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Regulation of axonal regeneration after mammalian spinal cord injury

Nature Reviews Molecular Cell Biology (2023)Cite this article

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Abstract

One hundred years ago, Ramón y Cajal, considered by many as the founder of modern neuroscience, stated that neurons of the adult central nervous system (CNS) are incapable of regenerating. Yet, recent years have seen a tremendous expansion of knowledge in the molecular control of axon regeneration after CNS injury. We now understand that regeneration in the adult CNS is limited by (1) a failure to form cellular or molecular substrates for axon attachment and elongation through the lesion site; (2) environmental factors, including inhibitors of axon growth associated with myelin and the extracellular matrix; (3) astrocyte responses, which can both limit and support axon growth; and (4) intraneuronal mechanisms controlling the establishment of an active cellular growth programme. We discuss these topics together with newly emerging hypotheses, including the surprising finding from transcriptomic analyses of the corticospinal system in mice that neurons revert to an embryonic state after spinal cord injury, which can be sustained to promote regeneration with neural stem cell transplantation. These gains in knowledge are steadily advancing efforts to develop effective treatment strategies for spinal cord injury in humans.

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Fig. 1: Forms of axonal repair and its regulation.
Fig. 2: Neuron-intrinsic control of axonal repair.
Fig. 3: Newly emerging hypotheses for regeneration of the CNS.
Fig. 4: Five strategies to promote functional recovery after spinal cord injury.

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Acknowledgements

Research in the B.Z. laboratory has been funded by NIH/NINDS (NS093055, NS054734), VA (RX002483), CIRM, Wings for Life and Craig H. Neilsen Foundations, aided by UCSD School of Medicine/Neuroscience Microscopy Core (NS047101). Research in the M.H.T. laboratory has been funded by NIH/NINDS (NS104442, NS114043, NS105478, NS042291), VA (RX001706, the Veterans Administration Gordon Mansfield Consortium IP50RX001045 and RR&D B7332R), CIRM, the Bernard and Anne Spitzer Charitable Trust, Wings for Life, the Craig H. Neilsen Foundation, the Gerbic Family Foundation, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. The contents do not represent the views of the US Department of Veterans Affairs or the United States Government.

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  1. Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA, USA

    Binhai Zheng & Mark H. Tuszynski

  2. VA San Diego Research Service, San Diego, CA, USA

    Binhai Zheng & Mark H. Tuszynski

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Glossary

Astrogliosis

Also known as reactive astrogliosis, astrocytosis or astrocyte reactivity, refers to the astrocyte response to injury, disease or other insults and challenges in the central nervous system (CNS). Astrocytes proliferate, undergo hypertrophy and express increased levels of markers of reactivity, including glial fibrillary acidic protein (GFAP) and vimentin. At the injury border, highly reactive astrocytes form the astrocyte border that contains the fibrotic scar and lesion core.

Central nervous system

(CNS). Part of the nervous system that consists primarily of the brain and spinal cord. The optic nerve is unusual among the cranial nerves in that it is part of the CNS and is often used as a model to study CNS axon regeneration.

Corticospinal tract

(CST). Controls voluntary movement in humans. In rodents, the CST is often used as a model to study axon regeneration after spinal cord injury. The neurons that give rise to the CST are called corticospinal neurons, sometimes referred to as corticospinal motor neurons.

Chondroitin sulfate proteoglycans

(CSPGs). A group of molecules that have a protein core and a chondroitin sulfate side chain. Examples include neurocan, aggrecan, brevican, phosphacan and versican. CSPGs are considered inhibitory to axonal repair after central nervous system (CNS) injury.

Dorsal root ganglion

(DRG). Dorsal root ganglia are located outside the spinal cord and contain the cell bodies of sensory neurons that are pseudo-unipolar in morphology, meaning that they extend one axon from the cell body, but this axon soon bifurcates into two major axonal branches with one branch travelling in the peripheral nervous system (PNS) and the other extending into the central nervous system (CNS). This unique anatomical feature makes DRG neurons an appealing model to study the differential regenerative capabilities between the CNS and the PNS.

Growth cones

Hand-like structures at the tip of developing or regenerating axons. The outer region is mainly supported by the actin cytoskeleton and the inner region is mainly supported by the microtubule cytoskeleton. Growth cones are responsible for sensing, interpreting and responding to environmental cues. They are critical for axon growth and regeneration.

Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway

This pathway responds to extracellular signalling molecules, such as cytokines and growth factors, to trigger cellular responses through the regulation of transcription. Ligand-receptor interaction activates JAKs, which then activate STATs, which in turn regulate transcription.

Neural stem cell

(NSC). Can give rise to a variety of cells of neural lineages, including neurons and glia. NSC transplantation has the potential to improve functional recovery by promoting regeneration and neuronal relay. In transplantation studies, NSCs may be referred to as neural progenitor cells due to the uncertain or mixed developmental stage of the transplanted cells.

Oligodendrocyte progenitor cells

These glial cells are marked by their expression of neural/glial antigen 2 (NG2) and can proliferate and differentiate into mature myelinating oligodendrocytes in injury or disease. Oligodendrocyte progenitor cells are also known to contribute to scar formation after spinal cord injury.

Peripheral nerve bridges

A piece of peripheral nerve is taken from the peripheral nervous system (PNS) and transplanted into the central nervous system (CNS), where it serves as a conduit or bridge for axons to regenerate through. This is based on the observation that the PNS provides an environment conducive to axonal regeneration.

Peripheral nervous system

(PNS). Part of the nervous system outside the brain and the spinal cord that comprises the nerves and the ganglia. The PNS has a much higher capacity for axon regeneration than the central nervous system (CNS).

Retinal ganglion cells

(RGCs). Neurons in the mammalian retina that convey information from the retina to the rest of the brain. Their accessibility and long axonal projections make RGCs an excellent model system to study axon regeneration after optic nerve injury.

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Zheng, B., Tuszynski, M.H. Regulation of axonal regeneration after mammalian spinal cord injury. Nat Rev Mol Cell Biol (2023). https://doi.org/10.1038/s41580-022-00562-y

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