Co-administration Of Mesenchymal Stem Cells Research Articles

Fucoxanthin Enhances the Antifibrotic Potential of Placenta-derived Mesenchymal Stem Cells in a CCl4-induced Mouse Model of Liver.

The effectiveness of fucoxanthin (Fx) in liver diseases has been reported due to its anti-inflammatory and antifibrotic effects. Mesenchymal stem cells (MSCs)-based therapy has also been proposed as a promising strategy for liver fibrosis treatment. Recent studies have shown that the co-administration of MSCs and drugs demonstrates a pronounced effect on liver fibrosis. This study aimed to determine the therapeutic potential of placenta-derived MSCs (PD-MSCs) in combination with Fx to treat liver fibrosis and evaluate their impact on the main links of liver fibrosis pathogenesis. After PD-MSCs isolation and identification, outbred ICR/CD1 mice were divided into five groups: Control group, CCl4 group (CCl4), Fx group (CCl4+Fx), PD-MSCs group (CCl4+MSCs) and cotreatment group (CCl4+MSCs+Fx). Biochemical histopathological investigations were performed. Semiquantitative analysis of the alpha-smooth muscle actin (α-SMA+), matrix metalloproteinases (MMP-9+, MMP-13+), tissue inhibitor of matrix metalloproteinases-1 (TIMP-1+) areas, and the number of positive cells in them were studied by immunohistochemical staining. Transforming growth factor-beta (TGF-β), hepatic growth factor (HGF), procollagen-1 (COL1α1) in liver homogenate and proinflammatory cytokines in blood serum were determined using an enzyme immunoassay. Compared to the single treatment with PD-MSCs or Fx, their combined administration significantly reduced liver enzyme activity, the severity of liver fibrosis, the proinflammatory cytokine levels, TGF-β level, α-SMA+, TIMP-1+ areas and the number of positive cells in them, and increased HGF level, MMP-13+, and MMP-9+ areas. Fx enhanced the therapeutic potential of PD-MSCs in CCl4-induced liver fibrosis, but more investigations are necessary to understand the mutual impact of PD-MSCs and Fx.

Matrix Metalloproteinase 1 as a Marker of Tonsil-Derived Mesenchymal Stem Cells to Assess Bone Marrow Cell Migration.

To achieve optimal bone marrow engraftment during bone marrow transplantation, migration of donor bone marrow cells (BMCs) toward the recipient's bone marrow is critical. Despite the enhanced engraftment of BMCs by co-administration of mesenchymal stem cells (MSCs), the efficiency can be variable depending on MSC donor. The purpose of this study is to examine the functional heterogeneity of tonsil-derived MSCs (TMSCs) and to identify a marker to evaluate efficacy for the enhancement of BMC migration. To examine the donor-to-donor variation of TMSCs in potentiating BMC migration, we isolated TMSCs from 25 independent donors. Transcriptome of TMSCs and proteome of conditioned medium derived from TMSC were analyzed. Enhanced BMC migration by conditioned medium derived from TMSCs was variable depending on TMSC donor. The TMSCs derived from 25 donors showed distinct expression profiles compared with other cells, including fibroblasts, adipose-derived MSCs and bone marrow-derived MSCs. TMSCs were distributed in two categories: high- and low-efficacy groups for potentiating BMC migration. Transcriptome analysis of TMSCs and proteome profiles of conditioned medium derived from TMSCs revealed higher expression and secretion of matrix metalloproteinase (MMP) 1 in the high-efficacy group. MMP1 knockdown in TMSCs abrogated the supportive efficacy of conditioned medium derived from TMSC cultures in BMC migration. These data suggest that secreted MMP1 can be used as a marker to evaluate the efficacy of TMSCs in enhancing BMC migration. Furthermore, the strategy of analyzing transcriptomes and proteomes of the MSCs may be useful to set the standard for donor variation.

PD35-12 KDM5A, A HISTONE H3K4 DEMETHYLASE, REGULATES SPERMATOGENESIS VIA ITS ACTION ON GERM CELL

INTRODUCTION AND OBJECTIVES: Cisplatin is a widely used chemotherapeutic agent for the treatment of various genitourinary tumors. Although it is a very effective, its use is limited by its renal and testicular toxicity. Mesenchymal stem cells (MSCs) are pluripotent undifferentiated cells that have the ability to differentiate and divide into another cell types and can self renew. Our aim was to investigate the possible protective role of MSCs against Cisplatin induced testicular apoptosis and damaged oxidant/antioxidant balance in rats. Furthermore, we explored the involvement of apoptotic markers in the pathogenesis of testicular toxicity and their role in monitoring treatment. METHODS: A total of 30 male Sprague Dawley rats were used for the experiment. They were divided into 3 groups: Group 1 served as control group received intraperitoneal (IP) saline, Group 2 (Cisplatin group) received a single IP dose of Cisplatin 7mg/kg and Group 3 (Stem Cells group) received the same IP single dose of Cisplatin and was administered BM-MSCs (2x10 cells) by penile vein injection 24h after the Cisplatin injection. Testicular weight and plasma testosterone level were determined along with testicular malondialdehyde (MDA) and reduced glutathione (GSH) levels as oxidative stress markers. Testicular gene expressions of Caspase-3 and mitogen activated protein kinase (MAPK) were estimated by real time-PCR. Histopathological examination for testicular tissues was also done. RESULTS: Cisplatin induced a significant reduction in testicular weights, plasma testosterone and testicular GSH levels in addition to significant elevation of testicular MDA levels and gene expressions of Caspase-3 and MAPK when compared with control group (p<0.05). Histopathology showed lower tubular diameters and depletion of germ cells, irregular small seminiferous tubules with Sertoli cells only were observed in Cisplatin group. MSCs injection significantly corrected these changes in both biochemical and histopathological parameters. CONCLUSIONS: There is a significant role of oxidative and apoptotic markers in the pathogenesis of Cisplatin induced oxidative injury in rat testis. Cisplatin treatment markedly impaired testicular function in rats through mechanisms that could be significantly salvaged with co-administration of MSCs. To our knowledge, this is the first report in the literature that address the protective role of MSCs in Cisplatin induced testicular toxicity; however, further studies are needed to validate our findings.

MSCs with ACE II gene affect apoptosis pathway of acute lung injury induced by bleomycin

ABSTRACTPurpose: The aim of this study was to evaluate the effect and related mechanisms of Mesenchymal stem cells (MSCs) and Angiotensin converting enzyme II (ACE II) on acute lung injury (ALI). Methods: MSCs were separated from umbilical cord cells, and the changes of phenotype before and after ACE II silence were observed using Flow Cytometer. ALI model was induced by 10 mg/mL bleomycin in 60 Balb/c mice, and the rest 8 mice were regarded as the baseline group. The mice were randomly divided into four groups (n = 15): control, ACE II, stem, and stem + ACE II. The apoptotic index (AI) was calculated using TUNEL, and the detection of protein and mRNA of Bax, Bak and p53, Bcl-2, Grp78, CHOP and Caspase 12 were used by western-blot and RT-PCR, respectively. Results: The umbilical cord cells differentiated into stable MSCs about 14 days, and ACE II transfection reached a peak at the 5th day after transfection. ACE II silence did not affect the phenotype of MSCs. All the proteins and mRNAs expression except Bcl-2 in the stem and stem + ACE II were significantly lower than those in control from 8 h (p < 0.05, p < 0.01), while Bcl-2 exhibited an opposite trend. Stem + ACE II performed a better effect than single stem in most indexes, including AI (p < 0.05, p < 0.01). Conclusions: The co-administration of MSCs and ACE II can significantly suppress apoptosis in ALI mice, and may be an effective clinical treatment for ALI.

Mesenchymal stem cells and a vitamin D receptor agonist additively suppress T helper 17 cells and the related inflammatory response in the kidney.

Mesenchymal stem cells (MSCs) suppress T helper (Th)17 cell differentiation and are being clinically pursued for conditions associated with aberrant Th17 responses. Whether such immunomodulatory effects are enhanced by coadministration of MSCs with other agents is not well known. In the present study, individual and combined effects of MSCs and the vitamin D receptor (VDR) agonist paricalcitol on Th17 induction were investigated in vitro and in a mouse model of sterile kidney inflammation (unilateral ureteral obstruction). In vitro, MSCs and paricalcitol additively suppressed Th17 differentiation, although only MSCs suppressed expression of Th17-associated transcriptions factors. Combined administration of MSCs and paricalcitol resulted in an early (day 3) reduction of intrarenal CD4(+) and CD8(+) T cells, CD11b(+)/lymphocyte antigen 6G(+) neutrophils, and inflammatory (lymphocyte antigen 6C(hi)) monocytes as well as reduced transcript for IL-17 compared with untreated animals. Later (day 8), obstructed kidneys of MSC/paricalcitol double-treated mice, but not mice treated with either intervention alone, had reduced tubular injury and interstitial fibrosis as well as lower numbers of neutrophils and inflammatory monocytes and an increase in the ratio between M2 (CD206(+)) and M1 (CD206(-)) macrophages compared with control mice. Adjunctive therapy with VDR agonists may enhance the immunosuppressive properties of MSCs in the setting of pathogenic Th17-type immune responses and related inflammatory responses.

A comparative study of mesenchymal stem cell transplantation with its paracrine effect on control of hyperglycemia in type 1 diabetic rats.

BackgroundMany studies suggested mesenchymal stem cells (MSCs) transplantation as a new approach to control hyperglycemia in type 1 diabetes mellitus through differentiation mechanism. In contrary others believed that therapeutic properties of MSCs is depends on paracrine mechanisms even if they were not engrafted. This study aimed to compare these two approaches in control of hyperglycemia in STZ-induced diabetic rats.MethodsAnimals were divided into five groups: normal; diabetic control; diabetic received MSCs; diabetic received supernatant of MSCs; diabetic received co-administration of MSCs with supernatant. Blood glucose, insulin levels and body weight of animals were monitored during experiment. Immunohistochemical and immunofluorescence analysis were performed to monitor functionality and migration of labeled-MSCs to pancreas.ResultsFirst administration of MSCs within the first 3 weeks could not reduce blood glucose, but second administration significantly reduced blood glucose after week four compared to diabetic controls. Daily injection of supernatant could not reduce blood glucose as efficient as MSCs. Interestingly; Co-administration of MSCs with supernatant significantly reduced blood glucose more than other treated groups. Insulin levels and body weight were significantly increased in MSCs + supernatant-treated animals compared to other groups. Immunohistological analysis showed an increase in number and size of islets per section respectively in supernatant, MSCs and MSCs + supernatant-treated groups.ConclusionPresent study exhibited that repeated-injection of MSCs reduced blood glucose and increased serum insulin levels in recipient rats. Injection of supernatant could not reverse hyperglycemia as efficient as MSCs. Interestingly; co-administration of MSCs with supernatant could reverse hyperglycemia more than either group alone.

Atorvastatin: an efficient step forward in mesenchymal stem cell therapy of diabetic retinopathy

Diabetic retinopathy (DR), a leading cause of vision loss and a significant source of morbidity, is the most common ocular complication of prolonged diabetes mellitus. Most therapeutic approaches address DR by preventing or destroying neovasculature; however, this fails to eliminate pathogenic causes. Mesenchymal stem cells (MSCs) are a promising candidate for cell therapy because they have unique regenerative potential and provide an option to manage retinal injuries. Transplantation of MSCs in rats with diabetes induced by streptozocin administration was shown to ameliorate DR. However, the poor viability and homing of MSCs after transplantation may reduce the efficacy of cell therapy. Intravitreal transplantation of MSCs was shown to augment vascular endothelial growth factor (VEGF). More recent studies have found a central role for VEGF in vascular lesion formation in DR and proposed blockage of VEGF as an effective approach to manage DR. Atorvastatin, a 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, has been proven to decrease VEGF production of MSCs under hypoxic conditions. It has also been demonstrated that atorvastatin increases the viability of MSCs through the adenosine monophosphate-activated protein kinase-endothelial nitric oxide synthase signaling pathway. There is also evidence that nitric oxide improves homing of MSCs by increasing chemokine-related receptor CXCR4 expression. It could be hypothesized that co-administration of MSCs with atorvastatin may be a significant step forward in development of an efficient MSC therapy of DR through preventing excess VEGF production by MSCs under hypoxic conditions as well as increasing the viability and homing of transplanted MSCs.