title: Transient brown adipocyte-like cells derive from peripheral nerve progenitors in response to bone morphogenetic protein 2.
abstract: Perineurial-associated brown adipocyte-like cells were rapidly generated during bone morphogenetic protein 2 (BMP2)-induced sciatic nerve remodeling in the mouse. Two days after intramuscular injection of transduced mouse fibroblast cells expressing BMP2 into wild-type mice, there was replication of beta-3 adrenergic receptor(+) (ADRB3(+)) cells within the sciatic nerve perineurium. Fluorescence-activated cell sorting and analysis of cells isolated from these nerves confirmed ADRB3(+) cell expansion and their expression of the neural migration marker HNK1. Similar analysis performed 4 days after BMP2 delivery revealed a significant decrease in ADRB3(+) cells from isolated sciatic nerves, with their concurrent appearance within the adjacent soft tissue, suggesting migration away from the nerve. These soft tissue-derived cells also expressed the brown adipose marker uncoupling protein 1 (UCP1). Quantification of ADRB3-specific RNA in total hind limb tissue revealed a 3-fold increase 2 days after delivery of BMP2, followed by a 70-fold increase in UCP1-specific RNA after 3 days. Expression levels then rapidly returned to baseline by 4 days. Interestingly, these ADRB3(+) UCP1(+) cells also expressed the neural guidance factor reelin. Reelin(+) cells demonstrated distinct patterns within the injected muscle, concentrated toward the area of BMP2 release. Blocking mast cell degranulation-induced nerve remodeling resulted in the complete abrogation of UCP1-specific RNA and protein expression within the hind limbs following BMP2 injection. The data collectively suggest that local BMP2 administration initiates a cascade of events leading to the expansion, migration, and differentiation of progenitors from the peripheral nerve perineurium to brown adipose-like cells in the mouse, a necessary prerequisite for associated nerve remodeling.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Salisbury
authors.forename: Zawaunyka W
authors.initials: ZW
authors.lastname: Lazard
authors.forename: Eroboghene E
authors.initials: EE
authors.lastname: Ubogu
authors.forename: Alan R
authors.initials: AR
authors.lastname: Davis
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Olmsted-Davis
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D052437:Adipocytes, Brown / Q000166:cytology* / Q000502:physiology; D000367:Age Factors; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D008407:Mast Cells / Q000166:cytology / Q000502:physiology; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009638:Norepinephrine / Q000378:metabolism; D010525:Peripheral Nerves / Q000166:cytology* / Q000502:physiology; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology; D019076:Transgenes / Q000235:genetics; D000071256:Uncoupling Protein 1
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D022702:Receptors, Adrenergic, beta-3; D000091042:Reelin Protein; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D009638:Norepinephrine