Abstract
Neural precursor cells (NPCs) are generated in the subventricular zone (SVZ) and travel through the rostral migratory stream (RMS) to replace olfactory bulb interneurons in the brains of most adult mammals. Following brain injury, SVZ-derived NPCs can divert from the RMS and migrate toward injured brain regions but arrive in numbers too low to promote functional recovery without experimental intervention. Our lab has biofabricated a "living scaffold" that replicates the structural and functional features of the endogenous RMS. This tissue-engineered rostral migratory stream (TE-RMS) is a new regenerative medicine strategy designed to facilitate stable and sustained NPC delivery into neuron-deficient brain regions following brain injury or neurodegenerative disease and an in vitro tool to investigate the mechanisms of neuronal migration and cell-cell communication. We have previously shown that the TE-RMS replicates the basic structure and protein expression of the endogenous RMS and can direct immature neuronal migration in vitro and in vivo. Here, we further describe profound morphological changes that occur following precise physical manipulation and subsequent self-assembly of astrocytes into the TE-RMS, including significant cytoskeletal rearrangement and nuclear elongation. The unique cytoskeletal and nuclear architecture of TE-RMS astrocytes mimics astrocytes in the endogenous rat RMS. Advanced imaging techniques reveal the unique morphology of TE-RMS cells that has yet to be described of astrocytes in vitro. The TE-RMS offers a novel platform to elucidate astrocyte cytoskeletal and nuclear dynamics and their relationship to cell behavior and function.
Highlights
Neurogenesis, or the birth of new neurons in the brain, continues in the subventricular zone (SVZ) of most mammals throughout adulthood [1,2]
Neural precursor cells (NPCs) in the SVZ of rodents can differentiate into neuroblasts and migrate through a pathway of aligned astrocytes known as the rostral migratory stream (RMS) to the olfactory bulb (OB), where they mature into functional granule, periglomerular, or glutamatergic interneurons and integrate into existing circuitry [3–6]
Number of branch points were compared by two-tailed, nested t-test and revealed that planar astrocytes had a significantly higher number of branch points compared to tissue-engineered rostral migratory stream (TE-RMS) astrocytes (Figure 3h; t = 8.801, df = 14; p < 0.0001)
Summary
Neurogenesis, or the birth of new neurons in the brain, continues in the subventricular zone (SVZ) of most mammals throughout adulthood [1,2]. A variety of biomaterial and tissue engineering strategies have been developed to enhance the redirection of SVZ neuroblasts throughout the brain following neuronal injury [23–25]. These strategies have increased the quantity of neuroblasts entering injured brain regions by augmenting chemoattractant cues and/or by providing a physical substrate for migration [23]. Drawing inspiration from the SVZ-RMS-OB pathway, our laboratory has developed a biologically relevant, implantable “living scaffold” that emulates the glial tube of the endogenous RMS [26–29] This tissue-engineered rostral migratory stream (TE-RMS) is designed to promote the sustained delivery of endogenous NPCs into injured brain regions by replicating and expanding upon the endogenous RMS, which is one of the brain’s intrinsic mechanisms for neuronal replacement. Previous experiments not presented have demonstrated that the TE-RMS can be reliably fabricated from sources of rat and human astrocytes, mimics increased expression of key functional proteins of the endogenous rat RMS, can redirect immature rat neurons in vitro, and when implanted into the rat brain can facilitate migration of endogenous neuroblasts out of the RMS and throughout the TE-RMS [29]
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