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Review
. 2017 Feb;114(2):245-259.
doi: 10.1002/bit.26074. Epub 2016 Sep 21.

Stem cells for spinal cord injury: Strategies to inform differentiation and transplantation

Nisha R Iyer  1 , Thomas S Wilems  1 , Shelly E Sakiyama-Elbert  1
Affiliations
Review

Stem cells for spinal cord injury: Strategies to inform differentiation and transplantation

Nisha R Iyer et al. Biotechnol Bioeng. 2017 Feb.

Abstract

The complex pathology of spinal cord injury (SCI), involving a cascade of secondary events and the formation of inhibitory barriers, hampers regeneration across the lesion site and often results in irreversible loss of motor function. The limited regenerative capacity of endogenous cells after SCI has led to a focus on the development of cell therapies that can confer both neuroprotective and neuroregenerative benefits. Stem cells have emerged as a candidate cell source because of their ability to self-renew and differentiate into a multitude of specialized cell types. While ethical and safety concerns impeded the use of stem cells in the past, advances in isolation and differentiation methods have largely mitigated these issues. A confluence of work in stem cell biology, genetics, and developmental neurobiology has informed the directed differentiation of specific spinal cell types. After transplantation, these stem cell-derived populations can replace lost cells, provide trophic support, remyelinate surviving axons, and form relay circuits that contribute to functional recovery. Further refinement of stem cell differentiation and transplantation methods, including combinatorial strategies that involve biomaterial scaffolds and drug delivery, is critical as stem cell-based treatments enter clinical trials. Biotechnol. Bioeng. 2017;114: 245-259. © 2016 Wiley Periodicals, Inc.

Keywords: biomaterial scaffolds; combination therapy; embryonic stem cells; induced pluripotent stem cells; neuronal differentiation; transcriptional reprogramming.

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Figures

Figure 1
Figure 1
There are several sources of multipotent (left) and pluripotent (right) stem cells currently used for spinal cord injury. Neural stem cells (NSCs) can be derived from fetal or adult tissue, and are capable of differentiating into neurons, oligodendrocytes, and astrocytes. While not typically considered stem cells, glial-restricted precursors (GRPs) are a commonly studied, tri-potent population that can be isolated from neural stem cells or fetal tissue directly. GRPs differentiate into oligodendrocyte progenitor cells and two types of astrocytes. Mesenchymal stromal cells (MSCs) are an appealing population clinically because they can be isolated from adult bone marrow or peripheral blood; however, while they are capable of differentiating into a wide variety of cells types, the efficacy of neuronal differentiation is a specific concern for SCI treatment. Embryonic stem cells (ESCs) are a pluripotent population, which can give rise to cell types from all three germ layers; however, because they are derived from the inner cell mass of early blastocysts, ethical considerations limit their clinical potential. Induced pluripotent stem cells (iPSCs) can be generated from adult somatic cells (fibroblasts, melanocytes, cord or peripheral blood cells, adipose stem cells, etc.) by several different reprogramming methods using the Yamanaka factors (c-Myc, Sox2, Oct4, Klf2). While induction and reprogramming efficiencies remain a concern, iPSCs represent an autologous, patient-specific population that has significant clinical potential as the field progresses.
Figure 2
Figure 2
Directing differentiation of pluripotent stem cells is traditionally achieved by triggering the signaling cascades responsible for cell fate determination. Neural induction from pluripotent cells typically begins with conversion into a neural stem cell (NSC), which may involve stimulating EGF and FGF2 signaling and inhibiting BMP and TGF-β/Activin/Nodal signaling. Subsequent exposure with RA caudalizes the NSCs and ensures a spinal identity. A complex interplay of signaling events is responsible for the dorsoventral patterning of the spinal cord, made more opaque by the importance of exposure duration and cell-cell signaling events. In the developing spinal cord, Shh from the notochord and floor plate interact with RA to induce differentiation of ventral progenitor cells (p0–p3, pMN), which mature into motor neurons, oligodendrocytes, astrocytes, and a variety of ventral interneuron populations. A combination of BMP, Wnt, FGF, and TGF-β signaling induces differentiation of the dorsal progenitor populations (dI1–dI6), but the precise mechanisms are poorly understood. Some specific factors that influence progenitor subspecialization have been determined experimentally in vitro, especially with regards to glial-restricted progenitor cells (GRPs), but for most interneuron populations, these are unknown.
Figure 3
Figure 3
(A) Transplantation of stem cell-derived spinal populations into the SCI lesion has multiple benefits. NSCs can differentiate into mature neuronal and glial populations to replace lost or damaged cells. These populations can serve as relay circuits between intact tissue across the lesion, and thus promote functional improvements as determined by electrophysiological and behavioral means. Stem cell-derived oligodendrocytes and astrocytes can remyelinate damaged axons and provide scaffolding for regenerating axons, as well provide trophic support through the secretion of growth factors. (B) Compared to direct injection of cells into the lesion or the intrathecal space or the delivery of micro-encapsulated cells, biomaterial scaffolds represent a better opportunity for a combinatorial therapy. Modifications including micropatterning, drug delivery, and gene delivery can be achieved to support and guide regeneration at the site of injury.
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