Abstract
The Sonic Hedgehog protein (Shh) has been extensively researched since its discovery in 1980. Its crucial role in early neurogenesis and endogenous stem cells of mature brains, as well as its recently described neuroprotective features, implicate further important effects on neuronal homeostasis. Here, we investigate its potential role in the survival, proliferation, and differentiation of neural precursors cells (NPCs) under inflammatory stress as a potential adjunct for NPC-transplantation strategies in spinal cord injury (SCI) treatment. To this end, we simulated an inflammatory environment in vitro using lipopolysaccharide (LPS) and induced the Shh-pathway using recombinant Shh or blocked it using Cyclopamine, a potent Smo inhibitor. We found that Shh mediates the proliferation and neuronal differentiation potential of NPCs in vitro, even in an inflammatory stress environment mimicking the subacute phase after SCI. At the same time, our results indicate that a reduction of the Shh-pathway activation by blockage with Cyclopamine is associated with reduced NPC-survival, reduced neuronal differentiation and increased astroglial differentiation. Shh might thus, play a role in endogenous NPC-mediated neuroregeneration or even be a potent conjunct to NPC-based therapies in the inflammatory environment after SCI.
Highlights
The Hedgehog (Hh) pathway is one of the critical inter-cell communication pathways during the embryonic development of vertebrates
Similar to Wingless-type MMTV Integration Site Family Member 2 (Wnt2) and other growth factors, Sonic Hedgehog (Shh) has diverging effects depending on its dosage and timing of exposure [5], especially on Mesenchymal Stem Cells (MSCs) and Neural Precursor Cells (NPCs) [3,6,7]
We used Cell-Count-Kit 88 (CCK-8) viable cell quantification to measure the survival of NPCs concerning stimulation or blockage of the Shh-pathway under normal and inflammatory growing conditions
Summary
The Hedgehog (Hh) pathway is one of the critical inter-cell communication pathways during the embryonic development of vertebrates. More recent publications observed that Shh affects stem cell niches in the postnatal and adult brain’s subventricular zone (SVZ) by modulating precursor cells and controlling their proliferation [4]. Such SVZderived NPCs with the ability to migrate over long distances might play an essential role in brain tissue homeostasis and endogenous neuroregeneration after injury to the CNS [10]. They are already used for experimental stem cell transplantation strategies in the context of spinal cord injuries (SCI), with the goal to improve neuroregeneration by exogenous cell grafts [11]. In our current study, we assessed the effects of Shh on the survival, proliferation, and differentiation of NPCs in vitro under inflammatory stress, mimicking the hostile environment of the injured spinal cord
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