PMID- 24873730 OWN - NLM STAT- MEDLINE DCOM- 20141217 LR - 20151119 IS - 1090-2430 (Electronic) IS - 0014-4886 (Linking) VI - 261 DP - 2014 Nov TI - Spatiotemporally limited BDNF and GDNF overexpression rescues motoneurons destined to die and induces elongative axon growth. PG - 367-76 LID - S0014-4886(14)00161-7 [pii] LID - 10.1016/j.expneurol.2014.05.019 [doi] AB - Axonal injury close to cell bodies of motoneurons induces the death of the vast majority of affected cells. Neurotrophic factors, such as brain derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF), delivered close to the damaged motor pool in a non-regulated manner induce good survival of injured motoneurons and sprouting of their axons but fail to induce functional reinnervation. To avoid these drawbacks of high levels of neurotrophic expression, we devised an ex vivo gene therapy system to induce transient expression of BDNF/GDNF in transfected rat adipose tissue-derived stem cells (rASCs) which were grafted around the reimplanted ventral root, embedded in collagen gel. Strong BDNF/GDNF expression was induced in vitro in the first days after transfection with a significant decline in expression 10-14 days following transfection. Numerous axons of injured motoneurons were able to enter the reimplanted root following reimplantation and BDNF or GDNF treatment (192+/-17 SEM vs 187+/-12 SEM, respectively) and produce morphological and functional reinnervation. Treatment with a combined cell population (BDNF+GDNF-transfected rASCs) induced slightly improved reinnervation (247+/-24 SEM). In contrast, only few motoneurons regenerated their axons in control animals (63+/-4 SEM) which received untransfected cells. The axons of surviving motoneurons showed elongative growth typical of regenerative axons, without aberrant growth or coil formation of sprouting axons. These findings provide evidence that damaged motoneurons require limited and spatially directed amounts of BDNF and GDNF to support their survival and regeneration. Moreover, neurotrophic support appears to be needed only for a critical period of time not longer than for two weeks after injury. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Pajenda, Gholam AU - Pajenda G AD - Ludwig Boltzmann Institute for Experimental and Clinical Traumatology at the Research Centre for Traumatology of the Austrian Workers, Donaueschingenstr, 13, A-1200 Vienna, Austria; Department for Trauma Surgery, Medical University Vienna, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. FAU - Hercher, David AU - Hercher D AD - Ludwig Boltzmann Institute for Experimental and Clinical Traumatology at the Research Centre for Traumatology of the Austrian Workers, Donaueschingenstr, 13, A-1200 Vienna, Austria; Austrian Cluster for Tissue Regeneration and Compensation Board (AUVA), Donaueschingenstr, 13, A-1200 Vienna, Austria. FAU - Marton, Gabor AU - Marton G AD - Department of Anatomy, Histology and Embryology, Faculty of Medicine, Albert Szent-Gyorgyi Clinical Centre, University of Szeged, Hungary. FAU - Pajer, Krisztian AU - Pajer K AD - Department of Anatomy, Histology and Embryology, Faculty of Medicine, Albert Szent-Gyorgyi Clinical Centre, University of Szeged, Hungary. FAU - Feichtinger, Georg A AU - Feichtinger GA AD - Ludwig Boltzmann Institute for Experimental and Clinical Traumatology at the Research Centre for Traumatology of the Austrian Workers, Donaueschingenstr, 13, A-1200 Vienna, Austria; Austrian Cluster for Tissue Regeneration and Compensation Board (AUVA), Donaueschingenstr, 13, A-1200 Vienna, Austria. FAU - Maleth, Jozsef AU - Maleth J AD - Department of Anatomy, Histology and Embryology, Faculty of Medicine, Albert Szent-Gyorgyi Clinical Centre, University of Szeged, Hungary. FAU - Redl, Heinz AU - Redl H AD - Ludwig Boltzmann Institute for Experimental and Clinical Traumatology at the Research Centre for Traumatology of the Austrian Workers, Donaueschingenstr, 13, A-1200 Vienna, Austria; Austrian Cluster for Tissue Regeneration and Compensation Board (AUVA), Donaueschingenstr, 13, A-1200 Vienna, Austria. FAU - Nogradi, Antal AU - Nogradi A AD - Ludwig Boltzmann Institute for Experimental and Clinical Traumatology at the Research Centre for Traumatology of the Austrian Workers, Donaueschingenstr, 13, A-1200 Vienna, Austria; Department of Anatomy, Histology and Embryology, Faculty of Medicine, Albert Szent-Gyorgyi Clinical Centre, University of Szeged, Hungary; 1st Department of Internal Medicine, Albert Szent-Gyorgyi Clinical Centre, University of Szeged, Hungary. Electronic address: nogradi.antal@med.u-szeged.hu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140527 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Amidines) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Glial Cell Line-Derived Neurotrophic Factor) RN - 0 (diamidino compound 253-50) SB - IM MH - Adipose Tissue/cytology MH - Amidines MH - Animals MH - Axons/*physiology MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism MH - Disease Models, Animal MH - Embryo, Mammalian MH - Female MH - Ganglia, Spinal/cytology MH - Gene Expression Regulation MH - Glial Cell Line-Derived Neurotrophic Factor/genetics/*metabolism MH - Locomotion/physiology MH - Male MH - Mice MH - Motor Neurons/cytology/*physiology MH - Peripheral Nervous System Diseases/*therapy MH - Rats MH - Rats, Sprague-Dawley MH - Stem Cell Transplantation MH - Stem Cells/physiology OTO - NOTNLM OT - Adipose tissue-derived stem cells OT - Axonal growth OT - BDNF OT - GDNF OT - Reinnervation OT - Transfection OT - Ventral root avulsion EDAT- 2014/05/31 06:00 MHDA- 2014/12/18 06:00 CRDT- 2014/05/31 06:00 PHST- 2014/01/24 00:00 [received] PHST- 2014/04/30 00:00 [revised] PHST- 2014/05/18 00:00 [accepted] PHST- 2014/05/31 06:00 [entrez] PHST- 2014/05/31 06:00 [pubmed] PHST- 2014/12/18 06:00 [medline] AID - S0014-4886(14)00161-7 [pii] AID - 10.1016/j.expneurol.2014.05.019 [doi] PST - ppublish SO - Exp Neurol. 2014 Nov;261:367-76. doi: 10.1016/j.expneurol.2014.05.019. Epub 2014 May 27.