Mesenchymal stem cells (MSCs) are known to have a potential for articular cartilage regeneration. However, most studies focused on focal cartilage defect through surgical implantation. For the treatment of generalized cartilage loss in osteoarthritis, an alternative delivery strategy would be more appropriate. The purpose of this study was to assess the safety and efficacy of intra‐articular injection of autologous adipose tissue derived MSCs (AD‐MSCs) for knee osteoarthritis. We enrolled 18 patients with osteoarthritis of the knee and injected AD MSCs into the knee. The phase I study consists of three dose‐escalation cohorts; the low‐dose (1.0 × 107 cells), mid‐dose (5.0 × 107), and high‐dose (1.0 × 108) group with three patients each. The phase II included nine patients receiving the high‐dose. The primary outcomes were the safety and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) at 6 months. Secondary outcomes included clinical, radiological, arthroscopic, and histological evaluations. There was no treatment‐related adverse event. The WOMAC score improved at 6 months after injection in the high‐dose group. The size of cartilage defect decreased while the volume of cartilage increased in the medial femoral and tibial condyles of the high‐dose group. Arthroscopy showed that the size of cartilage defect decreased in the medial femoral and medial tibial condyles of the high‐dose group. Histology demonstrated thick, hyaline‐like cartilage regeneration. These results showed that intra‐articular injection of 1.0 × 108 AD MSCs into the osteoarthritic knee improved function and pain of the knee joint without causing adverse events, and reduced cartilage defects by regeneration of hyaline‐like articular cartilage. Stem Cells 2014;32:1254–1266
The quality of embryos produced by assisted reproductive techniques should be advanced by the improvement of in vitro culture conditions for successful implantation and pregnancy maintenance. We investigated the anti-oxidative effect of human adipose stem cell (ASC) conditioned medium with its optimal basal medium, Dulbecco's modified Eagle's medium (DMEM-CM), or keratinocyte serum-free medium (KSFM-CM) as supplements during in vitro culture (IVC) of in vitro fertilized mouse embryo. At first, preimplantation embryo development was evaluated in KSFM-CM and DMEM-CM supplemented cultures at various concentrations. The blastocyst (BL) and hatched BL formation rates were significantly increased in 5% DMEM-CM, while no difference was observed from KSFM-CM. Next, comparing the efficacy of KSFM-CM and DMEM-CM at the same concentration, DMEM-CM enhanced the developmental rate of 16 cells, morula, BL, and hatched BL. The expression level of reactive oxygen species decreased and that of glutathione increased in BL cultured with DMEM-CM, which confirms its anti-oxidative effect. Furthermore, apoptosis in BL cultured with DMEM-CM was reduced compared with that in KSFM-CM. This study demonstrated that the comparative effect of human ASC-CM made of two different basal media during mouse embryo IVC and anti-oxidative effect of 5% DMEM-CM was optimal to improve preimplantation embryo development.
Diamond-Blackfan anemia (DBA) is a rare congenital erythropoietic disorder characterized by erythroblastopenia. Conventional treatments of DBA are the administrations of corticosteroids and blood transfusions for mitigation of anemia, and bone marrow transplantation. However, there are hurdles to overcome for long-term use and the conventional treatment. Mesenchymal stem cells (MSCs) have been noted as a novel alternative cell therapy in various diseases, and adipose tissue-derived MSCs (AdMSCs) are known for their versatile efficacies and feasibility. Here, we report the potential efficacies and the safety of intravenous administration of the autologous AdMSC in a patient with DBA for the first time. The isolation and characterization of autologous AdMSCs from a girl aged 11 years, 10 months with DBA were carried out due to the mutation of ribosomal protein s24 (RPS24). AdMSCs, diluted to 1 x 108 cells in 100 ml of saline, were infused intravenously for 1 hour. Intravenous administration of AdMSCs was carried out 5 times in 2-week intervals, and the patient was checked using various assessments (vital signs, physical examination, laboratory tests, adverse events, etc) at every visit. After 3, 6 and 9 months from the first administration of AdMSCs, red blood cell (RBC) count, hemoglobin value, and hematocrit were assessed for the efficacy. There were no side effects or adverse events observed during the treatment. Although showing subnormal values, the RBC number, hemoglobin level, and hematocrit were improved 9 months after the systemic administration of AdMSCs from baseline; the RBC count (x106 /μl), hemoglobin level (g/dl) and hematocrit level (%) were increased from 1.58 to 2.38, 5.6 to 8.3, and 16.9 to 26.1, respectively. The present case reported the first AdMSC administration for DBA patient and indicates it is possible that the intravenous administration of autologous AdMSC can be a safe alternative for DBA treatment.
Many studies have been conducted to cultivate and utilize patients’ own adipose-derived stem cells for the treatment of various incurable diseases and for regenerative medicine that can prolong lifespan. Despite the significant achievements made thus far, the lack of confidence with regard to safety, particularly the concern about Tumorigenicity, has made researchers hesitant to actively apply cultured human autologous adipose-derived cells in clinical trials. Therefore, studies on the Tumorigenicity of cultured adipose-derived stem cells are very important for expanding the field of stem cell–utilizing regenerative medicine. It is also important to study their effect on tumor biomarker levels. Long-term follow-up studies of Tumorigenicity after multiple intravenous administrations of cultured human autologous adipose-derived stem cells have not been reported worldwide. Therefore, the authors have examined about 500 Koreans who were administered more than 1 billion cultured autologous adipose-derived stem cells multiple times from 2010 to 2013 at a medical institution in Japan. We then conducted the first retrospective research in the world on the changes in eight types of tumor biomarkers over three–six years. According to the results of our analysis, there were no significant changes in the observed tumor biomarkers, irrespective of gender and age. These results suggest that multiple administrations of autologous adipose-derived stem cells cultured in accordance with the authors’ method do not affect Tumorigenicity.
Postprostatectomy erectile dysfunction (ED) is the major problem for patients with clinically localized prostate cancer. Recently, gene and stem cell-based therapy of the corpus cavernosum has been attempted for postprostatectomy ED, but those therapies are limited by rapid blood flow and disruption of the normal architecture of the corpus cavernosum. In this study, we attempted to regenerate the damaged cavernous nerve (CN), which is the main cause of ED. We investigated the effectiveness of human adipose-derived stem cell (hADSC) and nerve growth factor-incorporated hyaluronic acid-based hydrogel (NGF-hydrogel) application on the CN in a rat model of bilateral cavernous nerve crush injury. Four weeks after the operation, erectile function was assessed by detecting the intracavernous pressure (ICP)/arterial pressure level by CN electrostimulation. The ICP was significantly increased by application of hADSC with NGF-hydrogel compared to the other experimental groups. CN and penile tissue were collected for histological examination. PKH-26 labeled hADSC colocalized with beta III tubulin were shown in CN tissue sections. hADSC/NGF-hydrogel treatment prevented smooth muscle atrophy in the corpus cavernosum. In addition, the hADSC/NGF-hydrogel group showed increased endothelial nitric oxide synthase protein expression. This study suggests that application of hADSCs with NGF-hydrogel on the CN might be a promising treatment for postprostatectomy ED.
In this paper, we report on a confocal thermoreflectance imaging system that can examine the thermal characteristics of microelectronic devices by penetrating the backside of a device through the substrate. In this system, the local reflectivity variations due to heat generation in the device are measured point by point by a laser scanning confocal microscope capable of eliminating out-of-focus reflections and the thermoreflectance is extracted via Fourier-domain signal processing. In comparison to the conventional widefield thermoreflectance microscope, the proposed laser scanning confocal thermoreflectance microscope improves the thermoreflectance sensitivity by ~23 times and the spatial resolution by ~25% in backside thermoreflectance measurements.
Purpose: Erectile dysfunction (ED) remains a major complication from cavernous nerve injury during radical prostatectomy.Recently, stem cell treatment for ED has been widely reported.This study was conducted to investigate the availability, differentiation into functional cells, and potential of human muscle-derived stem cells (hMDSCs) and human adipose-derived stem cells (hADSCs) for ED treatment. Materials and Methods:We compared the neural differentiation of hMDSCs and hADSCs.Human muscle and adipose tissues were digested with collagenase, followed by filtering and centrifugation.For neural induction, isolated hMDSCs and hADSCs were incubated in neurobasal media containing forskolin, laminin, basic-fibroblast growth factor, and epidermal growth factor for 5 days.Following neural induction, hMDSCs and hADSCs were differentiated into neural cells, including neurons and glia, in vitro.Results: In neural differentiated hMDSCs (d-hMDSCs) and differentiated hADSCs (d-hADSCs), neural stem cell marker (nestin) showed a significant decrease by immunocytochemistry, and neuronal marker (β-tubulin III) and glial marker (GFAP) showed a significant increase, compared with primary hMDSCs and hADSCs.Real-time chain reaction analysis and Western blotting demonstrated significantly elevated levels of mRNA and protein of β-tubulin III and GFAP in d-hADSCs compared with d-hMDSCs.Conclusions: We demonstrated that hMDSCs and hADSCs can be induced to undergo phenotypic and molecular changes consistent with neurons.The neural differentiation capacity of hADSCs was better than that of hMDSCs.
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