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Mesenchymal Stem Cells (mesenchymal + stem_cell)
Kinds of Mesenchymal Stem Cells Terms modified by Mesenchymal Stem Cells Selected AbstractsDual-Growth-Factor-Releasing PCL Scaffolds for Chondrogenesis of Adipose-Tissue-Derived Mesenchymal Stem Cells,ADVANCED ENGINEERING MATERIALS, Issue 1-2 2010Sung Mook Lim Polycaprolactone/Pluronic F127 porous scaffolds are prepared using a modified melt-molding particulate-leaching method. The scaffolds are highly porous (about 90% porosity) and have open-cellular pore structures. Growth factors (TGF- ,2, BMP-7 or dual TGF- ,2/BMP-7) can be easily immobilized on the pore surfaces of the PCL/F127 scaffolds via binding with heparin. The growth-factor-immobilized scaffolds can induce the chondrogenesis of ATMSCs seeded onto them. Using TGF-,2 and BMP-7 growth factors together leads to a better chondrogenic differentiation behavior than using single-growth-factor immobilized scaffolds. [source] A New Approach for Adipose Tissue Regeneration Based on Human Mesenchymal Stem Cells in Contact to Hydrogels,an In Vitro Study,ADVANCED ENGINEERING MATERIALS, Issue 10 2009Kirsten Peters In this study an approach for adipose tissue regeneration based on human mesenchymal stem cells and hydrogels as supporting matrix was evaluated. The gelatin-based hydrogels developed in this study were cytocompatible and stem cell adhesion onto hydrogel surfaces was higher as compared to tissue culture polystyrene. Furthermore, the adipogenic differentiation degree was increased. These results are promising for future applications of hydrogels in adipose tissue regeneration strategies. [source] Carbon Nanotube Monolayer Patterns for Directed Growth of Mesenchymal Stem Cells,ADVANCED MATERIALS, Issue 18 2007Y. Park Carbon nanotube (CNT) monolayer patterns are utilized to control the growth of mesenchymal stem cells (MSCs) (see figure). MSCs exhibit preferential growth on CNT patterns, suggesting that the CNT monolayer does not have a harmful effect on the MSCs. Furthermore, the growth of MSCs on swCNT patterns between electrodes is demonstrated. These results show that CNT patterns have enormous potential as a new platform for basic research and applications using stem cells. [source] Restoration of Bone Mass and Strength in Glucocorticoid-Treated Mice by Systemic Transplantation of CXCR4 and Cbfa-1 Co-Expressing Mesenchymal Stem Cells,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2009Chun-Yang Lien Abstract Transplantation of gene-modified mesenchymal stem cells (MSCs) in animals for bone regeneration therapy has been evaluated extensively in recent years. However, increased endosteal bone formation by intravenous injection of MSCs ectopically expressing a foreign gene has not yet been shown. Aside from the clearance by lung and other tissues, the surface compositions of MSCs may not favor their bone marrow (BM) migration and engraftment. To overcome these hurdles, a gene encoding the chemokine receptor largely responsible for stromal-derived factor-1 (SDF-1)-mediated BM homing and engraftment of hematopoietic stem cells (HSCs), CXCR4, was transduced into mouse C3H10T1/2 cells by adenovirus infection. A dose-dependent increase of CXCR4 surface expression with a parallel enhanced chemotaxis toward SDF-1 in these cells after virus infection was clearly observed. Higher BM retention and homing of CXCR4-expressing MSCs were also found after they were transplanted by intramedullary and tail vein injections, respectively, into immunocompetent C3H/HeN mice. Interestingly, a full recovery of bone mass and a partial restoration of bone formation in glucocorticoid-induced osteoporotic mice were observed 4 wk after a single intravenous infusion of one million CXCR4-expressing C3H10T1/2 cells. In the meantime, complete recovery of bone stiffness and strength in these animals was consistently detected only after a systemic transplantation of CXCR4 and Cbfa-1 co-transduced MSCs. To our knowledge, this is the first report to show unequivocally the feasibility of ameliorating glucocorticoid-induced osteoporosis by systemic transplantation of genetically manipulated MSCs. [source] Activation of Sirt1 Decreases Adipocyte Formation During Osteoblast Differentiation of Mesenchymal Stem Cells,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2006Carl-Magnus Bäckesjö PhD Abstract In vitro, mesenchymal stem cells differentiate to osteoblasts when exposed to bone-inducing medium. However, adipocytes are also formed. We showed that activation of the nuclear protein deacetylase Sirt1 reduces adipocyte formation and promotes osteoblast differentiation. Introduction: Mesenchymal stem cells (MSCs) can differentiate into osteoblasts, adipocytes, chondrocytes, and myoblasts. It has been suggested that a reciprocal relationship exists between the differentiation of MSCs into osteoblasts and adipocytes. Peroxisome proliferator-activated receptor ,2 (PPAR,2) is a key element for the differentiation into adipocytes. Activation of Sirt1 has recently been shown to decrease adipocyte development from preadipocytes through inhibition of PPAR,2. Materials and Methods: We used the mouse mesenchymal cell line C3H10T1/2 and primary rat bone marrow cells cultured in osteoblast differentiation medium with or without reagents affecting Sirt1 activity. Adipocyte levels were analyzed by light microscopy and flow cytometry (FACS) after staining with Oil red O and Nile red, respectively. Osteoblast and adipocyte markers were studied with quantitative real-time PCR. Mineralization in cultures of primary rat bone marrow stromal cells was studied by von Kossa and alizarin red staining. Results: We found that Sirt1 is expressed in the mesenchymal cell line C3H10T1/2. Treatment with the plant polyphenol resveratrol as well as isonicotinamide, both of which activate Sirt1, blocked adipocyte development and increased the expression of osteoblast markers. Nicotinamide, which inhibits Sirt1, increased adipocyte number and increased expression of adipocyte markers. Furthermore, activation of Sirt1 prevented the increase in adipocytes caused by the PPAR,-agonist troglitazone. Finally, activation of Sirt1 in rat primary bone marrow stromal cells increased expression of osteoblast markers and also mineralization. Conclusions: In this study, we targeted Sirt1 to control adipocyte development during differentiation of MSCs into osteoblasts. The finding that resveratrol and isonicotinamide markedly inhibited adipocyte and promoted osteoblast differentiation may be relevant in the search for new treatment regimens of osteoporosis but also important for the evolving field of cell-based tissue engineering. [source] Adipogenic Effect of Alcohol on Human Bone Marrow-Derived Mesenchymal Stem CellsALCOHOLISM, Issue 7 2004Frederick H. Wezeman Background: In addition to a decrease in bone mass in alcoholics their osteopenic skeletons show an increase in bone marrow adiposity. Human bone marrow mesenchymal stem cells (hMSC) in vivo differentiate into several phenotypes including osteogenic and adipogenic cells, both of which remain as resident populations of bone marrow. In vitro, the lineage commitment and differentiation of hMSC toward the adipogenic pathway can be promoted by alcohol. Methods: Human male and female mesenchymal stem cells from joint replacement surgery were cultured. Cells were grouped as: 1) Control (no additions to the culture medium), 2) EtOH (50 mm alcohol added to the culture medium), 3) OS (osteogenic inducers added to the culture medium), and 4) OS + EtOH (osteogenic inducers and 50 mm alcohol added to the culture medium). Cultures stained with Nile Red confirmed the development of differentiated adipocytes. Population analysis was performed using fluorescence-activated cell sorting. Gene expression of early, middle, late, and terminal differentiation stage markers (PPAR),2, lipoprotein lipase, adipsin, leptin, and adipocyte P2 (aP2)] was studied by Northern hybridization, and protein synthesis of aP2 was determined by Western analysis. Results: Nile red staining confirmed increased adipocyte development 10 days after the onset of treatment with 50 mm alcohol and osteogenic induction. By day 21 the number of adipocytes increased to 13.6% of the total population. Alcohol up-regulated the gene expression of PPAR,2 whereas no up-regulation was observed for the other genes. Protein production of aP2 was significantly increased in hMSC cells by culture in the presence of alcohol. Conclusions: The data suggest that alcohol's adipogenic effect on cultured hMSC is through up-regulation of PPAR,2 at the point of lineage commitment as well as through enhancement of lipid transport and storage through increased aP2 synthesis. The alcohol-induced expression and synthesis changes account for the increased Nile red staining of cultured hMSC. [source] A Micro/Nanoscale Surface Mechanical Study on Morpho-Functional Changes in Multilineage-Differentiated Human Mesenchymal Stem CellsMACROMOLECULAR BIOSCIENCE, Issue 5 2007Serena Danti Abstract In recent years MSCs have become a very attractive tool in tissue engineering and regenerative medicine because of their ability to be committed along several lineages through chemical or physical stimuli. Nevertheless their therapeutic potential and plasticity are not yet totally understood. This report describes the use of AFM together with conventional microscopies to obtain mechanical information on cell surfaces and deposited extra cellular matrix molecules, after inducing the differentiation of human MSCs towards three typical mesoderm phenotypes. The aim is to correlate morphological, functional, and mechanical aspects of human MSCs to obtain a deeper understanding of their great potential. [source] Polypyrrole Thin Films Formed by Admicellar Polymerization Support the Osteogenic Differentiation of Mesenchymal Stem CellsMACROMOLECULAR BIOSCIENCE, Issue 8 2004Harold Castano Abstract Summary: The objective of this study was to evaluate the attachment, proliferation, and differentiation of rat mesenchymal stem cells (MSC) toward the osteoblastic phenotype seeded on polypyrrole (PPy) thin films made by admicellar polymerization. Three different concentrations of pyrrole (Py) monomer (20, 35, and 50,×,10,3M) were used with the PPy films deposited on tissue culture polystyrene dishes (TCP). Regular TCP dishes and PPy polymerized on TCP by chemical polymerization without surfactant using 5,×,10,3M Py, were used as controls. Rat MSC were seeded on these surfaces and cultured for up to 20 d in osteogenic media. Surface topography was characterized by atomic force microscopy, X-ray photoelectron spectroscopy, and static contact angle. Cell attachment, proliferation, alkaline phosphatase (ALP) activity, and calcium content were measured to evaluate the ability of MSC to adhere and differentiate on PPy-coated TCP. Increased monomer concentrations resulted in PPy films of increased thickness and surface roughness. PPy films generated by different monomer concentrations induced drastically different cellular events. A wide spectrum of cell attachment characteristics (from excellent cell attachment to the complete inability to adhere) were obtained by varying the monomer concentration from 20 m to 50,×,10,3M. In particular the 20,×,10,3M PPy thin films demonstrated superior induction of MSC osteogenicity, which was comparable to standard TCP dishes, unlike PPy films of similar thickness prepared by chemical polymerization without surfactant. Adhesion of mesenchymal stem cells on tissue culture plates (TCP) coated with polypyrrole thin films made by admicellar polymerization. [source] ORIGINAL ARTICLE: HLA-G Expression Is Up-Regulated by Progesterone in Mesenchymal Stem CellsAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2009Ekaterina Ivanova-Todorova Problem, Maternal immune response to fetal tissues is modified in such way that it favors the development of pregnancy. Human leukocyte antigen (HLA)-G, progesterone and mesenchymal stem cells (MSCs) have been identified as potent immunomodulatory agents in different experimental systems and the interactions between these three factors are studies in this paper. Method of study, Human MSCs are isolated from human adipose tissue, bone marrow and decidua are cultured in the presence of progesterone and the expression of HLA-G is followed-up at protein and mRNA levels. Results, The MSCs cultured in the presence of progesterone express increased levels of both cell surface and cytoplasmic HLA-G when compared with the control MSCs. Conclusion, Progesterone up-regulates the expression by MSCs of HLA-G which is a major player in maintenance of the immune balance between the mother and the fetus. MSCs are newly detected targets of progesterone with well documented immunomodulatory activity. [source] Infusion of Mesenchymal Stem Cells and Rapamycin Synergize to Attenuate Alloimmune Responses and Promote Cardiac Allograft ToleranceAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009W. Ge The inherent immunosuppressive properties and low immunogenicity of mesenchymal stems cells (MSCs) suggested their therapeutic potential in transplantation. We investigated whether MSCs could prolong allograft survival. Treatment involving infusion of MSCs into BALB/c recipients 24 hours after receiving a heart allograft from a C57BL/6 donor significantly abated rejection and doubled graft mean survival time compared to untreated recipients. Furthermore, combination therapy of MSCs and low-dose Rapamycin (Rapa) achieved long-term heart graft survival (>100 days) with normal histology. The treated recipients readily accepted donor skin grafts but rejected third-party skin grafts, indicating the establishment of tolerance. Tolerant recipients exhibited neither intragraft nor circulating antidonor antibodies, but demonstrated significantly high frequencies of both tolerogenic dendritic cells (Tol-DCs) and CD4+CD25+Foxp3+T cells in the spleens. Infusion of GFP+C57BL/6-MSCs in combination with Rapa revealed that the GFP-MSCs accumulated in the lymphoid organs and grafts of tolerant recipients. Thus, engraftment of infused MSCs within the recipient's lymphoid organs and allograft appeared to be instrumental in the induction of allograft-specific tolerance when administered in combination with a subtherapeutic dose of Rapamycin. This study supports the clinical applicability of MSCs in transplantation. [source] Donor-Derived Mesenchymal Stem Cells Remain Present and Functional in the Transplanted Human HeartAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2009M. J. Hoogduijn Mesenchymal stem cells (MSC) are characterized by their multilineage differentiation capacity and immunosuppressive properties. They are resident in virtually all tissues and we have recently characterized MSC from the human heart. Clinical heart transplantation offers a model to study the fate of transplanted human MSC. In this study, we isolated and expanded MSC from heart tissue taken before, and 1 week up to 6 years after heart transplantation. MSC from posttransplantation tissue were all of donor origin, demonstrating the longevity of endogenous MSC and suggesting an absence of immigration of recipient MSC into the heart. MSC isolated from transplanted tissue showed an immunophenotype that was characteristic for MSC and maintained cardiomyogenic and osteogenic differentiation capacity. They furthermore preserved their ability to inhibit the proliferative response of donor-stimulated recipient peripheral blood mononuclear cells. In conclusion, functional MSC of donor origin remain present in the heart for several years after transplantation. [source] Promigratory Activity of Oxytocin on Umbilical Cord Blood-Derived Mesenchymal Stem CellsARTIFICIAL ORGANS, Issue 6 2010Yong Sook Kim Abstract Recent studies show that oxytocin has various effects on cellular behaviors. Oxytocin is reported to stimulate cardiomyogenesis of embryonic stem cells and endothelial cell proliferation. Mesenchymal stem cells (MSCs) are widely used for cardiac repair, and we elucidated the effect of oxytocin on umbilical cord derived-MSCs (UCB-MSCs). UCB-MSCs were pretreated with oxytocin (100 nM) and washed with saline prior to experiments. To evaluate their angiogenic potential and migration activity, tube formation assay and Boyden chamber assay were performed. For in vivo study, ischemia-reperfusion was induced in rats, and UCB-MSCs with or without oxytocin pretreatment were injected into the infarcted myocardium to evaluate the engraftment of injected cells. Histological and hemodynamic studies were performed. Oxytocin-treated UCB-MSCs showed a decrease in tube formation but a drastic increase in transwell migration activity. The transcription level of matrix metalloproteinase (MMP)-2 was increased in oxytocin-treated UCB-MSCs. Knock-down of MMP-2 by use of siRNA restored the tube formation, while reducing transmigration activity. In rats injected with oxytocin-treated UCB-MSCs, cardiac fibrosis and CD68 infiltration in the peri-infarct zone were reduced, whereas cell engraftment and connexin43 expression were greater than in rats injected with untreated UCB-MSCs. By contrast, angiogenesis did not differ significantly between the two groups. Cardiac contractility was higher in the group injected with oxytocin-treated UCB-MSCs than in the group injected with phosphate-buffered saline alone. Collectively, oxytocin is an effective priming reagent for stem cells for application to damaged heart tissue. [source] Aging Adversely Impacts Biological Properties of Human Bone Marrow-derived Mesenchymal Stem Cells: Implications for Tissue Engineering Heart Valve ConstructionARTIFICIAL ORGANS, Issue 3 2010Yuan Xin Abstract Our aim was to study the aging effects on the in vitro biological properties of bone marrow-derived mesenchymal stem cells (BMSCs) for construction of tissue-engineered heart valves. BMSCs were taken from teenagers with congenital heart diseases, and middle-aged and elderly patients with valvular diseases. Proliferative abilities were compared among the three groups by using colony-forming unit counting and growth curves (5-bromo-2,-deoxyuridine assay). Cell differentiation, vascular endothelial growth factor (VEGF) release under hypoxic condition, and migratory abilities were compared as well. Colony-forming units in the teenage group were significantly greater than those in the other two groups (P < 0.05), and significantly higher counts were observed in the middle age group than in the aged group (P < 0.05). Growth curves presented similar trends in which cells' proliferative abilities in the aged group decreased significantly (P < 0.05), while no differences were noted between the two nonaged groups. The differentiation potential to endothelial cells, osteoblasts and adipocytes, VEGF releases, and migratory abilities differed significantly between the aged group and nonaged groups (P < 0.05). However, no differences were noted between the two nonaged groups. BMSCs from older patients with heart valve diseases could be harvested and expanded successfully, and the phenotype and morphology were uniform as nonaged groups. However, the proliferative and differentiation properties of aged cells, as well as cytokine release and migratory abilities, are significantly impaired. [source] Engineering of Vascular Grafts With Genetically Modified Bone Marrow Mesenchymal Stem Cells on Poly (Propylene Carbonate) GraftARTIFICIAL ORGANS, Issue 12 2006Jun Zhang Abstract:, Bone marrow mesenchymal stem cells (MSCs) have demonstrated their pluripotency to differentiate into different cell lineages and may be an alternative cell source for vascular tissue engineering. The objective of this study is to create small diameter vessels by seeding and culture of genetically modified MSCs onto a synthetic polymer scaffold produced by an electrospinning technique. A tubular scaffold (2 mm in diameter) with a microstructure of nonwoven fibers was produced by electrospinning of poly (propylene carbonate) (PPC). Rat MSCs obtained from bone marrow were expanded in culture and modified with vasculoprotective gene endothelial nitric oxide synthase (eNOS) or marker gene green fluorescent protein (GFP). These MSCs were seeded onto the electrospun fibrous grafts (internal diameter = 2 mm), and cultured in 5% CO2 at 37°C. The growth of MSCs in the scaffold was analyzed with scanning electron microscopy (SEM) and hematoxylin and eosin (H&E) staining. The gene transfer and transgenic gene expression were examined with fluorescence-activated cell sorting (FACS), immunochemical staining, reverse transcriptase-polymerase chain reaction (RT-PCR), and western blot. The production of nitric oxide (NO) by the engineered vessels was measured with an NO detection kit. Our data showed that the seeded cells integrated with the microfibers of the scaffold to form a three-dimensional cellular network, indicating a favorable interaction between this synthetic PPC scaffold with MSCs. High transduction efficiency was obtained with the use of concentrated retrovirus in the gene transfection of MSCs. The eNOS gene transcripts and protein were detected in the grafts seeded with eNOS-modified MSCs by RT-PCR and immunochemical staining. The amount of NO produced by grafts seeded with eNOS-modified MSCs was comparable to that produced by native blood vessels, and it was significantly higher than that in the grafts seeded with nonmodified MSCs. In summary, the vascular graft produced by culture of eNOS gene-modified MSCs onto the electrospun tubular scaffolds shows promising results in terms of function. The use of MSCs and therapeutic genes in tissue engineering of blood vessels could be helpful in improving vessel regeneration and patency. [source] Cultured Autologous Human Cells for Hard Tissue Regeneration: Preparation and Characterization of Mesenchymal Stem Cells from Bone MarrowARTIFICIAL ORGANS, Issue 1 2004Noriko Kotobuki Abstract:, Mesenchymal stem cells (MSCs) are multipotent cells and can be induced in vitro and in vivo to differentiate not only into the variety of mesodermal cells, but into either ectodermal or endodermal cells. This capability indicates the usefulness of MSCs for tissue engineering. Cell surface antigen analyses using various types of CD antibodies demonstrated that adherent fibroblastic cells derived from fresh human bone marrow are mesenchymal types and the cells showed extensive capability for proliferation and/or differentiation. We labeled the adherent cultured marrow cells as MSCs and, significantly, found the MSCs could even proliferate from aged marrow cells. After about sixteen days of culturing, we were able to harvest 100 million MSCs from only 3 ml of fresh human marrow. Moreover, the MSCs could be cryopreserved at ,80°C without noticeable loss of viability and capability of osteoblastic differentiation. These results indicate that MSCs hold promise for utilization in hard tissue regeneration. [source] Mesenchymal Stem Cells: Engineering RegenerationCLINICAL AND TRANSLATIONAL SCIENCE, Issue 1 2008Atta Behfar No abstract is available for this article. [source] Pre-activation of retinoid signaling facilitates neuronal differentiation of mesenchymal stem cellsDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 5 2010Yang Bi Mesenchymal stem cells (MSCs) can differentiate into neurons in an appropriate cellular environment. Retinoid signaling pathway is required in neural development. However, the effect and mechanism through retinoid signaling regulates neuronal differentiation of MSCs are still poorly understood. Here, we report that all-trans-retinoic acid (ATRA) pre-induction improved neuronal differentiation of rat MSCs. We found that, when MSCs were exposed to different concentrations of ATRA (0.01,100 ,mol/L) for 24 h and then cultured with modified neuronal induction medium (MNM), 1 ,mol/L ATRA pre-induction significantly improved neuronal differentiation efficiency and neural-cell survival. Compared with MNM alone induced neural-like cells, ATRA/MNM induced cells expressed higher levels of Nestin, neuron specific enolase (NSE), microtubule-associated protein-2 (MAP-2), but lower levels of CD68, glial fibrillary acidic protein (GFAP), and glial cell line-derived neurotrophic factor(GDNF), also exhibited higher resting membrane potential and intracellular calcium concentration, supporting that ATRA pre-induction promotes maturation and function of derived neurons but not neuroglia cells from MSCs. Endogenous retinoid X receptors (RXR) RXR, and RXR, (and to a lesser extent, RXR,) were weakly expressed in MSCs. But the expression of RAR, and RAR, was readily detectable, whereas RAR, was undetectable. However, at 24 h after ATRA treatment, the expression of RAR,, not RAR, or RAR,, increased significantly. We further found the subnuclear redistribution of RAR, in differentiated neurons, suggesting that RAR, may function as a major mediator of retinoid signaling during neuronal differentiation from MSCs. ATRA treatment upregulated the expression of Vimentin and Stra13, while it downregulated the expression of Brachyury in MSCs. Thus, our results demonstrate that pre-activation of retinoid signaling by ATRA facilitates neuronal differentiation of MSCs. [source] Anti-tumor activity of mesenchymal stem cells producing IL-12 in a mouse melanoma modelEXPERIMENTAL DERMATOLOGY, Issue 11 2006Lina Elzaouk Abstract:, Mesenchymal stem cells (MSCs) represent a new tool for delivery of therapeutic agents to tumor cells. In this study, we have evaluated the anti-tumor activity of human MSCs stably transduced with a retroviral vector expressing the cytokine interleukin-12 (IL-12) in a mouse melanoma model. Application of MSC(IL-12) but not control MSCs strongly reduced the formation of lung metastases of B16F10 melanoma cells. The activity of the MSC(IL-12) cells was dependent on the presence of natural killer (NK) cells in this experimental setting. Further, MSC(IL-12) cells elicited a pronounced retardation of tumor growth and led to prolonged survival when injected into established subcutaneous melanoma in a therapeutic regimen. The therapeutic effect of the MSC(IL-12) was in part mediated by CD8+ T cells, while NK cells and CD4+ T cells appeared to play a minor role. The anti-tumor effect of MSC(IL-12) cells was of similar efficiency as observed for application of naked plasmid DNA encoding IL-12. The presented data demonstrate that these two different strategies can induce a similar therapeutic anti-tumor efficacy in the mouse melanoma tumor model. [source] Efficient generation of human hepatocytes by the intrahepatic delivery of clonal human mesenchymal stem cells in fetal sheep,HEPATOLOGY, Issue 6 2007Jason Chamberlain Alternative methods to whole liver transplantation require a suitable cell that can be expanded to obtain sufficient numbers required for successful transplantation while maintaining the ability to differentiate into hepatocytes. Mesenchymal stem cells (MSCs) possess several advantageous characteristics for cell-based therapy and have been shown to be able to differentiate into hepatocytes. Thus, we investigated whether the intrahepatic delivery of human MSCs is a safe and effective method for generating human hepatocytes and whether the route of administration influences the levels of donor-derived hepatocytes and their pattern of distribution throughout the parenchyma of the recipient's liver. Human clonally derived MSCs were transplanted by an intraperitoneal (n = 6) or intrahepatic (n = 6) route into preimmune fetal sheep. The animals were analyzed 56,70 days after transplantation by immunohistochemistry, enzyme-linked immunosorbent assay, and flow cytometry. The intrahepatic injection of human MSCs was safe and resulted in more efficient generation of hepatocytes (12.5% ± 3.5% versus 2.6% ± 0.4%). The animals that received an intrahepatic injection exhibited a widespread distribution of hepatocytes throughout the liver parenchyma, whereas an intraperitoneal injection resulted in a preferential periportal distribution of human hepatocytes that produced higher amounts of albumin. Furthermore, hepatocytes were generated from MSCs without the need to first migrate/lodge to the bone marrow and give rise to hematopoietic cells. Conclusion: Our studies provide evidence that MSCs are a valuable source of cells for liver repair and regeneration and that, by the alteration of the site of injection, the generation of hepatocytes occurs in different hepatic zones, suggesting that a combined transplantation approach may be necessary to successfully repopulate the liver with these cells. (HEPATOLOGY 2007.) [source] Mesenchymal stem cells enhance growth and metastasis of colon cancerINTERNATIONAL JOURNAL OF CANCER, Issue 10 2010Kei Shinagawa Abstract Recently, mesenchymal stem cells (MSCs) were reported to migrate to tumor stroma as well as injured tissue. We examined the role of human MSCs in tumor stroma using an orthotopic nude mice model of KM12SM colon cancer. In in vivo experiments, systemically injected MSCs migrated to the stroma of orthotopic colon tumors and metastatic liver tumors. Orthotopic transplantation of KM12SM cells mixed with MSCs resulted in greater tumor weight than did transplantation of KM12SM cells alone. The survival rate was significantly lower in the mixed-cell group, and liver metastasis was seen only in this group. Moreover, tumors resulting from transplantation of mixed cells had a significantly higher proliferating cell nuclear antigen labeling index, significantly greater microvessel area and significantly lower apoptotic index. Splenic injection of KM12SM cells mixed with MSCs, in comparison to splenic injection of KM12SM cells alone, resulted in a significantly greater number of liver metastases. MSCs incorporated into the stroma of primary and metastatic tumors expressed ,-smooth muscle actin and platelet-derived growth factor receptor-, as carcinoma-associated fibroblast (CAF) markers. In in vitro experiments, KM12SM cells recruited MSCs, and MSCs stimulated migration and invasion of tumor cells through the release of soluble factors. Collectively, MSCs migrate and differentiate into CAFs in tumor stroma, and they promote growth and metastasis of colon cancer by enhancing angiogenesis, migration and invasion and by inhibiting apoptosis of tumor cells. [source] Selected Stro-1-enriched bone marrow stromal cells display a major suppressive effect on lymphocyte proliferationINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 1 2009A. NASEF Summary Mesenchymal stem cells (MSCs) have an immunosuppressive effect and can inhibit the proliferation of alloreactive T cells in vitro and in vivo. Cotransplantation of MSCs and hematopoietic stem cells (HSCs) from HLA-identical siblings has been shown to reduce the incidence of acute graft- vs.-host disease. MSCs are heterogeneous and data on the inhibitory effects of different MSC subsets are lacking. The antigen Stro1 is a marker for a pure primitive MSC subset. We investigated whether Stro-1-enriched induce a more significant suppressive effect on lymphocytes in a mixed lymphocyte reaction (MLR), and whether this action is related to a specific gene expression profile in Stro-1-enriched compared to other MSCs. We demonstrated that the Stro-1-enriched population elicits a significantly more profound dose-dependent inhibition of lymphocyte proliferation in a MLR than MSCs. One thousand expanded Stro-1-enriched induced an inhibitory effect comparable to that of 10 times as many MSCs. Inhibition by Stro-1-enriched was more significant in contact-dependent cultures than in noncontact-dependant cultures at higher ratio. The Stro-1-enriched inhibitory effect in both culture types was linked to increased gene expression for soluble inhibitory factors such as interleukin-8 (IL-8), leukemia inhibitory factor (LIF), indoleamine oxidase (IDO), human leukocyte antigen-G (HLA-G), and vascular cell adhesion molecule (VCAM1). However, tumor growth factor-,1 (TGF-,) and IL-10 were only up-regulated in contact-dependant cultures. These results may support using a purified Stro-1-enriched population to augment the suppressive effect in allogeneic transplantation. [source] Activation of Sirt1 Decreases Adipocyte Formation During Osteoblast Differentiation of Mesenchymal Stem Cells,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2006Carl-Magnus Bäckesjö PhD Abstract In vitro, mesenchymal stem cells differentiate to osteoblasts when exposed to bone-inducing medium. However, adipocytes are also formed. We showed that activation of the nuclear protein deacetylase Sirt1 reduces adipocyte formation and promotes osteoblast differentiation. Introduction: Mesenchymal stem cells (MSCs) can differentiate into osteoblasts, adipocytes, chondrocytes, and myoblasts. It has been suggested that a reciprocal relationship exists between the differentiation of MSCs into osteoblasts and adipocytes. Peroxisome proliferator-activated receptor ,2 (PPAR,2) is a key element for the differentiation into adipocytes. Activation of Sirt1 has recently been shown to decrease adipocyte development from preadipocytes through inhibition of PPAR,2. Materials and Methods: We used the mouse mesenchymal cell line C3H10T1/2 and primary rat bone marrow cells cultured in osteoblast differentiation medium with or without reagents affecting Sirt1 activity. Adipocyte levels were analyzed by light microscopy and flow cytometry (FACS) after staining with Oil red O and Nile red, respectively. Osteoblast and adipocyte markers were studied with quantitative real-time PCR. Mineralization in cultures of primary rat bone marrow stromal cells was studied by von Kossa and alizarin red staining. Results: We found that Sirt1 is expressed in the mesenchymal cell line C3H10T1/2. Treatment with the plant polyphenol resveratrol as well as isonicotinamide, both of which activate Sirt1, blocked adipocyte development and increased the expression of osteoblast markers. Nicotinamide, which inhibits Sirt1, increased adipocyte number and increased expression of adipocyte markers. Furthermore, activation of Sirt1 prevented the increase in adipocytes caused by the PPAR,-agonist troglitazone. Finally, activation of Sirt1 in rat primary bone marrow stromal cells increased expression of osteoblast markers and also mineralization. Conclusions: In this study, we targeted Sirt1 to control adipocyte development during differentiation of MSCs into osteoblasts. The finding that resveratrol and isonicotinamide markedly inhibited adipocyte and promoted osteoblast differentiation may be relevant in the search for new treatment regimens of osteoporosis but also important for the evolving field of cell-based tissue engineering. [source] Building a consensus regarding the nature and origin of mesenchymal stem cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue S38 2002Donald G. PhinneyArticle first published online: 23 APR 200 Abstract Mesenchymal stem cells (MSCs) are believed to be the common precursors to differentiated cell lineages found in bone and bone marrow, including adipocytes, chondrocytes, osteoblasts, and hematopoiesis-supporting stroma. Apart from this fact, most aspects of MSC biology, including their ontogeny, anatomical location in marrow, and in vivo functions remain vague. Attempts to clarify these issues have produced confounding results, principally due to the fact that many researchers employ different methods to culture MSCs, assess their differentiation potential, and evaluate their capacity for self-renewal. Accordingly, the current status of the field appears fragmentary with no clear consensus on how to define the cells. In describing past and present contributions to the field of MSC research, I will demonstrate that the apparent incongruity of the literature is misleading, and that an unbiased interpretation reveals a fairly cohesive picture of MSC biology. J. Cell. Biochem. Suppl. 38: 7,12, 2002. © 2002 Wiley-Liss, Inc. [source] Mesenchymal stem cells in tissue engineeringJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 4 2008Pankaj Godara Abstract Mesenchymal stem cells (MSC) offer great promise in therapies aimed at repairing, replacing or regenerating damaged or diseased tissues and organs. This potential is due to their capacity for self-renewal, ability to differentiate down a range of lineages, and potential in autologous therapies, free from major ethical concerns. This review examines the issues around the use of MSC in tissue engineering (TE) applications. Key issues facing widespread MSC therapeutic use include both the scarcity in adult tissues and the current lack of a simple unambiguous identifying marker. These major challenges facing the isolation, characterization and expansion of MSC to therapeutically significant numbers currently limit their usefulness as ,off the shelf' therapies. Balanced against this, recent evidence suggests that MSC have a much wider tissue distribution and greater plasticity than originally envisaged. Although therapeutic applications of MSC initially focused on mesenchymal lineages such as cartilage and bone, this is now broadening to include organs such as the heart and skin. Ultimately, the clinical utility of such MSC-based therapies will depend on their performance and cost. Copyright © 2008 Society of Chemical Industry [source] Mesenchymal stem cells and platelet-rich plasma enhance bone formation in sinus grafting: a histomorphometric study in minipigsJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 6 2008Francesco Pieri Abstract Objectives: Autologous, allogenic, and alloplastic materials for sinus augmentation have specific drawbacks, which has stimulated an ongoing search for new materials and tissue-engineering constructs. We investigated whether mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) seeded on a fluorohydroxyapatite (FH) scaffold can improve bone formation and bone-to-implant contact (BIC) in maxillary sinus grafting. Material and Methods: Bilateral sinus augmentation procedures were performed in eight minipigs. MSCs, PRP, and FH scaffold (test site) or FH alone (control site) were grafted in each maxillary sinus. Distal to the osteotomy, one dental implant per sinus was placed in the grafting material through the facial sinus wall. The animals were killed 3 months after grafting, and block sections of the implant sites were harvested and prepared for histomorphometric analysis. Results: After 12 weeks, a significant increase in bone formation occurred in the test sites compared with the control sites (42.51%versus 18.98%; p=0.001). In addition, BIC was significantly greater in the test sites compared with the control sites in the regenerated area (23.71%versus 6.63%; p=0.028). Conclusions: These findings show that sinus augmentation with MSCs,PRP, combined with FH may enhance bone formation and osseointegration of dental implants compared with FH alone in minipigs. [source] Immunomodulation by mesenchymal stem cells and clinical experienceJOURNAL OF INTERNAL MEDICINE, Issue 5 2007K. Le Blanc Abstract Mesenchymal stem cells (MSCs) from adult marrow can differentiate in vitro and in vivo into various cell types, such as bone, fat and cartilage. MSCs preferentially home to damaged tissue and may have therapeutic potential. In vitro data suggest that MSCs have low inherent immunogenicity as they induce little, if any, proliferation of allogeneic lymphocytes. Instead, MSCs appear to be immunosuppressive in vitro. They inhibit T-cell proliferation to alloantigens and mitogens and prevent the development of cytotoxic T-cells. In vivo, MSCs prolong skin allograft survival and have several immunomodulatory effects, which are presented and discussed in the present study. Possible clinical applications include therapy-resistant severe acute graft-versus-host disease, tissue repair, treatment of rejection of organ allografts and autoimmune disorders. [source] Phenotype and chondrogenic differentiation of mesenchymal cells from adipose tissue of different speciesJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 11 2009María José Martínez-Lorenzo Abstract Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into several mesoderm lineages. They have been isolated from different tissues, such as bone marrow, adult peripheral blood, umbilical cord blood, and adipose tissue. The aim of this study was to analyze the differences in proliferation and phenotype of adipose tissue-derived MSCs from three different species, and to evaluate their capacity to differentiate into chondrocytes in vitro. A comparative study of cultured human, rabbit, and sheep mesenchymal cells from adipose tissue was carried out, and the main morphological parameters, proliferative activity, and expression of surface markers were characterized. Proliferation and flow cytometry data showed species-related differences between animal and human MSCs. Histological staining suggested that rabbit and sheep mesenchymal cells were able to differentiate into chondrocytic lineages. Human mesenchymal cells, though they could also differentiate, accomplished it with more difficulty than animal MSCs. These results could help to explain the differences in the chondrogenic capacity of sheep and rabbit MSCs when they are used as animal models compared to human mesenchymal cells in a clinical assay. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:1499,1507, 2009 [source] Mesenchymal stem cells derived from synovium, meniscus, anterior cruciate ligament, and articular chondrocytes share similar gene expression profilesJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 4 2009Yuko Segawa Abstract Mesenchymal stem cells (MSCs) can be obtained from various tissues, and contain common features. However, an increasing number of reports have described variant properties dependent of cell sources. We examined (1) whether MSCs existed in several intraarticular tissues, (2) whether gene expression profiles in intraarticular tissue MSCs closely resembled each other, and (3) whether identified genes were specific to intraarticular tissue MSCs. Human synovium, meniscus, intraarticular ligament, muscle, adipose tissue, and bone marrow were harvested, and colony-forming cells were analyzed. All these cells showed multipotentiality and surface markers typical of MSCs. Gene profiles of intraarticular tissue MSCs and chondrocytes were closer to each other than those of extraarticular tissues MSCs. Among three characteristic genes specific for intraarticular tissue MSCs, we focused on proline arginine-rich end leucine-rich repeat protein (PRELP). Higher expression of PRELP was confirmed in chondrocytes and intraarticular tissue MSCs among three elderly and three young donors. Synovium MSCs stably expressed PRELP, contrarily, bone marrow MSCs increased PRELP expression during in vitro chondrogenesis. In conclusion, MSCs could be isolated from various intraarticular tissues including meniscus and ligament, gene expression profiles of intraarticular tissue MSCs closely resembled each other, and the higher expression of PRELP was characteristic of intraarticular tissue MSCs. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 435,441, 2009 [source] Pulsed electromagnetic fields enhance BMP-2 dependent osteoblastic differentiation of human mesenchymal stem cellsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 9 2008Z. Schwartz Abstract Mesenchymal stem cells (MSCs) express an osteoblastic phenotype when treated with BMP-2, and BMP-2 is used clinically to induce bone formation although high doses are required. Pulsed electromagnetic fields (PEMF) also promote osteogenesis in vivo, in part through direct action on osteoblasts. We tested the hypothesis that PEMF enhances osteogenesis of MSCs in the presence of an inductive stimulus like BMP-2. Confluent cultures of human MSCs were grown on calcium phosphate disks and were treated with osteogenic media (OM), OM containing 40 ng/mL rhBMP-2, OM,+,PEMF (8 h/day), or OM,+,BMP-2,+,PEMF. MSCs demonstrated minor increases in alkaline phosphatase (ALP) during 24 days in culture and no change in osteocalcin. OM increased ALP and osteocalcin by day 6, but PEMF had no additional effect at any time. BMP-2 was stimulatory over OM, and PEMF,+,BMP-2 synergistically increased ALP and osteocalcin. PEMF also enhanced the effects of BMP-2 on PGE2, latent and active TGF-,1, and osteoprotegerin. Effects of PEMF on BMP-2,treated cells were greatest at days 12 to 20. These results demonstrate that PEMF enhances osteogenic effects of BMP-2 on MSCs cultured on calcium phosphate substrates, suggesting that PEMF will improve MSC response to BMP-2 in vivo in a bone environment. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:1250,1255, 2008 [source] In vivo bioluminescence imaging study to monitor ectopic bone formation by luciferase gene marked mesenchymal stem cellsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 7 2008Cristina Olivo Abstract Mesenchymal stem cells (MSCs) represent a powerful tool for applications in regenerative medicine. In this study, we used in vivo bioluminescence imaging to noninvasively investigate the fate and the contribution to bone formation of adult MSCs in tissue engineered constructs. Goat MSCs expressing GFP-luciferase were seeded on ceramic scaffolds and implanted subcutaneously in immune-deficient mice. The constructs were monitored weekly with bioluminescence imaging and were retrieved after 7 weeks to quantify bone formation by histomorphometry. With increasing amounts of seeded MSCs (from 0 to 1,×,106 MSC/scaffold), a cell-dose related increase in bioluminescence was observed at all time points, correlating with increased bone formation at 7 weeks. To investigate the relevance of MSC proliferation to bone deposition, cell-seeded scaffolds were irradiated. The irradiated cells were functional with respect to oxygen consumption but no increase in bioluminescence was observed in vivo, and only minimal bone was produced. Proliferating MSCs are likely required for initiation of bone formation in tissue engineered constructs in vivo. Bioluminescence is a useful tool to monitor cellular responses and predict bone formation in vivo. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:901,909, 2008 [source] | |||||||||||||||||||||||||||||||