Brennan, F. H. | Search bioRxiv

bioRxiv2019

Human immune cells infiltrate the lesioned spinal cord and impair recovery after spinal cord injury in humanized mice

Summary PointsO_LIImmune compromised mice require ~4 months of engraftment with human umbilical cord blood CD34+ stem cells to develop a full and functional human immune system\nC_LIO_LIThe human neuroinflammatory response elicited after spinal cord injury in humanized mice is limited at 2 months post-engraftment but matures by 4 months\nC_LIO_LIIntraspinal neuroinflammation consists of a florid human T cell and macrophage response, and human T cells co-localize with human macrophages\nC_LIO_LIA human intraspinal neuroinflammatory response exacerbates lesion pathology and impairs functional recovery\nC_LI\n\nAbstractHumanized mice are a useful tool to help better understand how the human immune system responds to central nervous system (CNS) injury. However, the optimal parameters for using humanized mice in preclinical CNS injury models have not been established. Here, we show that it takes 3-4 months after engraftment of neonatal immune compromised mice with human umbilical cord stem cells to generate a robust human immune system. Indeed, sub-optimal human immune cell responses occurred when humanized mice received spinal contusion injuries at 2 months vs. 4 months post-engraftment. Human T cells directly contact human macrophages within the spinal cord lesion of these mice and the development of a mature human immune system was associated with worse lesion pathology and neurological recovery. Together, data in this report establish an optimal experimental framework for using humanized mice to help translate promising preclinical therapies for CNS injury.

neuroscience↗

bioRxiv2018

Microglia limit lesion expansion and promote functional recovery after spinal cord injury in mice

Traumatic spinal cord injury (SCI) elicits a robust intraspinal inflammatory reaction that is dominated by at least two major subpopulations of macrophages, i.e., those derived from resident microglia and another from monocytes that infiltrate the injury site from the circulation. Previously, we implicated monocyte-derived macrophages (MDMs) as effectors of acute post-injury pathology after SCI; however, it is still unclear whether microglia also contribute to lesion pathology. Assigning distinct functional roles to microglia and MDMs in vivo has been difficult because these CNS macrophage subsets are morphologically and phenotypically similar. Here, to characterize the role that microglia play in experimental models of thoracic spinal contusion or lumbar crush injury, mice were fed vehicle chow or chow laced with a CSF1R receptor antagonist, PLX5622. Feeding PLX5622 depletes microglia. In both groups, spontaneous recovery of hindlimb motor function was evaluated for up to 8 weeks post-SCI using open-field and horizontal ladder tests. Histopathological assessment of intraspinal pathology was assessed in 8 week post-injury tissues. In both SCI models, microglia depletion exacerbated lesion pathology and impaired spontaneous recovery of hind limb function. Notably, the loss of microglia prevented astroglial encapsulation of the lesion core, which was associated with larger lesions, enhanced demyelination and neuron loss and a larger inflammatory response that was dominated by monocyte-derived macrophages. The neuroprotective and healing properties of microglia become obvious in the subacute phases of recovery; microglia depletion up to 7 days post-injury (dpi) had no apparent effect on recovery while delayed depletion from 8-28dpi exacerbated lesion pathology and significantly impaired functional recovery. These data suggest that microglia have essential tissue repair functions after SCI. Selective enhancement of microglial activities may be a novel strategy to preserve tissue and promote recovery of function after neurotrauma.

neuroscience↗