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Spatiotemporally Controlling the Release of Biological Effectors Enhances Their Effects on Cell Migration and Neurite Outgrowth.

ABSTRACT: It is a major challenge to coordinate topographic cues from scaffolds with the on-demand, sustained release of biological effectors to maximize their performance in tissue regeneration. Here, a system involving masked, photo-triggered release of biological effectors from a temperature-sensitive scaffold for augmented cell migration and neurite outgrowth is reported. The scaffold contains microparticles of a phase-change material (PCM) sandwiched between two layers of electrospun fibers. The biological effectors are co-loaded with a photothermal dye in the PCM microparticles. Under irradiation with a near-infrared laser, the PCM will be melted to swiftly release the biological effectors. By imposing a photomask between the scaffold and the laser, only those microparticles in the irradiated region are melted, enabling a spatial control over the release. By adjusting the photomask, different regions of the scaffold can be sequentially irradiated at designated times, realizing on-demand and sustained release of the biological effectors with spatiotemporal controls. In one demonstration, this method is used to accelerate the directional migration of NIH-3T3 fibroblasts along the uniaxial or radial direction of fiber alignment by controlling the release of epidermal growth factor. In another demonstration, the release of nerve growth factor is managed to significantly promote neurite outgrowth from PC12 cells.

SUBMITTER: Xue J

PROVIDER: S-EPMC7743917 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The formation of connections within the mammalian neocortex is highly regulated by both extracellular guidance mechanisms and intrinsic gene expression programs. There are two types of cortical projection neurons (CPNs): those that project locally and interhemispherically and those that project to subcerebral structures such as the thalamus, hindbrain, and spinal cord. The regulation of cortical projection morphologies is not yet fully understood at the molecular level. Here, we report a role for Mllt11 (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q) in the migration and neurite outgrowth of callosal projection neurons during mouse brain formation. We show that Mllt11 expression is exclusive to developing neurons and is enriched in the developing cortical plate (CP) during the formation of the superficial cortical layers. In cultured primary cortical neurons, Mllt11 is detected in varicosities and growth cones as well as the soma. Using conditional loss-of-function and gain-of-function analysis we show that Mllt11 is required for neuritogenesis and proper migration of upper layer CPNs. Loss of Mllt11 in the superficial cortex of male and female neonates leads to a severe reduction in fibers crossing the corpus callosum (CC), a progressive loss in the maintenance of upper layer projection neuron gene expression, and reduced complexity of dendritic arborization. Proteomic analysis revealed that Mllt11 associates with stabilized microtubules, and Mllt11 loss affected microtubule staining in callosal axons. Taken together, our findings support a role for Mllt11 in promoting the formation of mature upper-layer neuron morphologies and connectivity in the cerebral cortex.SIGNIFICANCE STATEMENT The regulation of cortical projection neuron (CPN) morphologies is an area of active investigation since the time of Cajal. Yet the molecular mechanisms of how the complex dendritic and axonal morphologies of projection neurons are formed remains incompletely understood. Although conditional mutagenesis analysis in the mouse, coupled with overexpression assays in the developing fetal brain, we show that a novel protein called Mllt11 is sufficient and necessary to regulate the dendritic and axonal characteristics of callosal projection neurons in the developing mammalian neocortex. Furthermore, we show that Mllt11 interacts with microtubules, likely accounting for its role in neuritogenesis.

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Spatiotemporally Controlling the Release of Biological Effectors Enhances Their Effects on Cell Migration and Neurite Outgrowth.

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