An investigation into the characteristics and potential therapeutic application of human neural progenitor cell-derived astrocytes in experimental spinal cord injury

摘要

Damage to the spinal cord leads to severe, and often permanent, motor, sensory and autonomic disturbances. A multitude of mechanism may contribute to spinal cord injury (SCI), including apoptotic and necrotic death of neurons, astrocytes and oligodendrocytes, axonal injury, demyelination, excitotoxicity, ischemia, oxidative damage, and inflammation. The lack of axonal regeneration is not primarily due to an inherent lack of capacity for axonal growth potential, but rather to the overall balance of axon-growth promoting (e.g. migration of Schwann cells into the lesion site and the local presentation of growth promoting factors and extracellular matrix proteins) and axonal growth inhibitory/repulsive molecules (e.g. myelin-associated proteins, the presence of a physical barrier presented by the glial scar and the development of fluid-filled cystic cavities) at- and around the lesion site. Over recent years, increasingly more detailed knowledge has been gained that demonstrates the potential for axonal regeneration within the nervous system of both experimental animals and humans. While the strongest regenerative capacity has been identified in the lesioned peripheral nervous system (PNS), it could also be demonstrated that axonal regeneration and compensatory sprouting takes place in the injured central nervous system (CNS). Such findings have led to the development of a number of interventional approaches to support or enhance the regenerative capacity of the CNS. Within the CNS, the main thrust of these approaches has focused either on new surgical methods, novel medications (including the use of blocking/neutralising antibodies and peptides), cell-based intervention strategies (including stem/progenitor cells) or, most recently, the application of tissue engineering strategies using biomaterials. The aim of the present study was based on the two latter approaches, combining the growth promoting properties of human neural progenitor-derived astrocytes and a highly orientated three dimensional collagen matrix in a tissue engineering strategy to bridge acute spinal cord lesions in adult rats. The present investigation is separated into two parts: The first part of the thesis addresses the issue of cell characterization, cell-cell and cell-substrate interactions in vitro. The second part of the thesis addresses the integration and functional benefits of transplanting hNP-AC into spinal cord injured rats in vivo.