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Tanja Herrler,
Hao Wang,
Anne Tischer,
Nina Schupp,
Sebastian Lehner,
Andreas Meyer,
Jens Wallmichrath,
Antje Habicht,
Bechara Mfarrej,
Hans-Joachim Anders,
Peter Bartenstein,
Karl-Walter Jauch,
Marcus Hacker,
Markus Guba
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ABSTRACT: Purpose: Increased pressure due to postischemic edema aggravates renal ischemiareperfusion injury (IRI). Prophylactic surgical decompression using microcapsulotomy improves kidney dysfunction after IRI. Supportive cell therapy in combination with microcapsulotomy might act synergistically protecting kidney function against IRI.Methods: The effects of therapeutic endothelial cell application alone and in combination with microcapsulotomy were investigated in a xenogenic murine model of 45min warm renal ischemia. Renal function and perfusion were determined before as well as 2 and 18 days post ischemia by (99mTc)-MAG3 imaging and laser Doppler. Histological analysis included H&E stains and immunohistology for endothelial marker MECA-32, cell proliferation marker Ki-67, and macrophage marker F4/80. Histomorphological changes were quantified using a tubular injury score.Results: Ischemia of 45min led to severe tissue damage and a significant decrease in renal function and perfusion. Microcapsulotomy and cell therapy alone had no significant effect on renal function, while only surgical decompression significantly increased blood flow in ischemic kidneys. However, the combination of both microcapsulotomy and cell therapy significantly improved kidney function and perfusion. Combination therapy significantly reduced morphological injury of ischemic kidneys as determined by a tubular injury score and MECA-32 staining. Macrophage infiltration evidenced by F4/80 staining was significantly reduced. The Ki-67 proliferation index was increased suggesting a regenerative enviroment.Conclusion: While microcapsulotomy and cell therapy alone have limited effect on renal recovery after IRI, combination therapy showed synergistic improvement of renal function, perfusion, and structural damage. Microcapsulotomy may create a permissive environment for cell therapy to work.
Cell Transplantation 10/2012; · 5.13 Impact Factor
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ABSTRACT: Experimental models are essential tools in the development and evaluation of novel treatment options, but the preclinical model of renal ischemia-reperfusion injury is limited to the retrieval of (very) early functional data, leaving the pivotal long-term outcome unknown. The present study applies technetium-99m-mercapto-acetyl-tri-glycine [99mTc-MAG3] scintigraphy for the longitudinal follow-up examination of long-term kidney function after renal ischemia-reperfusion injury.
Unilateral warm ischemia was induced in scid beige mice by vascular clamping of the kidney hilum for 40 min. 99mTc-MAG3 scintigraphy was performed prior to injury, 8 and 14 days post ischemia. The fractional uptake rate [FUR] was calculated from scintigraphy data as a measure of renal clearance.
FUR demonstrated a significant functional impairment of the ischemic kidney 8 and 14 days after injury (P < 0.05 vs. baseline), while contralateral non-ischemic kidneys showed no significant changes. In histological analysis, ischemic kidneys exhibited tubular dilatation and cytoplasmic degeneration as signs of hypoxia without any evidence for necrosis.
FUR enables the detection of renal dysfunction and longitudinal long-term follow-up examination in the same individual. Our model may facilitate preclinical therapy evaluation for the identification of effective renoprotective therapies.
EJNMMI research. 01/2012; 2:2.
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ABSTRACT: Inflammatory edema after ischemia-reperfusion may impair renal allograft function after kidney transplantation. This study examines the effect of edema-related pressure elevation on renal function and describes a simple method to relieve pressure within the renal compartment.
Subcapsular pressure at 6, 12, 24, 48 hr, and 18 days after a 45 min warm ischemia was determined in a murine model of renal ischemia-reperfusion injury. Renal function was measured by Tc-MAG3 scintigraphy and laser Doppler perfusion. Structural damage was assessed by histologic analysis. As a therapeutic approach, parenchymal pressure was relieved by a standardized circular 0.3 mm incision at the lower pole of the kidney capsule.
Compared with baseline (0.9+/-0.3 mm Hg), prolonged ischemia was associated with a sevenfold increase in subcapsular pressure 6 hr after ischemia (7.0+/-1.0 mm Hg; P<0.001). Pressure levels remained significantly elevated for 24 hr. Without therapy, a significant decrease in functional parameters was found with considerably reduced tubular excretion rate (33+/-3.5%, P<0.001) and renal perfusion (64.5+/-6.8%, P<0.005). Histologically, severe tissue damage was found. Surgical pressure relief was able to significantly prevent loss of tubular excretion rate (62.5+/-6.8%, P<0.05) and renal blood flow (96.2+/-4.8%; P<0.05) and preserved the integrity of renal structures.
Our data support the hypothesis of the existence of a renal compartment syndrome as a consequence of ischemia-reperfusion injury. Surgical pressure relief effectively prevented functional and structural renal impairment, and we speculate that this approach might be of value for improving graft function after renal transplantation.
Transplantation 01/2010; 89(1):40-6. · 4.00 Impact Factor
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ABSTRACT: The mobilization of endothelial progenitor cells (EPC) and their functioning in postnatal neovascularization are tightly regulated. To identify new modulators of EPC homeostasis, we screened biologically active prostaglandin E compounds for their effects on EPC production, trafficking and function.
We found that EPC are a rich source for prostaglandin E(2) (PGE(2)), stimulating their number and function in an auto- and paracrine manner. In vivo blockade of PGE(2) production by selective cyclooxygenase-2 inhibition virtually abrogated ischemia-induced EPC mobilization demonstrating its crucial role in EPC homeostasis following tissue ischemia. Conversely, ex vivo treatment of isolated EPC with the clinically approved PGE(1) analogue alprostadil enhanced EPC number and function. These effects were mediated by increased expression of the chemokine receptor CXCR4 and were dependent on nitric oxide synthase activity. Most importantly, ex vivo PGE(1) pretreatment of isolated EPC significantly enhanced their neovascularization capacity in a murine model of hind limb ischemia as assessed by laser Doppler analysis, exercise stress test and immunohistochemistry.
The conserved role for PGE in the regulation of EPC homeostasis suggests that ex vivo modulation of the prostaglandin pathway in isolated progenitor cells may represent a novel and safe strategy to facilitate cell-based therapies.
Journal of Vascular Research 02/2009; 46(4):333-46. · 2.65 Impact Factor
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European Heart Journal 09/2008; 29(17):2061-3. · 10.48 Impact Factor
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ABSTRACT: Stem and progenitor cell therapy is a novel strategy to enhance cardiovascular regeneration. Cell isolation procedures are crucial for the functional activity of the administered cellular product. Therefore, new isolation techniques have to be evaluated in comparison to the Ficoll isolation procedure as the current gold standard. Here we prospectively evaluated a novel point-of-care device (Harvest BMAC System) for the concentration of bone marrow total nucleated cells (TNC) in comparison to the Ficoll isolation procedure for bone marrow mononucleated cells (MNC). The yield in total numbers of TNC was 2.4-fold higher for Harvest compared to Ficoll. Despite significant differences in their cellular compositions, the colony-forming capacity was similar for both products. Intriguingly, the migratory capacity was significantly higher for the Harvest TNC (164 +/- 66%; p = 0.007). In a mouse model of hind limb ischemia, the increase in blood flow recovery was similar between Harvest BM-TNC and Ficoll BM-MNC (0.53 +/- 0.20 vs. 0.46 +/- 0.15; p = 0.88). However, adjustment of the injected cell number based on the higher yield of Harvest TNC resulted in a significant better recovery (0.64 +/- 0.16 vs. 0.46 +/- 0.15; p = 0.003). Cells concentrated by the Harvest point-of-care device show similar or greater functional activity compared to Ficoll isolation. However, the greater yield of cells and the wider range of cell types for the Harvest device may translate into an even greater therapeutic effect.
Cell Transplantation 02/2008; 16(10):1059-69. · 5.13 Impact Factor
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ABSTRACT: Pancreatic adenocarcinoma is currently the fourth leading cause for cancer-related mortality. Stem cells have been implicated in pancreatic tumor growth, but the specific role of these cancer stem cells in tumor biology, including metastasis, is still uncertain. We found that human pancreatic cancer tissue contains cancer stem cells defined by CD133 expression that are exclusively tumorigenic and highly resistant to standard chemotherapy. In the invasive front of pancreatic tumors, a distinct subpopulation of CD133(+) CXCR4(+) cancer stem cells was identified that determines the metastatic phenotype of the individual tumor. Depletion of the cancer stem cell pool for these migrating cancer stem cells virtually abrogated the metastatic phenotype of pancreatic tumors without affecting their tumorigenic potential. In conclusion, we demonstrate that a subpopulation of migrating CD133(+) CXCR4(+) cancer stem cells is essential for tumor metastasis. Strategies aimed at modulating the SDF-1/CXCR4 axis may have important clinical applications to inhibit metastasis of cancer stem cells.
Cell stem cell 10/2007; 1(3):313-23. · 23.56 Impact Factor
