Modeling the spatiotemporal control of cell cycle acceleration during axolotl spinal cord regeneration

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

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Spatiotemporal control of cell cycle acceleration during axolotl spinal cord regeneration

eLife ◽

10.7554/elife.55665 ◽

2021 ◽

Vol 10 ◽

Author(s):

Emanuel Cura Costa ◽

Leo Otsuki ◽

Aida Rodrigo Albors ◽

Elly M Tanaka ◽

Osvaldo Chara

Keyword(s):

Cell Cycle ◽

Spinal Cord ◽

Spinal Cord Injuries ◽

Ependymal Cells ◽

Spatiotemporal Pattern ◽

Spinal Cord Regeneration ◽

Proliferation Zone ◽

Appearance Time ◽

Bona Fide

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. Here, we use modelling, tightly linked to experimental data, to demonstrate that this regenerative response is consistent with a signal that recruits ependymal cells during ~85 hours after amputation within ~830mm of the injury. We adapted FUCCI technology to axolotls (AxFUCCI) to visualize cell cycles in vivo. AxFUCCI axolotls confirmed the predicted appearance time and size of the injury-induced recruitment zone and revealed cell cycle synchrony between ependymal cells. Our modeling and imaging move us closer to understanding bona fide spinal cord regeneration.

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Foxm1 regulates neuronal progenitor fate during spinal cord regeneration

10.1101/2020.02.26.962977 ◽

2020 ◽

Author(s):

Diane Pelzer ◽

Lauren S. Phipps ◽

Raphael Thuret ◽

Syed Murtuza Baker ◽

Karel Dorey

Keyword(s):

Cell Cycle ◽

Spinal Cord ◽

Spinal Cord Injuries ◽

Relative Length ◽

Sensory Function ◽

Spinal Cord Regeneration ◽

Planar Polarity ◽

Self Renewal ◽

Neuronal Progenitor ◽

The Central Nervous System

SummaryMammals have limited tissue regeneration capabilities, particularly in the case of the central nervous system. Spinal cord injuries are often irreversible and lead to the loss of motor and sensory function below the site of the damage [1]. In contrast, amphibians such as Xenopus tadpoles can regenerate a fully functional tail, including their spinal cord, following amputation [2,3]. A hallmark of spinal cord regeneration is the re-activation of Sox2/3+ progenitor cells to promote regrowth of the spinal cord and the generation of new neurons [4,5]. In axolotls, this increase in proliferation is tightly regulated as progenitors switch from a neurogenic to a proliferative division via the planar polarity pathway (PCP) [6–8]. How the balance between self-renewal and differentiation is controlled during regeneration is not well understood. Here, we took an unbiased approach to identify regulators of the cell cycle expressed specifically in X.tropicalis spinal cord after tail amputation by RNAseq. This led to the identification of Foxm1 as a potential key transcription factor for spinal cord regeneration. Foxm1-/- X.tropicalis tadpoles develop normally but cannot regenerate their spinal cords. Using single cell RNAseq and immunolabelling, we show that foxm1+ cells in the regenerating spinal cord undergo a transient but dramatic change in the relative length of the different phases of the cell cycle, suggesting a change in their ability to differentiate. Indeed, we show that Foxm1 does not regulate the rate of progenitor proliferation but is required for neuronal differentiation leading to successful spinal cord regeneration.

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Localized activation of ependymal progenitors induces EMT-mediated glial bridging after spinal cord injury

10.1101/2020.02.18.955401 ◽

2020 ◽

Author(s):

Lili Zhou ◽

Brooke Burris ◽

Ryan Mcadow ◽

Mayssa H. Mokalled

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Epithelial To Mesenchymal Transition ◽

Ependymal Cells ◽

Spinal Cord Tissue ◽

Spinal Cord Regeneration ◽

Enhancer Element ◽

Mesenchymal Transition ◽

Cord Injury ◽

Spinal Cord Repair

ABSTRACTUnlike mammals, adult zebrafish undergo spontaneous recovery after major spinal cord injury. Whereas scarring presents a roadblock for mammalian spinal cord repair, glial cells in zebrafish form a bridge across severed spinal cord tissue to facilitate regeneration. Here, we performed FACS sorting and genome-wide profiling to determine the transcriptional identity of purified bridging glia. We found that Yap-Ctgf signaling activates epithelial to mesenchymal transition (EMT) in localized niches of ependymal cells to promote glial bridging and regeneration. Preferentially activated in early bridging glia, Yap is required for the expression of the glial bridging factor Ctgfa and for functional spinal cord repair. Ctgfa regulation is controlled by an injury responsive enhancer element that drives expression in early bridging glia after injury. Yap-Ctgf signaling activates a mesenchymal transcriptional program that drives glial bridging. This study revealed the molecular signatures of bridging glia and identified an injury responsive gene regulatory network that promotes spinal cord regeneration in zebrafish.

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Regenerative Potential of Ependymal Cells for Spinal Cord Injuries Over Time

EBioMedicine ◽

10.1016/j.ebiom.2016.10.035 ◽

2016 ◽

Vol 13 ◽

pp. 55-65 ◽

Cited By ~ 25

Author(s):

Xiaofei Li ◽

Elisa M. Floriddia ◽

Konstantinos Toskas ◽

Karl J.L. Fernandes ◽

Nicolas Guérout ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injuries ◽

Ependymal Cells ◽

Over Time

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

10.1101/067785 ◽

2016 ◽

Author(s):

Fabian Rost ◽

Aida Rodrigo Albors ◽

Vladimir Mazurov ◽

Lutz Brusch ◽

Andreas Deutsch ◽

...

Keyword(s):

Spinal Cord ◽

Tissue Level ◽

Molecular State ◽

Proliferation Zone ◽

Cell Divisions ◽

Neuroepithelial Cells ◽

Ability To Regenerate ◽

Quantitative Understanding ◽

Necessary And Sufficient ◽

Modelling Approach

AbstractAxolotls are unique in their ability to regenerate the spinal cord. However, the mechanisms that underlie this phenomenon remain poorly understood. Previously, we showed that resting stem cells in the axolotl spinal cord revert to a molecular state resembling embryonic neuroepithelial cells and functionally acquire rapid proliferative divisions during regeneration. Here we refine in space and time this increase in cell proliferation during regeneration, and identify a dynamic high-proliferation zone in the regenerating spinal cord. By tracking sparsely-labeled cells, we quantify cell influx into the regenerate. Taking a mathematical modelling approach, we integrate these quantitative biological datasets across cellular and tissue level to provide a mechanistic and quantitative understanding of regenerative spinal cord outgrowth. We find that the acceleration of the cell cycle is necessary and sufficient to drive the outgrowth of the regenerating spinal cord in axolotls.

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Meningeal Foam Cells and Ependymal Cells in Axolotl Spinal Cord Regeneration

Frontiers in Immunology ◽

10.3389/fimmu.2019.02558 ◽

2019 ◽

Vol 10 ◽

Author(s):

Nathaniel Enos ◽

Hidehito Takenaka ◽

Sarah Scott ◽

Hai V. N. Salfity ◽

Maia Kirk ◽

...

Keyword(s):

Spinal Cord ◽

Foam Cells ◽

Ependymal Cells ◽

Spinal Cord Regeneration

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Impairment Rating and Spinal Cord Injuries: Revisiting the Guides

Guides Newsletter ◽

10.1001/amaguidesnewsletters.2010.mayjun01 ◽

2010 ◽

Vol 15 (3) ◽

pp. 1-7

Author(s):

Richard T. Katz

Keyword(s):

Spinal Cord ◽

Spinal Cord Injuries ◽

Functional Independence ◽

Outcome Data ◽

Multiple Organ ◽

Loss Of Function ◽

Sixth Edition ◽

Organ Systems ◽

Cord Injury ◽

Impairment Ratings

Abstract This article addresses some criticisms of the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) by comparing previously published outcome data from a group of complete spinal cord injury (SCI) persons with impairment ratings for a corresponding level of injury calculated using the AMA Guides, Sixth Edition. Results of the comparison show that impairment ratings using the sixth edition scale poorly with the level of impairments of activities of daily living (ADL) in SCI patients as assessed by the Functional Independence Measure (FIM) motor scale and the extended FIM motor scale. Because of the combinations of multiple impairments, the AMA Guides potentially overrates the impairment of paraplegics compared with that of quadriplegics. The use and applicability of the Combined Values formula should be further investigated, and complete loss of function of two upper extremities seems consistent with levels of quadriplegia using the SCI model. Some aspects of the AMA Guides contain inconsistencies. The concept of diminishing impairment values is not easily translated between specific losses of function per organ system and “overall” loss of ADLs involving multiple organ systems, and the notion of “catastrophic thresholds” involving multiple organ systems may support the understanding that variations in rating may exist in higher rating cases such as those that involve an SCI.

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Spinal Impairment Evaluation: Fifth Edition Changes

Guides Newsletter ◽

10.1001/amaguidesnewsletters.2001.janfeb01 ◽

2001 ◽

Vol 6 (1) ◽

pp. 1-3

Author(s):

Robert H. Haralson

Keyword(s):

Spinal Cord ◽

Lower Extremity ◽

Range Of Motion ◽

Upper Extremity ◽

Spinal Cord Injuries ◽

Clinical Findings ◽

Fourth Edition ◽

Treatment Results ◽

Standard Terminology ◽

Made In

Abstract The AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), Fifth Edition, was published in November 2000 and contains major changes from its predecessor. In the Fourth Edition, all musculoskeletal evaluation and rating was described in a single chapter. In the Fifth Edition, this information has been divided into three separate chapters: Upper Extremity (13), Lower Extremity (14), and Spine (15). This article discusses changes in the spine chapter. The Models for rating spinal impairment now are called Methods. The AMA Guides, Fifth Edition, has reverted to standard terminology for spinal regions in the Diagnosis-related estimates (DRE) Method, and both it and the Range of Motion (ROM) Method now reference cervical, thoracic, and lumbar. Also, the language requiring the use of the DRE, rather than the ROM Method has been strengthened. The biggest change in the DRE Method is that evaluation should include the treatment results. Unfortunately, the Fourth Edition's philosophy regarding when and how to rate impairment using the DRE Model led to a number of problems, including the same rating of all patients with radiculopathy despite some true differences in outcomes. The term differentiator was abandoned and replaced with clinical findings. Significant changes were made in evaluation of patients with spinal cord injuries, and evaluators should become familiar with these and other changes in the Fifth Edition.

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