Journal article
Sonic Hedgehog Controls the Phenotypic Fate and Therapeutic Efficacy of Grafted Neural Precursor Cells in a Model of Nigrostriatal Neurodegeneration
PloS one, Vol.10(9), pp.e0137136-e0137136
2015
DOI: 10.1371/journal.pone.0137136
PMCID: PMC4560385
PMID: 26340267
Abstract
The expression of soluble growth and survival promoting factors by neural precursor cells (NPCs) is suggested to be a prominent mechanism underlying the protective and regenerative effects of these cells after transplantation. Nevertheless, how and to what extent specific NPC-expressed factors contribute to therapeutic effects is not well understood. Using RNA silencing, the current study investigated the roles of two donor NPC molecules, namely glial cell-line derived neurotrophic factor (GDNF) and sonic hedgehog (SHH), in the protection of substantia nigra dopamine neurons in rats treated with 6-hydroxydopamine (6-OHDA). Analyses indicate that as opposed to the knock-down of GDNF, SHH inhibition caused a profound decline in nigrostriatal neuroprotection. Further, SHH silencing also curbed endogenous neurogenesis and the migration of host brdU+/dcx+ neural precursors into the striatum, which was present in the animals receiving control or GDNF silenced NPCs. A change in graft phenotype, mainly reflected by a reduced proportion of undifferentiated nestin+ cells, as well as a significantly greater host microglial activity, suggested an important role for these processes in the attenuation of neuroprotection and neurogenesis upon SHH silencing. Overall these studies reveal core mechanisms fundamental to grafted NPC-based therapeutic effects, and delineate the particular contributions of two graft-expressed molecules, SHH and GDNF, in mediating midbrain dopamine neuron protection, and host plasticity after NPC transplantation.
Details
- Title: Subtitle
- Sonic Hedgehog Controls the Phenotypic Fate and Therapeutic Efficacy of Grafted Neural Precursor Cells in a Model of Nigrostriatal Neurodegeneration
- Creators
- Lalitha Madhavan - Department of Neurology, University of Arizona, Tucson, Arizona, 85724, United States of AmericaBrian F Daley - Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, 49503, United States of AmericaBeverly L Davidson - Center for Cell and Molecular Therapy, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, United States of AmericaRyan L Boudreau - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, 52242, United States of AmericaJack W Lipton - Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, 49503, United States of AmericaAllyson Cole-Strauss - Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, 49503, United States of AmericaKathy Steece-Collier - Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, 49503, United States of AmericaTimothy J Collier - Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, 49503, United States of America
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.10(9), pp.e0137136-e0137136
- DOI
- 10.1371/journal.pone.0137136
- PMID
- 26340267
- PMCID
- PMC4560385
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library of Science; United States
- Grant note
- P50 NS058830 / NINDS NIH HHS NS58830 / NINDS NIH HHS R01 NS055295 / NINDS NIH HHS NS055295 / NINDS NIH HHS
- Language
- English
- Date published
- 2015
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984065382702771
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