Is the intravascular administration of mesenchymal stem cells safe? Mesenchymal stem cells and intravital microscopy.
ABSTRACT We investigated the kinetics of human mesenchymal stem cells (MSCs) after intravascular administration into SCID mouse cremaster vasculature by intravital microscopy. MSCs were injected into abdominal aorta through left femoral artery at two different concentrations (1 x 10(6) or 0.2 x 10(6) cell). Arterial blood velocity decrease by 60 and 18% 1 min after high/low dose MSCs injection respectively. The blood microcirculation was interrupted after 174+/-71 and 485+/-81 s. Intravital microscopy observation and histopathologic analysis of cremaster muscles indicated MSCs were entrapped in capillaries in both groups. 40 and 25% animals died of pulmonary embolism respectively in both high and low MSCs dose groups, which was detected by histopathologic analysis of the lungs. Intraarterial MSCs administration may lead to occlusion in the distal vasculature due to their relatively large cell size. Pulmonary sequestration may cause death in small laboratory animals. MSCs should be used cautiously for intravascular transplantation.
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ABSTRACT: Erythropoietin (EPO) treatment has become the standard treatment of renal anemia. Though a link between hematopoiesis-stimulating drugs and thrombosis has not been proven, it is generally assumed that systemic application of EPO and its analogues increases the risk for thrombotic events. Here we show in C57BL/6J mice that 4-week treatment with the long-lasting EPO analogue darbepoetin-alpha (DPO) at a dose of 10 microg/kg/week induces a reduction of platelet reactivity using flow cytometry and Western blot analysis of tyrosine-specific platelet phosphorylation. Additionally, immunohistochemistry of endothelial adhesion molecule expression and ELISA of circulating endothelial activation markers demonstrated a reduced endothelial activation. Immunohistochemistry and RT-PCR analysis revealed a significant (P<0.05) increase of eNOS expression. Further, DPO did not exert prothrombogenic effects in a murine intravital microscopic thrombosis model of the cremaster muscle. The role of eNOS in prevention of DPO-mediated microvascular thrombosis is further underlined by a significantly accelerated thrombus formation on DPO treatment in eNOS (-/-) mice. Thus, DPO-related erythropoiesis with a raised hematocrit is not associated with an increased risk for thrombosis as long as endothelial NO production serves as compensatory mechanism.Arteriosclerosis Thrombosis and Vascular Biology 05/2007; 27(5):1191-8. · 6.34 Impact Factor
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ABSTRACT: Repair of the heart is an old dream of physicians caring for patients with cardiac disease. Experimental studies suggest that cardiac transfer of stem and progenitor cells can have a favorable impact on tissue perfusion and contractile performance of the injured heart. Some researchers favor stable stem cell engraftment by fusion or transdifferentiation into cardiomyocyte or vascular cell lineages as likely explanations for these beneficial effects. Others have proposed that transient cell retention may be sufficient to promote functional effects, eg, by release of paracrine mediators. Although the mechanistic underpinnings of stem cell therapy are still intensely debated, the concept of cell therapy has already been introduced into the clinical setting, where a flurry of small, mostly uncontrolled trials indicate that stem cell therapy may be feasible in patients. The overall clinical experience also suggests that stem cell therapy can be safely performed, if the right cell type is used in the right clinical setting. Preliminary efficacy data indicate that stem cells have the potential to enhance myocardial perfusion and/or contractile performance in patients with acute myocardial infarction, advanced coronary artery disease, and chronic heart failure. The field now is rapidly moving toward intermediate-size, double-blinded trials to gather more safety and efficacy data. Ultimately, large outcome trials will have to be conducted. We need to proceed cautiously with carefully designed clinical trials and keep in mind that patient safety must remain the key concern. At the same time, continued basic research to elucidate the underlying mechanism of stem cell therapy is clearly needed.Circulation Research 03/2005; 96(2):151-63. · 11.86 Impact Factor
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ABSTRACT: To explore the initial steps by which transplanted mesenchymal stem cells (MSCs) interact with the vessel wall in the course of extravasation, we studied binding of human MSCs to endothelial cells (ECs). In a parallel plate flow chamber, MSCs bound to human umbilical vein ECs (HUVECs) similar to peripheral-blood mononuclear cells (PBMCs) or CD34(+) hematopoietic progenitors at shear stresses of up to 2 dynes/cm(2). This involved rapid extension of podia, rolling, and subsequent firm adhesion that was increased when ECs were prestimulated with TNF-alpha. MSC binding was suppressed when ECs were pretreated with function-blocking anti-P-selectin antibody, and rolling of MSCs was induced on immobilized P-selectin, indicating that P-selectin was involved in this process. Preincubation of HUVECs with anti-VCAM-1 or of MSCs with anti-VLA-4 antibodies suppressed binding of MSCs to HUVECs but did not enhance inhibition by anti-P-selectin, indicating that both P-selectin and VCAM-1 are equally required for this process. Intravital microscopy demonstrated the capacity of MSCs to roll and adhere to postcapillary venules in vivo in a mouse model in a P-selectin-dependent manner. Thus, MSCs interact in a coordinated fashion with ECs under shear flow, engaging P-selectin and VCAM-1/VLA-4.Blood 01/2007; 108(12):3938-44. · 9.06 Impact Factor