Sonic Hedgehog Controls the Phenotypic Fate and Therapeutic Efficacy of Grafted Neural Precursor Cells in a Model of Nigrostriatal Neurodegeneration.
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.
Department of Neurology, University of Arizona, Tucson, Arizona, 85724, United States of America.
Lalitha
L
Madhavan
Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, 49503, United States of America.
Brian F
BF
Daley
Center for Cell and Molecular Therapy, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, United States of America.
Beverly L
BL
Davidson
Department of Internal Medicine, University of Iowa, Iowa City, Iowa, 52242, United States of America.
Ryan L
RL
Boudreau
Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, 49503, United States of America.
Jack W
JW
Lipton
Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, 49503, United States of America.
Allyson
A
Cole-Strauss
Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, 49503, United States of America.
Kathy
K
Steece-Collier
Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan, 49503, United States of America.
Timothy J
TJ
Collier
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D000089662:Doublecortin Protein; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006085:Graft Survival / Q000235:genetics*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008636:Mesencephalon / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D017072:Neostriatum / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D055495:Neurogenesis / Q000235:genetics; D016627:Oxidopamine; D010641:Phenotype; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D015398:Signal Transduction; D013238:Stereotaxic Techniques; D013378:Substantia Nigra / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D019076:Transgenes
C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D058851:GPI-Linked Proteins; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D053823:Hedgehog Proteins; D007527:Isoenzymes; D034741:RNA, Small Interfering; C546888:Shh protein, rat; D016627:Oxidopamine; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental