Astrocyte Mechanobiology Following Central Nervous System Injury Revealed By Magnetically Active Hydrogels

该奖项将支持提高我们对神经胶质细胞瘢痕形成机制的理解。中枢神经系统的损伤往往导致终身残疾。 患有脊髓损伤或创伤性脑损伤的患者可能遭受严重的功能丧失。与身体其他部位一样，中枢神经组织的机械硬度在受伤后会发生变化。 这既影响了传递信号的神经元，也影响了大脑和脊髓中被称为神经胶质细胞的支持细胞类型。一种称为星形胶质细胞的神经胶质细胞有助于神经胶质瘢痕的形成。 疤痕抑制了神经元的再生，而神经元的再生是损伤后功能恢复所必需的。目前，组织刚度动态变化对星形胶质细胞功能的影响尚不清楚。这项研究将利用磁性改变星形胶质细胞周围的硬度，以了解细胞如何促进胶质瘢痕形成。 最终，这些结果可能导致脊髓损伤后恢复功能的新治疗方法。此外，该研究还将辅以一个名为“科学与运动”的幼儿教育项目，向儿童介绍科学家和工程师使用磁性的方式。磁活性水凝胶提供了一种新的手段，可以在三维微环境中询问时间和空间变化的机械特性。这些变化是快速和可逆的，研究表明细胞对改变的机械性能迅速作出反应（在几秒钟内）。实验将使用离体切片模型表征挫伤后脊髓机械特性的动态变化，然后使用磁活性水凝胶在体外模拟这些变化以询问星形胶质细胞机械生物学。实验将集中在星形胶质细胞的转录组学变化，以更好地理解胶质瘢痕形成的机制。这些研究将涉及粘弹性力学的时间和空间梯度，由离体脊髓损伤模型的力学测试结果提供信息。总的来说，这项工作将提高我们对星形胶质细胞机械生物学的理解，并可能导致新的治疗方法来修复脊髓损伤。这个奖项反映了NSF的法定使命，并已被认为是值得支持的，通过评估使用基金会的智力价值和更广泛的影响审查标准。

This award will support work to improve our understanding of the mechanisms underlying scar formation in glial cells. Injury to the central nervous system often results in life-long disability. Patients with spinal cord injury or traumatic brain injury may suffer severe loss of function. Like other regions in the body, the mechanical stiffness of central nervous tissue changes after an injury. This affects both the neurons that transmit signals as well as supporting cell types in the brain and spinal cord, which are called glial cells. One type of glial cell, called an astrocyte, contributes to the formation of a glial scar. The scar inhibits the regeneration of neurons needed for functional recovery following an injury. Currently, the effects of the dynamically changing stiffness of the tissue on the function of the astrocytes is unknown. The work done with this grant will alter the stiffness of astrocytes’ surroundings using magnetism to understand how the cells contribute to glial scar formation. Eventually, these results can lead to new treatments for restoring function following spinal cord injury. Additionally, the research will be supplemented with an early childhood education program called “Science and Movement” that will introduce children to the ways in which scientists and engineers use magnetism.Magnetically active hydrogels provide a new means to interrogate time and spatial varying mechanical properties in three-dimensional microenvironments. The changes are fast and reversible, and studies indicate that cells respond to the altered mechanical properties rapidly (within seconds). The experiments will characterize the dynamic changes to the mechanical properties of the spinal cord following contusion injury using an ex vivo slice model, and then use magnetically active hydrogels to mimic these changes in vitro to interrogate astrocyte mechanobiology. Experiments will focus on the transcriptomic changes of the astrocytes in order to better understand the mechanisms underlying the formation of a glial scar. These studies will involve both temporal and spatial gradients of viscoelastic mechanics, informed by the results of the mechanical testing of the ex vivo spinal cord injury model. Overall, this work will improve our understanding of astrocyte mechanobiology and potentially lead to new treatments to repair spinal cord injury.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.