작성자 : 베데스다병원

요약 : 
Ageing brings about the progressive decline in cognitive function and physical activity, along with losses of stem cell population and function. Although transplantation of muscle derived stem/progenitor cells extended healthspan and lifespan of progeria mice, such effects in normal animals were not confirmed. Human amniotic membrane-derived mesenchymal stem cells (AMMSCs) or adipose tissue-derived mesenchymal stem cells (ADMSCs) (1 × 106 55 cells/rat) were intravenously transplanted to 10-month-old male F344 rats once a month for their life-long periods. Transplantation of AMMSCs and ADMSCs improved cognitive and physical functions of naturally-ageing rats, extending lifespan by 23.4% and 31.3%, respectively. The stem cell therapy increased the concentration of acetylcholine, and recovered neurotrophic factors in the brain and muscles, leading to restoration of microtubule-associated protein 2, cholinergic and dopaminergic nervous systems, microvessels, muscle mass as well as antioxidative capacity. The results indicate that repeated transplantation of AMMSCs and ADMSCs elongate both healthspan and lifespan, which could be a starting point for anti-ageing or rejuvenation effects of allogeneic or autologous stem cells with minimum immune rejection.

요약 : 
The amniotic epithelium consists of cells exhibiting mature epithelial cell characteristics, but also varying degrees of stemness. We tested the hypothesis that induction of epithelial-to-mesenchymal transition (EMT) in
amniotic epithelial cells (AECs) derived from human placenta enhances their capacity to support the ischemic myocardium. In response to incubation with transforming growth factor-b1 (TGF-b1) protein, AECs lost their
cobblestone morphology and acquired a fibroblastoid shape, associated with downregulation of E-cadherin, upregulation of N-cadherin, Akt phosphorylation, and intracellular periostin translocation. EMT–AECs displayed greatly enhanced mobility and secreted gelatinase activity compared with naive AECs. The surface presentation of CD105 and CD73 decreased, and RNA microarray analysis mirrored the loss of epithelial characteristics and transcriptional profile. Unmodified AECs and EMT–AECs were then injected intramyocardially in fully immunocompetent mice after permanent LAD ligation, and heart function was followed by MRI as well as 2D speckle tracking echocardiography after 4 weeks. EMT–AEC-treated infarct hearts displayed better global systolic function and improved longitudinal strain rate in the area of interest. Although no signals of human cells were detectable by histology, infarct size was smaller in EMT–AEC-treated hearts, associated with fewer TUNEL-positive cells and upregulation of periostin, while blood vessel density was increased in both ACE- and EMT–AEC-treated hearts. We conclude that EMT enhances the cardioprotective effects of human AECs

요약 : 
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 NGFhydrogel on the CN might be a promising treatment for postprostatectomy ED

요약 : 
Introduction: Cavernous nerve injury is the main reason for post-prostatectomy erectile dysfunction (ED). Stem cell and neuroprotection therapy are promising therapeutic strategy for ED. Aim. To evaluate the therapeutic efficacy of adipose-derived stem cells (ADSCs) and brain-derived neurotrophic factor (BDNF) immobilized Poly-Lactic-Co-Glycolic (PLGA) membrane on the cavernous nerve in a rat model of post-prostatectomy ED. Methods. Rats were randomly divided into five groups: normal group, bilateral cavernous nerve crush injury (BCNI) group, ADSC (BCNI group with ADSCs on cavernous nerve) group, BDNF-membrane (BCNI group with BDNF/PLGA membrane on cavernous nerve) group, and ADSC/BDNF-membrane (BCNI group with ADSCs covered with BDNF/PLGA membrane on cavernous nerve) group. BDNF was controlled-released for a period of 4 weeks in a BDNF/PLGA porous membrane system. Main Outcome Measures. Four weeks after the operation, erectile function was assessed by detecting the ratio of intra-cavernous pressure (ICP)/mean arterial pressure (MAP). Smooth muscle and collagen content were etermined by Masson’s trichrome staining. Neuronal nitric oxide synthase (nNOS) expression in the dorsal penile nerve was detected by immunostaining. Phospho-endothelial nitric oxide synthase (eNOS) protein expression and cyclic guanosine monophosphate (cGMP) level of the corpus cavernosum were quantified byWestern blotting and cGMP assay, respectively.

요약 : 
Background: Autoimmune thyroiditis is one of common organ-specific autoimmune disease. The aim of this study was to observe the effect of adipose tissue derived mesenchymal stem cells (ATMSC) and CTLA4Ig genetransduced ATMSC on autoimmune thyroiditis. Methods Experimental autoimmune thyroiditis was induced by immunization with thyroglobulin. Animals were divided into three groups: (i) a half million of human ATMSC, (ii) a half million of murine CLTA4Ig gene-transduced human ATMSC (CTLA4Ig-MSC), or (iii) normal saline (as control), which were administered intravenously four times within a 3-week period. Blood and tissue samples were collected 1 week after the last cell transplantation.

요약 : 
Previously, we found that the intravenous administration of human adipose tissue-derived mesenchymal stem cells was a promising therapeutic option for autoimmune thyroiditis even when the cells were transplanted into a xenogeneic model without an immunosuppressant. Therefore, we explored the comparison between the therapeutic effects of syngeneic and allogeneic adipose tissue-derived stem cells on an experimental autoimmune thyroiditis mouse model. Experimental autoimmune thyroiditis was induced in C57BL/6 mice by immunization with porcine thyroglobulin. Adipose tissue-derived stem cells derived from C57BL/6 mice (syngeneic)
or BALB/c mice (allogeneic) or saline as a vehicle control were administered intravenously four times weekly. Blood and tissue samples were collected 1 week after the last transplantation. Adipose tissue-derived stem cells from mice were able to differentiate into multiple lineages in vitro; however, mouse adipose tissuederived stem cells did not have immunophenotypes identical to those from humans. Syngeneic and allogeneic administrations of adipose tissue-derived stem cells reduced thyroglobulin autoantibodies and the inflammatory immune response, protected against lymphocyte infiltration into the thyroid, and restored the Th1/Th2 balance without any adverse effects. However, different humoral immune responses were observed for infused cells from different stem cell sources. The strongest humoral immune response was induced by xenogeneic transplantation, followed by allogeneic and syngeneic administration, in that order. The stem cells were mostly found in the spleen, not the thyroid. This migration might be because the stem cells primarily function in systemic immune modulation, due to being given prior to disease induction. In this study, we confirmed that there were equal effects of adipose tissue-derived stem cells in treating autoimmune thyroiditis between syngeneic and allogeneic transplantations

요약 : 
Prolonged life expectancy, life style and environmental changes have caused a changing disease pattern in developed countries towards an increase of degenerative and autoimmune diseases. Stem cells have become a promising tool for their treatment by promoting tissue repair and protection from immune-attack associated damage. Patient-derived autologous stem cells present a safe option for this treatment since these will not induce immune rejection and thus multiple treatments are possible without any risk for allogenic sensitization, which may arise from allogenic stem cell transplantations. Here we report the outcome of treatments with culture expanded human adipose-derived mesenchymal stem cells (hAdMSCs) of 10 patients with autoimmune associated tissue damage and exhausted therapeutic options, including autoimmune hearing loss, multiple sclerosis, polymyotitis, atopic dermatitis and rheumatoid arthritis. For treatment, we developed a standardized culture-expansion protocol for hAdMSCs from minimal amounts of fat tissue, providing sufficient number of cells for repetitive injections. High expansion efficiencies were routinely achieved from autoimmune patients and from elderly donors without measurable loss in safety profile, genetic stability, vitality and differentiation potency, migration and homing characteristics. Although the conclusions that can be drawn from the compassionate use treatments in terms of therapeutic efficacy are only preliminary, the data provide convincing evidence for safety and therapeutic properties of systemically administered AdMSC in human patients with no other treatment options. The authors believe that exvivo-expanded autologous AdMSCs provide a promising alternative for treating autoimmune diseases. Further clinical studies are needed that take into account the results obtained from case studies as those presented here

요약 : 
Objective. To investigate the efficacy of human adipose tissue–derived mesenchymal stem cell (ADMSC) transplantation in systemic lupus erythematosus (SLE) and to determine the optimal transplantation
window for stem cells either before or after disease onset.
Methods. (NZB NZW)F1 mice with SLE were administered human AD-MSCs (5 105) intravenously every 2 weeks from age 6 weeks until age 60 weeks, while the control group received saline vehicle on the same schedule. Another experiment was carried out with a different initiation time point for serial transplantation (age 6 weeks or age 32 weeks).
Results. Long-term serial administration (total of 28 times) of human AD-MSCs ameliorated SLE without any adverse effects. Compared with the control group, the human AD-MSC–treated group had a significantly
higher survival rate with improvement of histologic and serologic abnormalities and immunologic function, and also had a decreased incidence of proteinuria. Anti–double-stranded DNA antibodies and blood urea nitrogen levels decreased significantly with transplantation of human AD-MSCs, and serum levels of granulocyte–macrophage colony-stimulating factor, interleukin-4 (IL-4), and IL-10 increased significantly. A significant
increase in the proportion of CD4 FoxP3 cells and a marked restoration of capacity for cytokine production were observed in spleens from the human AD-MSC–treated group. In the second experiment, an early stage
treatment group showed better results (higher survival rates and lower incidence of proteinuria) than an advanced stage treatment group.
Conclusion. Serial human AD-MSC transplantation had beneficial effects in the treatment of SLE, without adverse effects. Transplantation of human ADMSCs before disease onset was preferable for amelioration of SLE and restoration of immune homeostasis.

요약 : 
MRL/lpr mice spontaneously develop high titers of anti-dsDNA antibodies and symptoms such as glomerular nephritis and organ weight gain. They also develop spontaneous skin inflammation similar to the cutaneous
lesions common in human lupus erythematosus. This study aimed to compare the effects of long-term serial administration of human adipose tissue-derived mesenchymal stem cells (ASCs), CTLA4Ig-overexpressing
ASCs, and cyclophosphamide treatment in MRL/lpr mice. MRL/lpr mice were divided into saline (C), cyclophosphamide (Y), ASC early (E), ASC late (L), and CTLA4Ig-overexpressing ASC (CT) treatment groups.
Background-matched control MRL/MPJ mice treated with saline (N) were also compared. The treatment period was 5–23 weeks, except for the L group (15–23 weeks). Blood and tissue samples were collected when the mice were 24 weeks old. Organ weight, anti-dsDNA antibodies, urine protein, skin and kidney histologic abnormalities, and trabecular bone volume were evaluated. The Y group showed the greatest decrease in anti-dsDNA antibodies, organ weight, degree of kidney inflammation and glomerular infiltration of C3, and incidence rate of severe proteinuria; the E, L, and CT treatment groups showed better results than the C group. ASC transplantation reduced anti-dsDNA antibody levels significantly. Mice treated with ASCs or CTLA4Ig-ASCs starting from the early disease stage did not show dermatitis upon gross examination; they demonstrated significant improvement in hyperkeratosis, acanthosis, and inflammatory cell infiltration scores in histopathology. Micro-CT analysis revealed that cyclophosphamide treatment significantly decreased bone volume and increased bone spacing in the trabecular bone. Thus, we found that ASC and CTLA4-ASC treatments prevent lupus dermatitis development in MRL/lpr mice without adverse effects

요약 : 
Therapy using stem cells for the liver fibrosis is a prospective alternative to overcome the insufficiency of transplantable liver donor. Here, we demonstrated xenogeneic human cell therapy for the treatment of rat liver
fibrosis without the use of an immunosuppressant. Liver fibrosis was induced by dimethylnitrosamine for 5 weeks in six-week-old male Sprague-Dawley rats. Human umbilical cord blood- and adipose tissue-derived multipotent stem cells were injected intravenously by the tail vein after one week. Blood samples were collected and liver samples were stained with Masson’s trichrome in order to evaluate the amount of fibrosis. After the cell injection, the level of total protein, albumin, alanine transaminase and aspartic acid transaminase was recovered to the similar level of the normal rats. The liver weight per body weight increased after the cell injection. Collagen fiber, near the portal triad and marginal region, was reduced, significantly. Taken together, it is suggested that xenotransplantation of multipotent stem cells might be a candidate for the treatment of liver fibrosis without the use of an immunosuppresant