Leaping toward Understanding
20 of Spinal Cord Regeneration
Paula G Slater, Gabriela Edwards-Faret, and Juan Larraín
CONTENTS
20.1. Introduction .............................................................................................................................................................. 289
20.2. Historical Background and Past Observations ......................................................................................................... 289
20.3. Present Status of the Field ........................................................................................................................................ 290
20.3.1. X. laevis: A Model Organism to Study Spinal Cord Regeneration ........................................................... 290
20.3.2. Cellular Response to Spinal Cord Injury .................................................................................................. 291
20.3.3. The Role of Neural Stem and Progenitor Cells and Neurogenesis ........................................................... 293
20.3.4. Axon Regeneration .................................................................................................................................... 294
20.3.5. Identifcation of Biological Processes Involved in Spinal Cord Regeneration
and Comparison to Other Models ............................................................................................................. 294
20.4. Future Directions and Important Questions ............................................................................................................. 296
Acknowledgments ................................................................................................................................................................ 297
References ............................................................................................................................................................................ 297
20.1. INTRODUCTION
The spinal cord is composed of neurons that receive sensory information and control the motor response (Watson
et al. 2009). Therefore, spinal cord injury (SCI) generates
paralysis caudal to the injury site, and internal organs are
disconnected from central nervous system regulation. Due
to the limited regenerative capacity of humans and mammals in general, and the absence of therapies allowing functional and effcient recovery, this affiction is permanent
(Organization and Society 2013; Thuret et al. 2006).
In mammals, the damage produced by a SCI is composed
of two main phases. The primary injury starts with the initial mechanical insult and generates a hemostatic response,
damage of axons and death of oligodendrocytes, resulting
in tissue structural changes and functional loss. This is followed by a secondary phase, leading to further damage both
rostral and caudal to the injury site (Grossman et al. 2001;
Quadri et al. 2020). This second response is composed of
three different cellular phases: cell death and inf ammation,
cell proliferation and tissue replacement, and tissue remodeling (Burda and Sofroniew 2014). In mammals, this response
protects the spinal cord from further damage (Sabelström et
al. 2013) but blocks proper regeneration.
In contrast to mammals, non-mammals, including urodele amphibians (e.g. salamanders) and teleost f sh (e.g.
zebrafsh), excel in regenerative capacities, and thus, they
have been extensively used to study regeneration (Chernoff
et al. 2003; Zupanc and Sîrbulescu 2011; Diaz Quiroz and
Echeverri 2013; Lee-Liu et al. 2013). Unlike these animal models that retain regenerative capacities throughout
their life spans, Xenopus laevis (X. laevis) tadpoles are
able to regenerate many tissues, including spinal cord, at
Nieuwkoop and Faber (NF) pre-metamorphic developmental stages 46–54 (Nieuwkoop and Faber 1994), but this ability decreases through the pro-metamorphic phase (NF stage
54–58) and metamorphosis climax (NF stage 58–66) and is
almost completely lost after metamorphosis (NF stage 66)
(Hooker 1925; Beattie et al. 1990). This changing capacity
to regenerate allows a comparison between regenerative (R-)
and non-regenerative (NR-) mechanisms in the same species and placed Xenopus in a phylogenetic position between
mammals and urodeles and fsh (Phipps et al. 2020), making
it an ideal model to study spinal cord regeneration.
This chapter provides an historical background and past
observations about spinal cord regeneration in amphibians,
followed by a description of the current status of knowledge in this area. A particular focus is given to f ndings that
describe the cellular response to injury, the genetic networks
involved in spinal cord regeneration, and the role of neural
progenitor stem cells (NSPCs). Finally, a discussion about
the pitfalls on this area and the future directions in spinal
cord regeneration research in Xenopus is presented.
20.2. HISTORICAL BACKGROUND
AND PAST OBSERVATIONS
Understanding organ and tissue regeneration has been a
question driving human curiosity since the beginning of scientifc inquiry. Aristotle, already around 350 BC, in his book
about the history of animals, commented, “if the tails of serpents or lizards be cut off, they will be reproduced” (Duncan
and Sánchez Alvarado 2019). Amphibians, including the
DOI: 10.1201/9781003050230-23
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