Transplanting neural progenitor cells to restore connectivity after spinal cord injury

Abstract

Spinal cord injury remains a scientific and therapeutic challenge with great cost to individuals and society. The goal of research in this field is to find a means of restoring lost function. Recently we have seen considerable progress in understanding the injury process and the capacity of CNS neurons to regenerate, as well as innovations in stem cell biology. This presents an opportunity to develop effective transplantation strategies to provide new neural cells to promote the formation of new neuronal networks and functional connectivity. Past and ongoing clinical studies have demonstrated the safety of cell therapy, and preclinical research has used models of spinal cord injury to better elucidate the underlying mechanisms through which donor cells interact with the host and thus increase long-term efficacy. While a variety of cell therapies have been explored, we focus here on the use of neural progenitor cells obtained or derived from different sources to promote connectivity in sensory, motor and autonomic systems.

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Fig. 1: Spinal cord injury: pathophysiological events and potential therapeutic targets.
Fig. 2: Forming a relay using neural progenitor cells.
Fig. 3: Restoring connectivity in the respiratory system.
Fig. 4: Restoring connectivity in autonomic systems.

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Acknowledgements

The authors thank J. Houle for helpful suggestions and reviewing the manuscript, S. Hou for help with the autonomic function section, A. Lepore for reading the respiratory section, J. Bouyer for help in preparation of figures and E. Wirth III for comments on clinical trials. The authors’ work has been supported by NIH grant 2PO1 NS055976, the Craig H. Neilsen Foundation and a Louis and Bessie Stein Family grant (I.F.); Mission Connect (a project of the TIRR Foundation), the Craig H. Neilsen Foundation and the Paralyzed Veterans of America Research Foundation (J.N.D.); and the Lisa Dean Moseley Foundation, Wings for Life Spinal Cord Research Foundation, and NIH grant R01 NS104291(M.A.L.).

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I.F. researched data for the article. I.F., J.N.D. and M.A.L. substantially contributed to the discussion of the content of the article, wrote the article and reviewed/edited the article before submission.

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Correspondence to Itzhak Fischer.

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Supplementary information

Glossary

Oligodendrocyte progenitor cells

Cells that can differentiate into oligodendrocytes and produce myelin. They are also known as oligodendrocyte precursor cells, often described as NG2 cells (chondroitin sulfate proteoglycan neuron/glia antigen 2) or polydendrocytes and were previously known as oligodendrocyte type 2 astrocyte (O-2A) progenitor cells.

Neural progenitor cells

(NPCs). Neural cells with less proliferative potential than neural stem cells. NPCs give rise to glial and neuronal cell types that are present in the CNS in the developing embryo, neonate and adult rodent. Embryonic NPCs include neuronal-restricted precursors and glial-restricted precursors.

Neuronal relays

At their simplest, three synaptically connected neurons; in the case of transplantation after spinal cord injury, these are the injured neuron, the transplant-derived neuron and the target neuron.

Glial scar

The fibroglial cell layer surrounding the core of a lesion after spinal cord injury, composed of chondroitin sulfate proteoglycans and fibrous connective tissue.

Autologous grafting

Transplantation of cells or tissue derived from the individual’s own body, including autografts (transplants of tissue from one point to another in the same individual’s body, such as a skin or nerve graft) as well as grafts of reprogrammed autologous cells (for example, induced pluripotent stem cells).

Allografting

Transplantation of tissue or cells from a genetically non-identical member of the same species. When cells from a different species are transplanted, they are xenografts.

Fetal spinal cord

(FSC). Tissue or cells originating from animals at the fetal stage or embryonic stage of development. This cell population has been extensively characterized and widely applied to studies of animal spinal cord injury.

Neural stem cells

(NSCs). Multipotent neural cells with high proliferative potential that can generate both neurons and glial cells, such as the neuroepithelial cells present in the developing and adult spinal cord of rodents.

Extracellular matrix

The non-cellular component that provides physical and chemical scaffolding for cells and signalling for tissue differentiation and homeostasis. In the context of spinal cord injury, it refers to the molecular components of the scar, such as chondroitin sulfate proteoglycans.

Neuropathic pain

Pain resulting from injury to the somatosensory nervous system. Neuropathic pain resulting from spinal cord injury typically manifests itself as sharp, shooting or burning sensations experienced in the absence of noxious stimulation or exaggerated pain responses on noxious stimulation.

Maladaptive plasticity

Spontaneous reorganization of spared neural circuits in such a way that it produces undesired neurological outcomes such as pain or spasticity.

Contusion lesion

Spinal cord injury produced by a blunt force impact, typically resulting in incomplete neurological deficits with partial function remaining below the level of injury. This lesion model has been widely used in experimental studies due to its anatomical similarities to most human spinal cord injury.

Principal component analysis

An approach that uses an orthogonal transformation to convert observations that may be correlated into a set of uncorrelated variables referred to as principal components.

Compression injury

A condition that puts pressure on the spinal cord, which can be achieved in animal models of spinal cord injury using calibrated clips or by placing a specific weight in the epidural space. (A mixed contusion–compression spinal cord injury model can also be generated by delivering an initial blunt impact followed by sustained pressure.)

Chondroitinase ABC

A bacterial enzyme that degrades polysaccharide chains on chondroitin sulfate proteoglycans. This enzyme has been used as a potential therapeutic treatment for spinal cord injury due to its degradation of axon growth-inhibiting chondroitin sulfate proteoglycans that are present in the extracellular matrix of the injured spinal cord.

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Fischer, I., Dulin, J.N. & Lane, M.A. Transplanting neural progenitor cells to restore connectivity after spinal cord injury. Nat Rev Neurosci 21, 366–383 (2020). https://doi.org/10.1038/s41583-020-0314-2

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