Central Nervous System Extracellular Matrix as a Therapeutic Bioscaffold for Central Nervous System Injury

摘要

Traumatic central nervous system (CNS) injuries lack effective treatment options and typically result in irrecoverable tissue damage and lifelong neurologic impairment. An ideal therapeutic would provide structural support for axonal regrowth as well as modulate the default secondary injury associated with CNS injuries. Extracellular matrix (ECM) bioscaffolds derived by decellularization promoted functional remodeling in numerous non-CNS applications; however, there has been minimal investigation of this technology in the CNS. The objectives of this work were to evaluate the tissue specific properties of CNS-ECM in terms of (1) hydrogel characteristics and biochemical composition, (2) neurotrophic potential, and (3) ability to alter the innate immune response.udBioscaffolds composed of CNS-ECM were formed into injectable solutions that polymerize to form hydrogels at body temperature. Hydrogels derived from CNS-ECM were compared to a hydrogel form of a non-CNS ECM, urinary bladder matrix (UBM-ECM), using compositional analyses for retained ECM molecules, mechanical assessments for rheological and turbidimetric properties, and multiphoton microscopy to visualize in-vitro three-dimensional neurite outgrowth. ECM hydrogels from both tissue sources had mechanical properties similar to native CNS and supported three-dimensional neurite outgrowth. udCNS-ECM and UBM-ECM bioscaffold mediated alteration of the innate immune and neural stem cell response was interrogated in-vitro using macrophages and spinal cord stem cells (SPCs). While all ECM scaffolds evaluated decreased astrocyte differentiation, only UBM-ECM increased SPC neuronal differentiation. Bioscaffolds derived from both CNS and non-CNS tissue sources promoted a pro-repair macrophage phenotype as demonstrated through immunofluorescent results. Finally, CNS-ECM bioscaffolds were compared to UBM-ECM in a rat model of contusion spinal cord injury. Macrophage polarization was evaluated over 4 weeks and a histologic evaluation of the lesion site completed. While the ECM bioscaffolds did not improve functional recovery, pro-repair macrophages were found closely associated with the ECM injection sites.udThis body of work demonstrates CNS-ECM bioscaffolds can be isolated and are capable of minimally invasive injection, supporting neurite extension in-vitro, and modulating macrophage and stem cell responses. Future research is necessary to determine the added benefits that can be obtained when this technology is combined with others known to be beneficial for CNS tissue repair.ud