Hematopoietic Stem Cell Mobilization Therapy Accelerates Recovery of Renal Function Independent of Stem Cell Contribution

Abstract

Acute renal failure and tubular cell loss as a result of ischemia constitute major challenges in renal pathophysiology. Increasing evidence suggests important roles for bone marrow stem cells in the regeneration of renal tissue after injury. This study investigated whether the enhanced availability of hematopoietic stem cells, induced by stem cell factor and granulocyte colony-stimulating factor, to the injured kidney provides an adequate strategy for stem cell-based therapy to counteract renal ischemia/reperfusion injury. It is interesting that cytokine treatment before injury resulted in significant enhancement of function recovery of the kidney. This, however, was not due to increased incorporation of tubular epithelial cells from bone marrow origin. Importantly, cytokine treatment resulted in impaired influx of granulocytes into the injured kidney. Although cytokine treatment improved renal function rapidly after ischemic injury, the results show that the underlying mechanism likely is not based on stem cell transdifferentiation but rather on altered inflammatory kinetics.J Am Soc Nephrol 16: 1684 -1692 , 2005 . doi: 10.1681 A cute renal failure is a major clinical problem that affects up to 5% of all hospitalized patients (1). The major cause is tubular necrosis as a consequence of ischemic injury after episodes of hypotension or surgical vascular clamping. Moreover, renal transplantation is always associated with some degree of ischemia/reperfusion (I/R) injury. The development of specific therapies for I/R injury has proved problematic; therefore, therapy remains largely supportive.Recent studies suggested the involvement of bone marrow (BM)-derived stem cells in the regeneration of nonhematopoietic tissues. BM-derived cells with an endothelial (2), epithelial (3,4), or mesangial (5) phenotype were detected in murine kidneys after injury. Case studies have described the presence of Y chromosome-containing tubular epithelial cells (TEC) in kidneys from female donors that were transplanted into male recipients (6,7). These observations have led to the hypothesis that aside from intrinsic cellular proliferation, BM-derived cells contribute to kidney healing or maintenance.Experimental studies have provided evidence for a limited contribution of BM-derived cells to the injured kidney, perhaps as a direct consequence of the low circulating levels of BMderived stem cells. A study by Orlic et al. (8) demonstrated that cytokine-induced mobilization of BM hematopoietic stem cells (HSC) before the induction of myocardial infarction increased heart function significantly. On the basis of the study by Orlic et al., we mobilized HSC with stem cell factor (SCF) combined with granulocyte colony-stimulating factor (G-CSF), which operate synergistically in inducing egress of HSC from the BM compared with G-CSF alone (9).Here we report that cytokine treatment before renal I/R in mice accelerates renal function recovery compared with controls. The underlying mechanism does not depend on a biologically significant contribu...

Effect of Stem Cell Factor and Granulocyte-Macrophage Colony-Stimulating Factor-Induced Bone Marrow Stem Cell Mobilization on Recovery from Acute Tubular Necrosis in Rats

“…But other studies have demonstrated that stem cells contribute to the regenerative process by producing protective and regenerative factors rather than directly using their differentiated progeny to replace damaged cells. [44][45][46][47] Our data indicate that cytokine-induced mobilization is effective in gentamicin-induced ATN, but our current study could not tell that the partial morphologic and functional improvements were due to multiple differentiation of bone marrow-derived cells or secretion of stimulatory or regenerative factors. Meanwhile, bone marrow contains various types of stem cells.…”

Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney

“…Renal I/R injury was induced as described previously (58). Briefly, renal arteries were clamped for 45 minutes using microaneurysm clamps through a midline abdominal incision under general anesthesia (0.07 ml/10 g mouse of fentanyl citrate fluanisone midazolam mixture containing: 1.25 mg/ml midazolam [Roche Diagnostics Corp.], 0.08 mg/ml fentanyl citrate, and 2.5 mg/ml fluanisone [Janssen Pharmaceutica]).…”

RAGE Does Not Contribute to Renal Injury and Damage upon Ischemia/Reperfusion-Induced Injury

“…The degree of necrosis was scored by a pathologist in a blinded fashion on a 5-point scale: 0 = no damage, 1 = 10% necrosis of the corticomedullary junction, 2 = 10-25%, 3 = 25-50%, 4 = 50-75%, 5 = more than 75%. For immunostaining, 4-m tissue sections were incubated with specific antibodies for granulocytes (FITC-labeled anti-mouse Ly6G mAb; BD Biosciences-Pharmingen), apoptosis (rabbit anti-human active caspase-3; Cell Signaling Technology), GFP (rabbitanti GFP IgG; Molecular Probes), HMGB1 (rabbit-anti mouse HMGB1; Abcam), S100B (rabbit anti-S100B; Sigma-Aldrich) or CML ( N -epsilon carboxymethyl lysine) which has been identified as a major structure in advanced glycation end-products (AGE), mouse IgG, Biologo) followed by appropriate secondary antibodies as described before [15,16,[20][21][22][23]. To determine percentage of positive staining on kidney tissue slides, approximately 10 pictures of tissue section were taken under light microscopy (magnification !…”