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Targeted intraspinal injections to assess therapies in rodent models of neurological disorders

Nature Protocols volume 14, pages 331–349 (2019)Cite this article

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Abstract

Despite decades of research, pharmacological therapies for spinal cord motor pathologies are limited. Alternatives using macromolecular, viral, or cell-based therapies show early promise. However, introducing these substances into the spinal cord, past the blood–brain barrier, without causing injury is challenging. We describe a technique for intraspinal injection targeting the lumbar ventral horn in rodents. This technique preserves motor performance and has a proven track record of translation into phase 1 and 2 clinical trials in amyotrophic lateral sclerosis (ALS) patients. The procedure, in brief, involves exposure of the thoracolumbar spine and dissection of paraspinous muscles over the target vertebrae. Following laminectomy, the spine is affixed to a stereotactic frame, permitting precise and reproducible injection throughout the lumbar spine. We have used this protocol to inject various stem cell types, primarily human spinal stem cells (HSSCs); however, the injection is adaptable to any candidate therapeutic cell, virus, or macromolecule product. In addition to a detailed procedure, we provide stereotactic coordinates that assist in targeting of the lumbar spine and instructional videos. The protocol takes ~2 h per animal.

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Fig. 1: Schematics depicting laminectomy for exposure of rodent lumbar spinal cord and cross-sectional views depicting coordinates for optimal targeting of the ventral horn.
Fig. 2: Intraspinal injection of stem cells into SOD1G93A mouse lumbar spine.
Fig. 3: Intraspinal injection of stem cells into SOD1G93A rat lumbar spine.
Fig. 4: Intraspinal injection of stem cells does not impair motor performance in SOD1G93A mice or rats.
Fig. 5: Successful targeting of stem cell injections to the ventral horn of the lumbar spinal cord of the mutant SOD1G93A mouse.

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The data presented with the protocol are available from the corresponding author on reasonable request.

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Acknowledgements

We thank C. Backus, C. Pacut, and M. Sweeney for technical support. This work was supported by the Sinai Medical Foundation, the A. Alfred Taubman Medical Research Institute, the Program for Neurology Research & Discovery, University of Michigan Clinician Scientist Training Program grants NINDS R25NS089450 (K.S.C.) and NIH T32NS07222 (O.N.K.), and the Robert E. Nederlander Sr. Program for Alzheimer’s Research (L.M.M.).

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Author notes

  1. These authors contributed equally: Kevin S. Chen, Lisa M. McGinley.

Authors and Affiliations

  1. Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA

    Kevin S. Chen & Osama N. Kashlan

  2. Department of Neurology, University of Michigan, Ann Arbor, MI, USA

    Lisa M. McGinley, John M. Hayes, Elizabeth S. Bruno, Josh S. Chang, Faye E. Mendelson, Maegan A. Tabbey, Stacey A. Sakowski & Eva L. Feldman

  3. Neuralstem, Germantown, MD, USA

    Karl Johe

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Contributions

E.L.F., K.S.C., L.M.M., O.N.K, and K.J. conceived of and designed the experiments. K.S.C. and O.N.K. performed the surgery with J.M.H., E.S.B., and J.S.C. F.E.M. J.S.C., and M.A.T. performed behavioral testing. L.M.M., E.S.B., and J.M.H. performed tissue processing, histological analyses, and microscopy. K.S.C. and L.M.M. analyzed and interpreted the data, and E.L.F. supervised the study. K.S.C., L.M.M., and S.A.S wrote the manuscript, and all authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Eva L. Feldman.

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Competing interests

K.J. is chief scientific officer for Neuralstem, which provided the stem cell product (NSI566-RSC) via a material transfer agreement. The other authors declare no competing interests.

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Related links

Key references using this protocol

Hefferan, M. P. et al. PLoS ONE 7, e42614 (2012): https://doi.org/10.1371/journal.pone.0042614

Yan, J. et al. Stem Cells 24, 1976–1985 (2006): https://doi.org/10.1634/stemcells.2005-0518

Lunn, J. S. et al. Neurobiol. Dis. 46, 59–68 (2012): https://doi.org/10.1016/j.nbd.2011.12.044

Integrated supplementary information

Supplementary Figure 1 Effect of intraspinal injection on animal survival and average number of surviving motor neurons.

Kaplan-Meier survival and quantification of postmortem motor neuron (MN) survival in wild type mice (a,b) and rats (c,d) undergoing vehicle intraspinal injection (WT Veh) versus animals undergoing no surgical procedure (WT). Motor neuron survival was assessed as described in the Supplementary Methods. Non-significant hazard ratio of mortality for animals undergoing intraspinal injection; minimal mortality (10% mortality for both mice (a) and rats (c) in the WT Veh animals could also be attributable to immunosuppressive regimen, as these animals served as controls in other stem cell experiments requiring immunosuppression. Likewise, quantified average number of surviving MN (mean ± SD) are not impacted by the injection protocol at approximately 180 days post-surgery, in mice (b; p=0.2762; WT vs. WT Veh; t-test) or in rats (d; p=0.1445; WT vs. WT Veh; t-test). MN = motor neuron; WT = wild-type; WT Veh = WT plus vehicle injection.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 and Supplementary Methods

Reporting Summary

Supplementary Video 1

Technique for intraspinal injection of stem cells in SOD1G93A mouse lumbar spine. An incision is made over the lumbar area, and paraspinous muscles are sharply dissected free from spinous processes and spinal laminae. Cutting the ligamentous attachment to the facet joint facilitates exposure. By palpating the final rib, a laminectomy is performed at the T13 and L1 level using microscissors. The central spinal vein is used as the reference for midline. The needle tip is introduced 0.3 mm lateral to the 29 central vein and 0.8 mm deep to the dorsal surface of the spinal cord to reach the ventral gray matter. Five bilateral injections (10 total injections) are made with a 1.0-mm distance between each set of injections. All animal experiments were approved by the University of Michigan Institutional Animal Care and Use Committee and were performed in accordance with University of Michigan guidelines (accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International) and state and federal regulations.

Supplementary Video 2

Technique for intraspinal injection of stem cells in SOD1G93A rat lumbar spine. An incision is made over the lumbar area, and paraspinous muscles are sharply dissected free from spinous processes and spinal laminae. Cutting the ligamentous attachment to the facet joint facilitates exposure. By palpating the final rib, a laminectomy is performed at the T13 level using a diamond-tip drill. The central spinal vein is used as the reference for midline. The needle tip is introduced 0.5 mm lateral to the central vein and 1.5 mm deep to the dorsal surface of the spinal cord to reach the ventral gray matter. Ten bilateral injections (20 total injections) are made with 0.5-mm distance between each set of injections. Fasciae of the subcutaneous muscle and skin are closed with absorbable sutures. All animal experiments were approved by the University of Michigan Institutional Animal Care and Use Committee and were performed in accordance with University of Michigan guidelines (accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International) and state and federal regulations.

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Chen, K.S., McGinley, L.M., Kashlan, O.N. et al. Targeted intraspinal injections to assess therapies in rodent models of neurological disorders. Nat Protoc 14, 331–349 (2019). https://doi.org/10.1038/s41596-018-0095-5

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