Glial cell line-derived neurotrophic growth factor increases motility and survival of cultured mesenchymal stem cells and ameliorates acute kidney injury

Abstract

Glial cell line-derived neurotrophic growth factor (GDNF), a member of the transforming growth factor family, is necessary for renal organogenesis and exhibits changes in expression in models of renal disease. Nestin is an intermediate filament protein originally believed to be a marker of neuroepithelial stem cells and recently proposed as a marker of mesenchymal stem cells (MSC). Having demonstrated the participation of nestin-expressing cells in renoprotection during acute renal ischemia, we hypothesized that growth factors and transcription factors similar to those operating in the nervous system should be also operant in the kidney and may be induced after noxious stimuli, such as an ischemic episode. Using cultured kidney-derived MSC, which abundantly express nestin, we confirmed expression of GDNF by these cells and demonstrated the GDNF-induced expression of GDNF. The cellular expression of nestin paralleled that of GDNF: serum starvation decreased the expression, whereas application of GDNF resulted in a dose-dependent increase in nestin expression. Immunohistochemical and Western blot analyses of kidneys obtained from control and postischemic mice showed that expression of GDNF was much enhanced in the renal cortex, a pattern similar to the previously reported expression of nestin. Based on the observed GDNF-induced GDNF expression, we next explored the effect of supplemental GDNF administered early after ischemia on renal function postischemia. GDNF-treated mice were protected against acute ischemia. To address potential mechanisms of the observed renoprotection, in vitro studies showed that GDNF accelerated MSC migration in a wound-healing assay. Hypoxia did not accelerate, but rather slightly reduced, the motility of MSC and reduced the expression of GDNF in MSC by approximately twofold. Furthermore, GDNF was cytoprotective against oxidative stress-induced apoptotic death of MSC. Collectively, these data establish 1) an autoregulatory circuit of GDNF-induced GDNF expression in renal MSC; 2) induction of GDNF expression in postischemic kidneys; 3) the ability of exogenous GDNF to ameliorate ischemic renal injury; and 4) a possible contribution of GDNF-induced motility and improved survival of MSC to renoprotection.

Effects of Glial Cell Line-derived Neurotrophic Factor on Dental Pulp Cells

“…This is not a very surprising finding as it is well known that the cellular repertoire involved in pro-survival signaling is closely associated with cell cycle control processes (Maddika et al, 2007). Our results raise the possibility that GDNF may a role in MSC recruitment and proliferation during dentine repair (Shi et al, 2008). GDNF is able to bind extracellular proteoglycan heparin sulphate chains (Rider, 2006), indicating the likelihood that GDNF produced by odontoblasts is sequestered within dentin (Nosrat et al, 1997(Nosrat et al, , 1998.…”

Semaphorin 3A inactivation suppresses ischemia-reperfusion-induced inflammation and acute kidney injury

“…Expression of MCP-1 was not decreased significantly in sema3A mutant mice compared with WT mice. Ischemia-reperfusion of the kidney is known to upregulate a protective molecule GDNF (27), which was shown to be regulated by sema3A during development (30). To determine whether sema3A-mediated suppression of GDNF contributes to ischemia-reperfusion injury, GDNF expression was quantified.…”

Glial cell line-derived neurotrophic factor influences proliferation of osteoblastic cells

“…Shi et al (37) described that GDNF promoted mesenchymal stem cell migration and survival; a mechanism by which GDNF may deliver renoprotection and kidney repair. The physiological implications of our findings that GDNF stimulated calvarial osteoblast proliferation under serum-deprived conditions are as yet unclear, but may allude to a novel role of this neurotrophic factor in bone remodeling and repair.…”