297
Understanding Spinal Cord Regeneration
neurons, while mammals do not. Interestingly, the mammalian cells lining the central canal are able to generate new
neurons in vitro (Barnabé-Heider et al. 2010; Meletis et al.
2008) and when transplanted to a neurogenic-permissive
environment (Shihabuddin et al. 2000). These observations
raise the question about the signals that trigger and the signaling cascades that should be activated to induce, and in the
future direct, differentiation towards neurons. In addition, it
will be important to determine if it is possible to improve
regeneration in NR-stage by activating NSPC proliferation
and forcing their differentiation to neurons.
Additionally, as mentioned previously, the cell bodies of the damaged axons that are located in the hindbrain
present a differential transcriptional response in R- versus
NR-stages. It is very important to determine the role of these
transcripts to understand the molecular and cellular mechanisms underlying the intrinsic regenerative capacity of these
neurons and to determine if modif cations in the expression
levels of these genes is necessary and suffcient for induction
of axon regeneration at NR-stages.
Finally, if we consider all the aforementioned evidence
about metabolic regulation of the cellular phases involved
in SCI response, some open questions remain: Which
metabolic regulation, in which cell type, and at what time
after SCI are needed for regeneration? And, is it possible
to improve regeneration in NR-stage animals by mimicking
R-stage metabolic responses?
As X. laevis presents R- and NR-stages during its
development, it is an outstanding model animal to answer
all these questions and to evaluate new potential therapies that would help deepen the understanding of the
mechanisms involved in a successful regenerative process and how to improve regeneration in non-regenerative
organisms.
ACKNOWLEDGMENTS
This work was supported by FONDECYT 1180429 for JL
and 3190820 for PGS, and a post-doctoral fellow of the Fonds
Wetenschappelijk Onderzoek (FWO) Grant 1214420N for
GE-F. We thank Mimí Palacios for the Figure 20.1 drawings. The authors declare no confict of interest.
REFERENCES
Afridi, Ruqayya, Jong-Heon Kim, Md Habibur Rahman, and
Kyoungho Suk. 2020. Metabolic regulation of glial phenotypes: Implications in neuron-glia interactions and neurological disorders. Frontiers in Cellular Neuroscience 14:20.
Amaya, Enrique, and Kristen L. Kroll. 1999. A method for generating transgenic frog embryos. In Molecular Embryology.
Totowa, NJ: Humana Press. pp. 393–414.
Barnabé-Heider, Fanie, Christian Göritz, Hanna Sabelström, et al.
2010. Origin of new glial cells in intact and injured adult
spinal cord. Cell Stem Cell 7 (4):470–482.
Beattie, Michael S., Jacqueline C. Bresnahan, and Glenn Lopate.
1990. Metamorphosis alters the response to spinal cord transection in Xenopus laevis frogs. Journal of Neurobiology 21
(7):1108–1122.
Beck, Caroline W., Bea Christen, and Jonathan M.W. Slack.
2003. Molecular pathways needed for regeneration of spinal cord and muscle in a vertebrate. Developmental Cell 5
(3):429–439.
Benraiss, A., J.P. Arsanto, J. Coulon, and Y. Thouveny. 1999.
Neurogenesis during caudal spinal cord regeneration in adult
newts. Development Genes and Evolution 209 (6):363–369.
Bestman, Jennifer E., Rebecca C. Ewald, Shu-Ling Chiu, and Hollis
T. Cline. 2006. In vivo single-cell electroporation for transfer
of DNA and macromolecules. Nature Protocols 1 (3):1267.
Blum, Martin, Edward M. De Robertis, John B. Wallingford, and
Christof Niehrs. 2015. Morpholinos: Antisense and sensibility. Developmental Cell 35 (2):145–149.
Bradke, Frank, James W. Fawcett, and Micha E. Spira. 2012.
Assembly of a new growth cone after axotomy: The precursor to axon regeneration. Nature Reviews Neuroscience 13
(3):183–193.
Brown, Donald D., and Liquan Cai. 2007. Amphibian metamorphosis. Developmental Biology 306 (1):20.
Burda, Joshua E., and Michael V. Sofroniew. 2014. Reactive gliosis
and the multicellular response to CNS damage and disease.
Neuron 81 (2):229–248.
Butler, Elmer G., and Margery B. Ward. 1965. Reconstitution of
the spinal cord following ablation in urodele larvae. Journal
of Experimental Zoology 160 (1):47–65.
Chera, Simona, Luiza Ghila, Kevin Dobretz, et al. 2009. Apoptotic
cells provide an unexpected source of Wnt3 signaling to
drive hydra head regeneration. Developmental Cell 17
(2):279–289.
Chernoff, Ellen A.G., David L. Stocum, Holly L.D. Nye, and Jo
Ann Cameron. 2003. Urodele spinal cord regeneration and
related processes. Developmental Dynamics: An Offcial
Publication of the American Association of Anatomists 226
(2):295–307.
Clarke, J.D.W., Ruth Alexander, and Nigel Holder. 1988.
Regeneration of descending axons in the spinal cord of the
axolotl. Neuroscience Letters 89 (1):1–6.
Davis, Brian M., Mark T. Duffy, and Sidney B. Simpson Jr. 1989.
Bulbospinal and intraspinal connections in normal and
regenerated salamander spinal cord. Experimental Neurology
103 (1):41–51.
De Vidts, Sebastián, Emilio Méndez-Olivos, Miriam Palacios, Juan
Larraín, and Domingo Mery. 2019. Characterization of spinal cord damage based on automatic video analysis of froglet
swimming. Biology Open 8 (12).
Diaz Quiroz, Juan Felipe, and Karen Echeverri. 2013. Spinal
cord regeneration: Where fsh, frogs and salamanders
lead the way, can we follow? Biochemical Journal 451
(3):353–364.
Duncan, Elizabeth M., and Alejandro Sánchez Alvarado. 2019.
Regulation of genomic output and (Pluri) potency in regeneration. Annual Review of Genetics 53:327–346.
Edwards-Faret, Gabriela, Arantxa Cebrián-Silla, Emilio E.
Méndez-Olivos, Karina González-Pinto, José Manuel
García-Verdugo, and Juan Larraín. 2018. Cellular composition and organization of the spinal cord central canal during metamorphosis of the frog Xenopus laevis. Journal of
Comparative Neurology 526 (10):1712–1732.
Edwards-Faret, Gabriela, Karina González-Pinto, Arantxa CebriánSilla, Johany Peñailillo, José Manuel García-Verdugo, and
Juan Larraín. 2021. Cellular response to spinal cord injury in
regenerative and non-regenerative stages in Xenopus laevis.
Neural Development 16 (1):2.
Edwards-Faret, Gabriela, Rosana Muñoz, Emilio E. MéndezOlivos, Dasfne Lee-Liu, Victor S. Tapia, and Juan Larraín.
Understanding Spinal Cord Regeneration
neurons, while mammals do not. Interestingly, the mammalian cells lining the central canal are able to generate new
neurons in vitro (Barnabé-Heider et al. 2010; Meletis et al.
2008) and when transplanted to a neurogenic-permissive
environment (Shihabuddin et al. 2000). These observations
raise the question about the signals that trigger and the signaling cascades that should be activated to induce, and in the
future direct, differentiation towards neurons. In addition, it
will be important to determine if it is possible to improve
regeneration in NR-stage by activating NSPC proliferation
and forcing their differentiation to neurons.
Additionally, as mentioned previously, the cell bodies of the damaged axons that are located in the hindbrain
present a differential transcriptional response in R- versus
NR-stages. It is very important to determine the role of these
transcripts to understand the molecular and cellular mechanisms underlying the intrinsic regenerative capacity of these
neurons and to determine if modif cations in the expression
levels of these genes is necessary and suffcient for induction
of axon regeneration at NR-stages.
Finally, if we consider all the aforementioned evidence
about metabolic regulation of the cellular phases involved
in SCI response, some open questions remain: Which
metabolic regulation, in which cell type, and at what time
after SCI are needed for regeneration? And, is it possible
to improve regeneration in NR-stage animals by mimicking
R-stage metabolic responses?
As X. laevis presents R- and NR-stages during its
development, it is an outstanding model animal to answer
all these questions and to evaluate new potential therapies that would help deepen the understanding of the
mechanisms involved in a successful regenerative process and how to improve regeneration in non-regenerative
organisms.
ACKNOWLEDGMENTS
This work was supported by FONDECYT 1180429 for JL
and 3190820 for PGS, and a post-doctoral fellow of the Fonds
Wetenschappelijk Onderzoek (FWO) Grant 1214420N for
GE-F. We thank Mimí Palacios for the Figure 20.1 drawings. The authors declare no confict of interest.
REFERENCES
Afridi, Ruqayya, Jong-Heon Kim, Md Habibur Rahman, and
Kyoungho Suk. 2020. Metabolic regulation of glial phenotypes: Implications in neuron-glia interactions and neurological disorders. Frontiers in Cellular Neuroscience 14:20.
Amaya, Enrique, and Kristen L. Kroll. 1999. A method for generating transgenic frog embryos. In Molecular Embryology.
Totowa, NJ: Humana Press. pp. 393–414.
Barnabé-Heider, Fanie, Christian Göritz, Hanna Sabelström, et al.
2010. Origin of new glial cells in intact and injured adult
spinal cord. Cell Stem Cell 7 (4):470–482.
Beattie, Michael S., Jacqueline C. Bresnahan, and Glenn Lopate.
1990. Metamorphosis alters the response to spinal cord transection in Xenopus laevis frogs. Journal of Neurobiology 21
(7):1108–1122.
Beck, Caroline W., Bea Christen, and Jonathan M.W. Slack.
2003. Molecular pathways needed for regeneration of spinal cord and muscle in a vertebrate. Developmental Cell 5
(3):429–439.
Benraiss, A., J.P. Arsanto, J. Coulon, and Y. Thouveny. 1999.
Neurogenesis during caudal spinal cord regeneration in adult
newts. Development Genes and Evolution 209 (6):363–369.
Bestman, Jennifer E., Rebecca C. Ewald, Shu-Ling Chiu, and Hollis
T. Cline. 2006. In vivo single-cell electroporation for transfer
of DNA and macromolecules. Nature Protocols 1 (3):1267.
Blum, Martin, Edward M. De Robertis, John B. Wallingford, and
Christof Niehrs. 2015. Morpholinos: Antisense and sensibility. Developmental Cell 35 (2):145–149.
Bradke, Frank, James W. Fawcett, and Micha E. Spira. 2012.
Assembly of a new growth cone after axotomy: The precursor to axon regeneration. Nature Reviews Neuroscience 13
(3):183–193.
Brown, Donald D., and Liquan Cai. 2007. Amphibian metamorphosis. Developmental Biology 306 (1):20.
Burda, Joshua E., and Michael V. Sofroniew. 2014. Reactive gliosis
and the multicellular response to CNS damage and disease.
Neuron 81 (2):229–248.
Butler, Elmer G., and Margery B. Ward. 1965. Reconstitution of
the spinal cord following ablation in urodele larvae. Journal
of Experimental Zoology 160 (1):47–65.
Chera, Simona, Luiza Ghila, Kevin Dobretz, et al. 2009. Apoptotic
cells provide an unexpected source of Wnt3 signaling to
drive hydra head regeneration. Developmental Cell 17
(2):279–289.
Chernoff, Ellen A.G., David L. Stocum, Holly L.D. Nye, and Jo
Ann Cameron. 2003. Urodele spinal cord regeneration and
related processes. Developmental Dynamics: An Offcial
Publication of the American Association of Anatomists 226
(2):295–307.
Clarke, J.D.W., Ruth Alexander, and Nigel Holder. 1988.
Regeneration of descending axons in the spinal cord of the
axolotl. Neuroscience Letters 89 (1):1–6.
Davis, Brian M., Mark T. Duffy, and Sidney B. Simpson Jr. 1989.
Bulbospinal and intraspinal connections in normal and
regenerated salamander spinal cord. Experimental Neurology
103 (1):41–51.
De Vidts, Sebastián, Emilio Méndez-Olivos, Miriam Palacios, Juan
Larraín, and Domingo Mery. 2019. Characterization of spinal cord damage based on automatic video analysis of froglet
swimming. Biology Open 8 (12).
Diaz Quiroz, Juan Felipe, and Karen Echeverri. 2013. Spinal
cord regeneration: Where fsh, frogs and salamanders
lead the way, can we follow? Biochemical Journal 451
(3):353–364.
Duncan, Elizabeth M., and Alejandro Sánchez Alvarado. 2019.
Regulation of genomic output and (Pluri) potency in regeneration. Annual Review of Genetics 53:327–346.
Edwards-Faret, Gabriela, Arantxa Cebrián-Silla, Emilio E.
Méndez-Olivos, Karina González-Pinto, José Manuel
García-Verdugo, and Juan Larraín. 2018. Cellular composition and organization of the spinal cord central canal during metamorphosis of the frog Xenopus laevis. Journal of
Comparative Neurology 526 (10):1712–1732.
Edwards-Faret, Gabriela, Karina González-Pinto, Arantxa CebriánSilla, Johany Peñailillo, José Manuel García-Verdugo, and
Juan Larraín. 2021. Cellular response to spinal cord injury in
regenerative and non-regenerative stages in Xenopus laevis.
Neural Development 16 (1):2.
Edwards-Faret, Gabriela, Rosana Muñoz, Emilio E. MéndezOlivos, Dasfne Lee-Liu, Victor S. Tapia, and Juan Larraín.