Because the capacity of articular cartilage for repair is limited, defects are a major clinical problem, and there is at present no satisfactory clinical technique to regenerate cartilage defects. Current clinical practice involves the bone stimulation technique, which breaks subchondral bone to facilitate cartilage repair from bone marrow derived cells and cytokines. This consists of multiple perforations, abrasions, and micro-fractures. However, with this procedure, cartilage defects are repaired with fibrocartilage, which is known to be biochemically and biomechanically different from normal hyaline cartilage and degeneration occurs in the reparative tissue. Autologous chondrocyte implantation (ACI) for repair of human articular cartilage was reported in 1994, and approved by the USA Food and Drug Association in 1997. This procedure has been performed for more than 20000 people all over the world, but its effectiveness is still controversial. Mosaic plasty was explored in the 1990s. Using this procedure, we can repair defects with hyaline cartilage, but the donor site morbidity is unsolved. To explore a new method for cartilage repair, we transplanted autologous culture-expanded bone marrow mesenchymal cells into articular cartilage defects. Clinical symptoms were improred but the repair cartilage was not hyaline cartilage. Further improvement is required. Many investigations have been made in the search for better means of repair, including gene transduction and the addition of growth factors during cell culture. In addition to bone marrow mesenchymal cells, synovial cells, adipocytes, muscle cells, etc. have been evaluated.

Several recent studies demonstrated the potential of bioengineering using somatic stem cells in regenerative medicine. Adult human mesenchymal stem cells (hMSCs) derived from bone marrow have the pluripotency to differentiate into cells of mesodermal origin, e.g., bone, cartilage, adipose, and muscle cells; they, therefore, have many potential clinical applications. On the other hand, stem cells possess a self-renewal capability similar to cancer cells. For safety evaluation of tissue engineered medical devices using normal hMSCs, in this study, we investigated the expression levels of several genes that affect cell proliferation in hMSCs during in vitro culture. We focused on the relationship between the hMSC proliferation and their transforming growth factor beta (TGFbeta) signaling during in vitro culture. The proliferation rate of hMSCs gradually decreased and cellular senescence was observed for about 3 months. The mRNA expressions of TGFbeta1, TGFbeta2, and TGFbeta receptor type I (TGFbetaRI) in hMSCs increased with the length of cell culture. The mRNA expressions of Smad3 increased, but those of c-myc and nucleostemin decreased with the length hMSCs were in in vitro culture. In addition, the expression profiles of the genes which regulate cellular proliferation in hMSCs were significantly different from those of cancer cells. In conclusion, hMSCs derived from bone marrow seldom underwent spontaneous transformation during 1-2 months in vitro culture for use in clinical applications. In hMSCs as well as in epithelial cells, growth might be controlled by the TGFbeta family signaling.

The regenerative potential of stem cells has recently been under intense investigation. In vitro, stem and progenitor cells have the ability for self-renewal and differentiation into organ-specific cell types. In vivo, transplantation of these cells may reconstitute organ systems, as shown in animal models of disease. In contrast, differentiated cells do not exhibit such characteristics. Human endothelial progenitor cells (EPCs) have been isolated from the peripheral blood of adult individuals, expanded in vitro and committed to an endothelial lineage in culture. The transplantation of these human EPCs has been shown to facilitate successful salvage of limb vasculature and perfusion in athymic nude mice with severe hindlimb ischemia, while differentiated endothelial cells (human microvascular endothelial cells) failed to accomplish limb-saving neovascularization. Future studies will clarify the mechanisms and circumstances that may be responsible for modulating the contribution of vasculogenesis to postnatal neovascularization. Specifically in this regard, it is intriguing to consider the possibility that certain angiogenic growth factors acknowledged to promote both angiogenesis and vasculogenesis in the embryo, but have been assumed to promote neovascularization exclusively by angiogenesis in the adult, may in fact promote migration, proliferation, and mobilization of EPCs from bone marrow. The possibility that modulation of vasculogenesis can be used therapeutically to augment as well as inhibit neovascularization deserves further investigation.

A successful cure for muscular dystrophies has yet to be demonstrated, but we could notice spectacular progress for the past few years. Advances have been made in methods of delivering foreign genes into muscle cells, either as naked plasmid DNA or via viral vectors. Among the virus-based methods, results with adeno-associated viral vectors have been the most promising. Systemic administration of anti-sense oligonucleotides has shown incredible success in inducing dystrophin expression and ameliorating muscle pathology via exon skipping in canine models of muscular dystrophy. Biochemical and functional rescue of dystrophic muscle has also been demonstrated with the transplantation of normal or genetically modified myogenic stem cells, as well as with a number of pharmacological approaches in animal models. Here we review the current researches on the treatment of muscular dystrophies and clinical trials on Duchenne muscular dystrophy.

Restorative neurosurgery proceeds in the two ways, through biological means or through nerve-computer interface technology. Stem cells are now expected to repair the injured spinal cord and cochlear implants have already restored hearing in many patients. These examples represent each of these methodologies, respectively. The auditory brainstem implant is an extension of the technology of the cochlear implant. In this review article, the author summarizes the present status of auditory brainstem implant (ABI), comparing it to cochlear implant (CI). CI restores hearing by stimulating the cochlear nerve in the cochlea for patients whose deafness has been caused by inner ear disease; ABI does it by stimulating the cochlear nucleus of the brainstem for those deaf due to bilateral cochlear nerve dysfunction. In the world, up until now, more than 700 patients, almost all of whom are neurofibromatosis type 2, have undergone ABI and had hearing restored. Hearing performance by ABI, however, is not so good as that by CI. To improve the quality of hearing by ABI, new techniques such as advanced coding strategies and depth electrodes are now being introduced.

Stem cell-based cell therapy is one of attractive therapeutic approaches to muscular dystrophy. In transplantation into dystrophic skeletal muscle, muscle satellite cells and musclE side population (SP) cells are good candidates as sources of stem cells. We purified mouse satellite cells from adult C57B16 mice by FACS using a monoclonal antibody, SM/C-2.6, which can specifically recognize quiescent satellite cells. DNA micro-array analysis on both quiescent and activated satellite cells allowed us to distinguish novel quiescent satellite cell-specific genes. These genes may encode molecules that keep satellite cells in a dormant and undifferentiated state. We transplanted purified muscle satellite cells transduced with lentivirus vector, and found these cells were effectively incorporated into dystrophin-deficient skeletal muscle and expressed transduced dystrophin. We also identified a novel side population (SP) cells in uninjured and regenerating skeletal muscle. The majority of muscle-SP cells in uninjured stage showed endothelial cell-like properties. CD31 negative/CD45 negative SP cells were a minor population in normal conditions, but actively proliferate during muscle regeneration. Co-transplantation experiments showed that the SP cells synergistically promoted muscle regeneration with satellite cells. It is indispensable to study molecular basis of muscle stem cells and muscle regeneration to achieve effective stem cell-based cell therapy on muscular dystrophy.

Korea is a rapidly growing aging society and stroke is still the second cause of death, comprised of about 15% of the total death in Korea. But the mortality of stroke is slightly decreasing despite increase of stroke incidence, probably due to improvement of management of stroke and related risk factors. The advent of DWI/ MRA enables us to make more accurate patho-etiological diagnoses of ischemic strokes. With the findings in DWI/ MRA and the new classification policy that entrusts the final judgment to stroke specialists of each hospital, we could further classify the large artery disease of the TOAST classification into in-situ thrombosis, artery to artery embolism, and low-flow infarction and make the most plausible diagnosis of undetermined etiology in the TOAST classification. In this article we reviewed medical and surgical treatment of stroke, especially focusing the clinical practice in Korea. We also provided our results of in vivo experiments with promising drugs and stem cells, too. In conclusion, there are too many uncertain areas of stroke managements yet to be settled. We need larger clinical data pools that are collected based on accurate etiological diagnoses of stroke subtypes on the one hand, and brilliant basic research on the other.