickness corneal transplantation.

A 53-year-old woman was admitted to our hospital with left chest-wall pain. Computed tomography scans showed a homogenous mass on the left chest-wall with pleural effusion. Laboratory data showed anemia, hypercalcemia, and high levels of serum IgG. An IgG-lambda monoclonal protein was detected with serum immunoelectrophoresis. In addition, the serum level of neuron specific enolase (NSE) was elevated. A chest-wall tumor biopsy and a bone marrow aspiration revealed diffuse proliferation of atypical plasma cells, which were positive for cytoplasmic CD38 and IgG-lambda. The patient was diagnosed as having IgG-lambda type multiple myeloma with a chest-wall plasmacytoma. Immunostaining revealed diffuse NSE staining in the cytoplasm of the atypical plasma cells. These findings suggested that the myeloma cells produced NSE. The left chest-wall tumor and bone marrow myeloma cells disappeared following several courses of chemotherapy and radiotherapy and the serum levels of IgG and NSE also normalized. No recurrence of the multiple myeloma was seen after an autologous peripheral blood stem cell transplantation. This is the second report of an NSE-producing multiple myeloma. Interestingly, our case has similar clinical phenotypes with the previously reported case, such as chest-wall plasmacytoma, pleural effusion and hypercalcemia.