Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. (1/1333)

Mesenchymal stem cells (MSCs) are largely studied for their potential clinical use. Recently, they have gained further interest after demonstration of an immunosuppressive role. In this study, we investigated whether in vivo injection of MSCs could display side effects related to systemic immunosuppression favoring tumor growth. We first showed in vitro that the murine C3H10T1/2 (C3) MSC line and primary MSCs exhibit immunosuppressive properties in mixed lymphocyte reaction. We demonstrated that this effect is mediated by soluble factors, secreted only on "activation" of MSCs in the presence of splenocytes. Moreover, the immunosuppression is mediated by CD8+ regulatory cells responsible for the inhibition of allogeneic lymphocyte proliferation. We then demonstrated that the C3 MSCs expressing the human bone morphogenetic protein 2 (hBMP-2) differentiation factor were not rejected when implanted in various allogeneic immunocompetent mice and were still able to differentiate into bone. Importantly, using a murine melanoma tumor model, we showed that the subcutaneous injection of B16 melanoma cells led to tumor growth in allogeneic recipients only when MSCs were coinjected. Although the potential side effects of immunosuppression induced by MSCs have to be considered in further clinical studies, the usefulness of MSCs for various therapeutic applications still remains of great interest.  (+info)

Current state of cartilage tissue engineering. (2/1333)

Damage to cartilage is of great clinical consequence given the tissue's limited intrinsic potential for healing. Current treatments for cartilage repair are less than satisfactory, and rarely restore full function or return the tissue to its native normal state. The rapidly emerging field of tissue engineering holds great promise for the generation of functional cartilage tissue substitutes. The general approach involves a biocompatible, structurally and mechanically sound scaffold, with an appropriate cell source, which is loaded with bioactive molecules that promote cellular differentiation and/or maturation. This review highlights aspects of current progress in cartilage tissue engineering.  (+info)

Mobilized endothelial progenitor cells by granulocyte-macrophage colony-stimulating factor accelerate reendothelialization and reduce vascular inflammation after intravascular radiation. (3/1333)

BACKGROUND: Endothelial progenitor cells (EPCs) play a pivotal role in repair and regeneration of damaged vessels. We investigated the role of mobilized EPCs in the healing process after intravascular radiation therapy. METHODS AND RESULTS: One iliac artery of hypercholesterolemic rabbits was subjected to balloon injury and intravascular radiation with a Re-188 balloon and the contralateral iliac artery to balloon injury only. Rabbits received granulocyte-macrophage colony-stimulating factor (recombinant human GM-CSF) (60 microg/d subcutaneously) daily for 1 week, either 7 days before the angioplasty or at the time of angioplasty. Control rabbits received human albumin. GM-CSF significantly increased the double-positive (CD31+ and KDR+) fraction in peripheral blood monocytes and showed a higher number of EPCs than albumin after culture and, furthermore, enhanced migration and incorporation of EPCs. In the albumin group, intravascular radiation therapy reduced neointimal hyperplasia but delayed reendothelialization and aggravated monocyte infiltration. GM-CSF treatment significantly accelerated the reendothelialization and inhibited monocyte infiltration (reendothelialization index, 81+/-13% in the GM-CSF radiation [n=7] versus 30+/-11% in the control radiation [n=9] at 2 weeks, P<0.01). GM-CSF treatment produced an additional significant reduction in neointimal formation at 14 and 28 days after injury in the intravascular radiation groups (intima to media ratio, 0.14+/-0.11 in the GM-CSF radiation [n=5] versus 0.36+/-0.07 in the control radiation [n=5] at 4 weeks, P<0.01). CONCLUSIONS: GM-CSF treatment mobilizes EPCs, accelerates reendothelialization, and reduces monocytes infiltration after intravascular radiation therapy, suggesting that stem cell mobilization is a promising strategy for enhancing the vascular healing process after cytotoxic angioplasty.  (+info)

Magnetic resonance fluoroscopy allows targeted delivery of mesenchymal stem cells to infarct borders in Swine. (4/1333)

BACKGROUND: The local environment of delivered mesenchymal stem cells (MSCs) may affect their ultimate phenotype. MR fluoroscopy has the potential to guide intramyocardial MSC injection to desirable targets, such as the border between infarcted and normal tissue. We tested the ability to (1) identify infarcts, (2) navigate injection catheters to preselected targets, (3) inject safely even into fresh infarcts, and (4) confirm injection success immediately. METHODS AND RESULTS: A 1.5-T MRI scanner was customized for interventional use, with rapid imaging, independent color highlighting of catheter channels, multiple-slice 3D rendering, catheter-only viewing mode, and infarct-enhanced imaging. MRI receiver coils were incorporated into guiding catheters and injection needles. These devices were tested for heating and used for targeted MSC delivery. In infarcted pigs, myocardium was targeted by MR fluoroscopy. Infarct-enhanced imaging included both saturation preparation MRI after intravenous gadolinium and wall motion. Porcine MSCs were MRI-labeled with iron-fluorescent particles. Catheter navigation and multiple cell injections were performed entirely with MR fluoroscopy at 8 frames/s with 1.7x3.3x8-mm voxels. Infarct-enhanced MR fluoroscopy permitted excellent delineation of infarct borders. All injections were safely and successfully delivered to their preselected targets, including infarct borders. Iron-fluorescent particle-labeled MSCs were readily visible on delivery in vivo and post mortem. CONCLUSIONS: Precise targeted delivery of potentially regenerative cellular treatments to recent myocardial infarction borders is feasible with an MR catheter delivery system. MR fluoroscopy permits visualization of catheter navigation, myocardial function, infarct borders, and labeled cells after injection.  (+info)

Homing of in vitro expanded Stro-1- or Stro-1+ human mesenchymal stem cells into the NOD/SCID mouse and their role in supporting human CD34 cell engraftment. (5/1333)

The Stro-1 antigen potentially defines a mesenchymal stem cell (MSC) progenitor subset. We here report on the role of human ex vivo-expanded selected Stro-1(+) or Stro-1(-) MSC subsets on the engraftment of human CD34(+) cord blood cells in the nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse model. The data show that cotransplantation of expanded Stro-1(-) cells with CD34(+) cells resulted in a significant increase of human CD45, CD34, CD19, and CD11b cells detected in blood or in bone marrow (BM) and spleen as compared with the infusion of CD34(+) cells alone. Infusion into mice of expanded Stro-1(+) and Stro-1(-) cells (without CD34(+) cells) showed that the numbers of Stro-1(+)-derived (as assessed by DNA analysis of human beta-globin with quantitative polymerase chain reaction [PCR]) were higher than Stro-1(-)-derived cells in spleen, muscles, BM, and kidneys, while more Stro-1(-)-derived than Stro-1(+)-derived cells were found in lungs. The transduction of expanded Stro-1(+) cells with an enhanced green fluorescent protein (eGFP) gene did not modify their cytokine release and their homing in NOD/SCID mouse tissues. The difference between the hematopoietic support and the homing capabilities of expanded Stro-1(+) and Stro-1(-) cells may be of importance for clinical therapeutic applications: Stro-1(+) cells may rather be used for gene delivery in tissues while Stro-1(-) cells may rather be used to support hematopoietic engraftment.  (+info)

Gene therapy approaches for bone regeneration. (6/1333)

Gene therapy represents a promising approach for delivering regenerative molecules to specific tissues including bone. Several laboratories have shown that virus-based BMP expression vectors can stimulate osteoblast differentiation and bone formation in vivo. Both in vivo and ex vivo transduction of cells can induce bone formation at ectopic and orthotopic sites. Adenovirus and direct DNA delivery of genes encoding regenerative molecules can heal critical-sized defects of cranial and long bones. Although osteogenic activity can be demonstrated for individual BMP vectors, substantial synergies may be achieved using combinatorial gene therapy to express complimentary osteogenic signals including specific combinations of BMPs or BMPs and transcription factors. Further control of the bone regeneration process may also be achieved through the use of inducible promoters that can be used to control the timing and magnitude of expression for a particular gene. Using these types of approaches, it should be possible to mimic natural processes of bone development and fracture repair and, in so doing, be able to precisely control both the amount and type of bone regenerated.  (+info)

Experimental posterolateral spinal fusion with porous ceramics and mesenchymal stem cells. (7/1333)

Alternatives to autogenous bone graft for spinal fusion have been investigated for many years. It has been shown that osteoconductive materials alone do not give a rate of fusion which is comparable to that of autogenous bone graft. We analysed the effectiveness of porous ceramic loaded with cultured mesenchymal stem cells as a new graft material for spinal fusion in an animal model. Posterolateral fusion was carried out at the L4/L5 level in 40 White New Zealand rabbits using one of the following graft materials: porous ceramic granules plus cultured mesenchymal stem cells (group I); ceramic granules plus fresh autogenous bone marrow (group II); ceramic granules alone (group II); and autogenous bone graft (group IV). The animals were killed eight weeks after surgery and the spines were evaluated radiographically, by a manual palpation test and by histological analysis. The rate of fusion was significantly higher in group I compared with group III and higher, but not significantly, in group I compared with groups II and IV. In group I histological analysis showed newly formed bone in contact with the implanted granules and highly cellular bone marrow between the newly formed trabecular bone. In group II, thin trabeculae of newly formed bone were present in the peripheral portion of the fusion mass. In group III, there was a reduced amount of newly formed bone and abundant fibrous tissue. In group IV, there were thin trabeculae of newly formed bone close to the decorticated transverse processes and dead trabecular bone in the central portion of the fusion mass. In vitro cultured mesenchymal stem cells may be loaded into porous ceramic to make a graft material for spinal fusion which appears to be more effective than porous ceramic alone. Further studies are needed to investigate the medium- to long-term results of this procedure, its feasibility in the clinical setting and the most appropriate carrier for mesenchymal stem cells.  (+info)

Platelet-derived growth factor-AB promotes the generation of adult bone marrow-derived cardiac myocytes. (8/1333)

The directed generation of cardiac myocytes from endogenous stem cells offers the potential for novel therapies for cardiovascular disease. To facilitate the development of such approaches, we sought to identify and exploit the pathways directing the generation of cardiac myocytes from adult rodent bone marrow cells (BMCs). In vitro cultures supporting the spontaneous generation of functional cardiac myocytes from murine BMCs demonstrated induced expression of platelet-derived growth factor (PDGF)-A and -B isoforms with alpha- and beta-myosin heavy chains as well as connexin43. Supplementation of PDGF-AB speeded the kinetics of myocyte development in culture by 2-fold. In a rat heart, myocardial infarction pretreatment model PDGF-AB also promoted the derivation of cardiac myocytes from BMCs, resulting in a significantly greater number of islands of cardiac myocyte bundles within the myocardial infarction scar compared with other treatment groups. However, gap junctions were detected only between the cardiac myocytes receiving BMCs alone, but not BMCs injected with PDGF-AB. Echocardiography and exercise testing revealed that the functional improvement of hearts treated with the combination of BMCs and PDGF-AB was no greater than with injections of BMCs or PDGF-AB alone. These studies demonstrated that PDGF-AB enhances the generation of BMC-derived cardiac myocytes in rodent hearts, but suggest that alterations in cellular patterning may limit the functional benefit from the combined injection of PDGF-AB and BMCs. Strategies based on the synergistic interactions of PDGF-AB and endogenous stem cells will need to maintain cellular patterning in order to promote the restoration of cardiac function after acute coronary occlusion.  (+info)