Spinal Cord Cells from Pre-metamorphic Stages Differentiate into Neurons and Promote Axon Growth and Regeneration after Transplantation into the Injured Spinal Cord of Non-regenerative Xenopus laevis Froglets

Abstract

Mammals are unable to regenerate its spinal cord after a lesion, meanwhile, anuran amphibians are capable of spinal cord regeneration only as larvae, and during metamorphosis, this capability is lost. Sox2/3+ cells present in the spinal cord of regenerative larvae are required for spinal cord regeneration. Here we evaluate the effect of the transplantation of spinal cord cells from regenerative larvae into the resected spinal cord of non-regenerative stages (NR-stage). Donor cells were able to survive up to 60 days after transplantation in the injury zone. During the first 3-weeks, transplanted cells organize in neural tube-like structures formed by Sox2/3+ cells. This was not observed when donor cells come from non-regenerative froglets. Mature neurons expressing NeuN and Neurofilament-H were detected in the grafted tissue 4 weeks after transplantation concomitantly with the appearance of axons derived from the donor cells growing into the host spinal cord, suggesting that Sox2/3+ cells behave as neural stem progenitor cells. We also found that cells from regenerative animals provide a permissive environment that promotes growth and regeneration of axons coming from the host. These results suggest that Sox2/3 cells present in the spinal cord of regenerative stage (R-stage) larvae are most probably neural stem progenitor cells that are able to survive, proliferate, self-organize and differentiate into neurons in the environment of the non-regenerative host. In addition, we have established an experimental paradigm to study the biology of neural stem progenitor cells in spinal cord regeneration.

Spinal Cord Regeneration in Amphibians: A Historical Perspective

“…These ependymoglia were found to express the neural stem cell marker Sox2/3 (Gaete et al , ) and express neurogenesis‐related genes in regeneration‐competent time points (Lee‐Liu et al , ). Grafting of Sox2/3‐expressing ependymoglial cells from regenerative tadpoles into nonregenerative froglets was sufficient to drive axonal outgrowth and formation of new neurons (Mendez‐Olivos et al , ). Studies in axolotls have come to similar conclusions, showing that Sox2 is necessary for ependymoglial cell proliferation during tail regeneration (Fei et al , ; ).…”

The various routes to functional regeneration in the central nervous system

“…In the larval stages they can regenerate the spinal cord; glial cells adjacent to the injury upregulate the neural progenitor marker sox2, similar to axolotls and these cells migrate and divide to repair the injury. However after metamorphosis regenerative ability is lost [24][25][26] . This has been linked to the maturation of the immune system, which is known to play a role in reactive gliosis in humans (22)(23)(24).…”

Non-canonical Hedgehog signaling regulates spinal cord and muscle regeneration

“…Injury in low regenerative capacity tissues such as spinal cord represents a persistent challenge in modern medicine, with millions of cases of spinal cord-related disability worldwide (Lee et al, 2014). There are currently no therapies for repairing severe damage in the mammalian central nervous system, but a variety of paradigms have shown great promise in diverse model systems, including stem cell transplantation (Dasari et al, 2014;Lu et al, 2012;Méndez-Olivos et al, 2017), pharmacological and genetic manipulation of cell apoptosis, reactive oxygen species, ion channel function, growth factor and morphogenetic protein signaling and the immune response (Akazawa, 2004;Beck et al, 2003;Fukazawa et al, 2009;Love et al, 2013;Tapia et al, 2017;Tseng et al, 2007Tseng et al, , 2010, and direct electrical stimulation (Gomes-Osman et al, 2016). Although diverse cellular processes are involved in neural regeneration, one pathway that has consistently proven to be pro-regenerative is Hedgehog (Hh) signaling.…”