Accelerated cell divisions drive the outgrowth of the regenerating spinal cord in axolotls

Rost, Fabian; Albors, Aida Rodrigo; Mazurov, Vladimir; Brusch, Lutz; Deutsch, Andreas; Tanaka, Elly M.; Chara, Osvaldo

doi:10.7554/elife.20357

Cited by 37 publications

(99 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Axolotls are still growing as adults and the PCNA labeling reflected that. There was no evidence of distinct zones of proliferation distinguishing intact stump cord and regenerating ependymal cell outgrowth in the adult, unlike the high PCNA labeling zone described by Rost et al (2016) for larval cord after tail amputation. Axolotl ependymal cells in the regenerative outgrowth were proliferative and Msi-1 positive ( Figures 8F , 11E,F ), but intact adult Axolotl cord ependymal cells were proliferative and Msi-1 negative ( Figures 8D , 11E ).…”

Section: Discussioncontrasting

confidence: 64%

Musashi and Plasticity of Xenopus and Axolotl Spinal Cord Ependymal Cells

Chernoff

Sato

Salfity

et al. 2018

Front. Cell. Neurosci.

View full text Add to dashboard Cite

The differentiated state of spinal cord ependymal cells in regeneration-competent amphibians varies between a constitutively active state in what is essentially a developing organism, the tadpole of the frog Xenopus laevis, and a quiescent, activatable state in a slowly growing adult salamander Ambystoma mexicanum, the Axolotl. Ependymal cells are epithelial in intact spinal cord of all vertebrates. After transection, body region ependymal epithelium in both Xenopus and the Axolotl disorganizes for regenerative outgrowth (gap replacement). Injury-reactive ependymal cells serve as a stem/progenitor cell population in regeneration and reconstruct the central canal. Expression patterns of mRNA and protein for the stem/progenitor cell-maintenance Notch signaling pathway mRNA-binding protein Musashi (msi) change with life stage and regeneration competence. Msi-1 is missing (immunohistochemistry), or at very low levels (polymerase chain reaction, PCR), in both intact regeneration-competent adult Axolotl cord and intact non-regeneration-competent Xenopus tadpole (Nieuwkoop and Faber stage 62+, NF 62+). The critical correlation for successful regeneration is msi-1 expression/upregulation after injury in the ependymal outgrowth and stump-region ependymal cells. msi-1 and msi-2 isoforms were cloned for the Axolotl as well as previously unknown isoforms of Xenopus msi-2. Intact Xenopus spinal cord ependymal cells show a loss of msi-1 expression between regeneration-competent (NF 50–53) and non-regenerating stages (NF 62+) and in post-metamorphosis froglets, while msi-2 displays a lower molecular weight isoform in non-regenerating cord. In the Axolotl, embryos and juveniles maintain Msi-1 expression in the intact cord. In the adult Axolotl, Msi-1 is absent, but upregulates after injury. Msi-2 levels are more variable among Axolotl life stages: rising between late tailbud embryos and juveniles and decreasing in adult cord. Cultures of regeneration-competent Xenopus tadpole cord and injury-responsive adult Axolotl cord ependymal cells showed an identical growth factor response. Epidermal growth factor (EGF) maintains mesenchymal outgrowth in vitro, the cells are proliferative and maintain msi-1 expression. Non-regeneration competent Xenopus ependymal cells, NF 62+, failed to attach or grow well in EGF+ medium. Ependymal Msi-1 expression in vivo and in vitro is a strong indicator of regeneration competence in the amphibian spinal cord.

show abstract

Section: Discussioncontrasting

confidence: 64%

Musashi and Plasticity of Xenopus and Axolotl Spinal Cord Ependymal Cells

Chernoff

Sato

Salfity

et al. 2018

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…This constant mitotic activity implies the replication of a genome 10 times larger than that of humans (3200 Mb), in a short time, each round of division. 6,16 The need to constantly duplicate such a large genome, increases also the mutational rate inherent to the replication process, activated metabolism and the fine-tuned regulation of factors that modulate proliferation. 17 As a sum of all these factors one interrogation emerges, how in A. mexicanum the fidelity in the mitotically inherited genetic information and genomic stability are maintained in blastema cells during regeneration?…”

Section: Cellular Contributions To Blastema Formationmentioning

confidence: 99%

DNA repair during regeneration in Ambystoma mexicanum

García-Lepe

Cruz‐Ramírez

Bermúdez‐Cruz

2020

Developmental Dynamics

View full text Add to dashboard Cite

The remarkable regenerative capabilities of the salamander Ambystoma mexicanum have turned it into one of the principal models to study limb regeneration. During this process, a mass of low differentiated and highly proliferative cells, called blastema, propagates to reestablish the lost tissue in an accelerated way. Such a process implies the replication of a huge genome, 10 times larger than humans, with about 65.6% of repetitive sequences. These features make the axolotl genome inherently difficult to replicate and prone to bear mutations. In this context, the role of DNA repair mechanisms acquires great relevance to maintain genomic stability, especially if we consider the necessity of ensuring the correct replication and integrity of such a large genome in the blastema cells, which are key for tissue regeneration. On the contrary, DNA damage accumulation in these cells may result in senescence, apoptosis and premature differentiation, all of them are mechanisms employed to avoid DNA damage perpetuation but with the potential to affect the limb regeneration process. Here we review and discuss the current knowledge on the implications of DNA damage responses during salamander regeneration.

show abstract

“… Abstract Axolotls are uniquely able to resolve spinal cord injuries, but little is known about the mechanisms underlying spinal cord regeneration. We previously found that tail amputation leads to reactivation of a developmental-like program in spinal cord ependymal cells (Rodrigo Albors et al ., 2015), characterized by a high-proliferation zone emerging 4 days post-amputation (Rost et al ., 2016). What underlies this spatiotemporal pattern of cell proliferation, however, remained unknown.…”

mentioning

confidence: 99%

Spatiotemporal control of cell cycle acceleration during axolotl spinal cord regeneration

Costa¹,

Otsuki

Albors

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

22Axolotls are uniquely able to resolve spinal cord injuries, but little is known about the mechanisms 23 underlying spinal cord regeneration. We found that tail amputation leads to reactivation of a 24 developmental-like program in spinal cord ependymal cells (Rodrigo Albors et al., 2015). We also 25 identified a high-proliferation zone and demonstrated that cell cycle acceleration is the major driver of 26 regenerative growth (Rost et al., 2016). What underlies this spatiotemporal pattern of cell proliferation, 27 however, remained unknown. Here, using a modelling approach supported by experimental data, we 28show that the proliferative response in the regenerating spinal cord is consistent with a signal that starts 29 recruiting cells 24 hours after amputation and spreads about one millimeter from the injury. Finally, our 30 model predicts that the observed shorter S phase can explain spinal cord outgrowth in the first four days 31 of regeneration but after, G1 shortening is also necessary to explain outgrowth dynamics. 32 33 2 Introduction 34

show abstract

Accelerated cell divisions drive the outgrowth of the regenerating spinal cord in axolotls

Cited by 37 publications

References 27 publications

Musashi and Plasticity of Xenopus and Axolotl Spinal Cord Ependymal Cells

Musashi and Plasticity of Xenopus and Axolotl Spinal Cord Ependymal Cells

DNA repair during regeneration in Ambystoma mexicanum

Spatiotemporal control of cell cycle acceleration during axolotl spinal cord regeneration

Contact Info

Product

Resources

About