Traumatic spinal cord injury in mice with human immune systems

Abstract

Mouse models have provided key insight into the cellular and molecular control of human immune system function. However, recent data indicate that extrapolating the functional capabilities of the murine immune system into humans can be misleading. Since immune cells significantly affect neuron survival and axon growth and also are required to defend the body against infection, it is important to determine the pathophysiological significance of spinal cord injury (SCI)-induced changes in human immune system function. Research projects using monkeys or humans would be ideal; however, logistical and ethical barriers preclude detailed mechanistic studies in either species. Humanized mice, i.e., immunocompromised mice reconstituted with human immune cells, can help overcome these barriers and can be applied in various experimental conditions that are of interest to the SCI community. Specifically, newborn NOD-SCID-IL2rgnull (NSG) mice engrafted with human CD34+ hematopoietic stem cells develop normally without neurological impairment. In this report, new data show that when mice with human immune systems receive a clinically-relevant spinal contusion injury, spontaneous functional recovery is indistinguishable from that achieved after SCI using conventional inbred mouse strains. Moreover, using routine immunohistochemical and flow cytometry techniques, one can easily phenotype circulating human immune cells and document the composition and distribution of these cells in the injured spinal cord. Lesion pathology in humanized mice is typical of mouse contusion injuries, producing a centralized lesion epicenter that becomes occupied by phagocytic macrophages and lymphocytes and enclosed by a dense astrocytic scar. Specific human immune cell types, including three distinct subsets of human monocytes, were readily detected in blood, spleen and liver. Future studies that aim to understand the functional consequences of manipulating the neuro-immune axis after SCI should consider using the humanized mouse model. Humanized mice represent a powerful tool for improving the translational value of pre-clinical SCI data.

Spinal cord injury causes chronic bone marrow failure

“…To determine if the SCI-dependent effects on HSPCs were species-specific, male and female mice with human HSPCs and immune systems (i.e., humanized mice) were generated 38 – 40 . Similar to wild-type mice, SCI prevented human HSPCs from entering the circulation and trafficking to the spleen (Fig.…”

“…All mice were housed in a specific pathogen-free housing facility with routine testing of sentinel mice for specific pathogens. Generation of NSG mice with human immune systems (hNSG mice) was performed as follows 38 – 40 . Newborn NSG pups (24–72 h postnatal) received 1 Gy whole-body X-ray irradiation (RS 2000, Rad Source, Suwanee, GA), followed immediately by engrafting 1–5 × 10 4 human umbilical cord CD34 + stem cells (Lonza Incorporated, Walkersville, MD or Stemcell Technologies, Vancouver, BC) via intrahepatic injection.…”

IVIg attenuates complement and improves spinal cord injury outcomes in mice

“…Proving the efficacy of promising new therapeutic interventions in clinical trials remains one of the biggest challenges in translational SCI research due to the heterogeneity in the patient population (i.e., differences in the initiating cause, lesion level, and severity) . Furthermore, although rodent SCI models replicate much of the etiology of human SCI, including the inflammatory response, there are important intrinsic anatomical differences between species. Hence, the degree of recovery of locomotor function in quadruped animals may not automatically translate to bipedal humans .…”

Increased nicotine response in iPSC-derived human neurons carrying the CHRNA5 N398 allele

“…While carefully controlled animal models have been quite successful in understanding the global mediating pathways of motivational and reward behaviors, attempts to study more complex human diseases in animal models may correlate poorly, given the evolutionary distance between humans and rodents, as has been demonstrated in inflammation models 15 , spinal cord injury 16 , and neurodevelopmental disorders 17 . The mouse-human evolutionary divergence is further illustrated through the report of a human-specific nicotinic acetylcholine receptor ( CHRFAM7A ) that is thought to play a role in inflammatory response 18 .…”