Sonic Hedgehog Controls the Phenotypic Fate and Therapeutic Efficacy of Grafted Neural Precursor Cells in a Model of Nigrostriatal Neurodegeneration

PloS One
Lalitha MadhavanTimothy J Collier

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...Continue Reading

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Citations

Aug 18, 2018·International Journal of Molecular Sciences·Shang-Der ChenDing-I Yang
Apr 9, 2020·Frontiers in Neurology·Linda OttoboniGianvito Martino
Jun 16, 2021·Aging Cell·Annadurai AnandhanLalitha Madhavan
Nov 28, 2021·International Journal of Molecular Sciences·Francesca AntonelliSimonetta Pazzaglia

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Methods Mentioned

BETA
transgenic
PCR
confocal microscopy
fluorescence microscopy
shSHH
transfection
RIP

Software Mentioned

Graphpad prism
Stereoinvestigator
Sigmaplot
Zeiss LSM
Microbrightfield

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