title: Intrinsic mechanisms underlying the neurotrophic activity of adipose derived stem cells.
abstract: Adipose derived stem cells (ADSC) can be differentiated into Schwann cell-like cells which enhance nerve function and regeneration. However, the signalling mechanisms underlying the neurotrophic potential of ADSC remain largely unknown. In this study, we hypothesised that ADSC, upon stimulation with a combination of growth factors, could rapidly produce brain derived neurotrophic factor (BDNF) with a similar molecular mechanism to that functioning in the nervous system. Within 48 h of stimulation, ADSC demonstrated potent neurotrophic effects on dorsal root ganglion neurons, at a magnitude equivalent to that of the longer term differentiated Schwann cell-like cells. Stimulated ADSC showed rapid up-regulation of the neuronal activity dependent promoter BDNF exon IV along with an augmented expression of full length protein encoding BDNF exon IX. BDNF protein was secreted at a concentration similar to that produced by differentiated Schwann cell-like cells. Stimulation also activated the BDNF expression gating transcription factor, cAMP responsive element binding (CREB) protein. However, blocking phosphorylation of CREB with the protein kinase A small molecule inhibitor H89 did not suppress secretion of BDNF protein. These results suggest rapid BDNF production in ADSC is mediated through multiple compensatory pathways independent of, or in addition to, the CREB neuronal activation cascade.
authors.affiliation: Department of Integrative Medical Biology, Section of Anatomy, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Kai-Hei
authors.initials: KH
authors.lastname: Tse
authors.affiliation: Department of Integrative Medical Biology, Section of Anatomy, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Lev N
authors.initials: LN
authors.lastname: Novikov
authors.affiliation: Department of Integrative Medical Biology, Section of Anatomy, Umeå University, SE-901 87 Umeå, Sweden; Department of Surgical and Perioperative Sciences, Section of Hand & Plastic Surgery, Umeå University, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Wiberg
authors.affiliation: Department of Integrative Medical Biology, Section of Anatomy, Umeå University, SE-901 87 Umeå, Sweden. Electronic address: paul.kingham@umu.se.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kingham
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D002118:Calcium
keywords: Brain derived neurotrophic factor; Differentiation; Neurite; Regeneration; Stem cells