Pluripotent Stem Cells for Spinal Cord Injury Repair

Abstract

Spinal cord injury (SCI) is a devastating condition of the central nervous system that strongly reduces the patient's quality of life and has large financial costs for the healthcare system. Cell therapy has shown considerable therapeutic potential for SCI treatment in different animal models. Although many different cell types have been investigated with the goal of promoting repair and recovery from injury, stem cells appear to be the most promising. Here, we review the experimental approaches that have been carried out with pluripotent stem cells, a cell type that, due to its inherent plasticity, self-renewal, and differentiation potential, represents an attractive source for the development of new cell therapies for SCI. We will focus on several key observations that illustrate the potential of cell therapy for SCI, and we will attempt to draw some conclusions from the studies performed to date.

Keywords: ESC; NSC; PSC; animal models; cell therapy; iPSC; tetraplegia.

Figure 1

Treatments of SCI with pluripotent and reprogrammed cells. Patient- or donor-derived somatic cells can be reprogrammed into iPSC, which can then be differentiated into neural cells for transplantation to restore function in patients with SCI. PSC derived from embryos or oocytes are an alternative source of neural cells for therapy. Direct reprogramming of somatic cells to neural cells (without passing through a pluripotent state) has also been achieved and could be used for SCI treatment. Several mechanisms for neural cell-mediated repair have been suggested, such as cell replacement, the release of immunomodulatory and trophic factors, regeneration and remyelination of axons, and/or reduction of glial scarring. Created with BioRender.com (last accessed on 15 November 2021).

Figure 2

General scheme of differentiation protocols used to produce NSC from PSC. (A) Example of an EB-based protocol. Undifferentiated PSC are grown in suspension in embryonic stem (ES) medium with ROCK inhibitor to form embryoid bodies (EB) that are further cultured in neural differentiation medium (NDM) containing N2 supplement, seeded on coated plates, and directed to form neural rosettes containing neuroepithelial cells. (B) Example of a dual SMAD inhibition-based protocol. Undifferentiated PSC are plated on Matrigel as single cells in an MEF (mouse embryonic fibroblasts)-conditioned medium (CM) and different inhibitors are added to the cells in the presence of knockout serum (KSR) medium. KSR medium is then gradually replaced by medium with N2 supplement. ROCK: Rho kinase; PLO-lam: poly-L-ornithine-laminin; RA: retinoic acid; FGF: fibroblast growth factor; EGF: epidermal growth factor; TGF-β: transforming growth factor beta.