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Hepatocyte Growth Factor-Preconditioned Neural Progenitor Cells Attenuate Astrocyte Reactivity and Promote Neurite Outgrowth.

ABSTRACT: The astroglial scar is a defining hallmark of secondary pathology following central nervous system (CNS) injury that, despite its role in limiting tissue damage, presents a significant barrier to neuroregeneration. Neural progenitor cell (NPC) therapies for tissue repair and regeneration have demonstrated favorable outcomes, the effects of which are ascribed not only to direct cell replacement but trophic support. Cytokines and growth factors secreted by NPCs aid in modifying the inhibitory and cytotoxic post-injury microenvironment. In an effort to harness and enhance the reparative potential of NPC secretome, we utilized the multifunctional and pro-regenerative cytokine, hepatocyte growth factor (HGF), as a cellular preconditioning agent. We first demonstrated the capacity of HGF to promote NPC survival in the presence of oxidative stress. We then assessed the capacity of this modified conditioned media (CM) to attenuate astrocyte reactivity and promote neurite outgrowth in vitro. HGF pre-conditioned NPCs demonstrated significantly increased levels of tissue inhibitor of metalloproteinases-1 and reduced vascular endothelial growth factor compared to untreated NPCs. In reactive astrocytes, HGF-enhanced NPC-CM effectively reduced glial fibrillary acidic protein (GFAP) expression and chondroitin sulfate proteoglycan deposition to a greater extent than either treatment alone, and enhanced neurite outgrowth of co-cultured neurons. in vivo, this combinatorial treatment strategy might enable tactical modification of the post-injury inhibitory astroglial environment to one that is more conducive to regeneration and functional recovery. These findings have important translational implications for the optimization of current cell-based therapies for CNS injury.

SUBMITTER: Hong J

PROVIDER: S-EPMC8695970 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aligned, electrospun fiber scaffolds provide topographical guidance for regenerating neurons and glia after central nervous system injury. To date, no study has explored how fiber surface nanotopography affects astrocyte response to fibrous scaffolds. Astrocytes play important roles in the glial scar, the blood brain barrier, and in maintaining homeostasis in the central nervous system. In this study, electrospun poly L-lactic acid fibers were engineered with smooth, pitted, or divoted surface nanotopography. Cortical or spinal cord primary rat astrocytes were cultured on the surfaces for either 1 or 3 d to examine the astrocyte response over time. The results showed that cortical astrocytes were significantly shorter and broader on the pitted and divoted fibers compared to those on smooth fibers. However, spinal cord astrocyte morphology was not significantly altered by the surface features. These findings indicate that astrocytes from unique anatomical locations respond differently to the presence of nanotopography. Western blot results show that the differences in morphology were not associated with significant changes in glial fibrillary acidicprotein (GFAP) or vinculin in either astrocyte population, suggesting that surface pits and divots do not induce a reactive phenotype in either cortical or spinal cord astrocytes. Finally, astrocytes were co-cultured with dorsal root ganglia to determine how the surfaces affected astrocyte-mediated neurite outgrowth. Astrocytes cultured on the fibers for shorter periods of time (1 d) generally supported longer neurite outgrowth. Pitted and divoted fibers restricted spinal cord astrocyte-mediated neurite outgrowth, while smooth fibers increased 3 d spinal cord astrocyte-mediated neurite outgrowth. In total, fiber surface nanotopography can influence astrocyte elongation and influence the capability of astrocytes to direct neurites. Therefore, fiber surface characteristics should be carefully controlled to optimize astrocyte-mediated axonal regeneration.

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Hepatocyte Growth Factor-Preconditioned Neural Progenitor Cells Attenuate Astrocyte Reactivity and Promote Neurite Outgrowth.

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