The cell cycle during amphibian limb regeneration

Wallace, H.; Maden, Malcolm

doi:10.1242/jcs.20.3.539

Cited by 44 publications

(10 citation statements)

References 17 publications

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“…The substantial reduction in cell proliferation of the GSK101 group (figure 2 a – c ; electronic supplementary material, figure S3) did not result in smaller humeri sizes (figure 2 d ). Axolotls have long cell cycles, which have been recorded to be up to 88 hours in regenerating tissues [67,68]. Throughout the 10-day experimental treatment, few complete cycles would have occurred.…”

Section: Discussionmentioning

confidence: 99%

Local mechanical stimuli correlate with tissue growth in axolotl salamander joint morphogenesis

et al. 2022

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Movement-induced forces are critical to correct joint formation, but it is unclear how cells sense and respond to these mechanical cues. To study the role of mechanical stimuli in the shaping of the joint, we combined experiments on regenerating axolotl ( Ambystoma mexicanum ) forelimbs with a poroelastic model of bone rudiment growth. Animals either regrew forelimbs normally (control) or were injected with a transient receptor potential vanilloid 4 (TRPV4) agonist during joint morphogenesis. We quantified growth and shape in regrown humeri from whole-mount light sheet fluorescence images of the regenerated limbs. Results revealed significant differences in morphology and cell proliferation between groups, indicating that TRPV4 desensitization has an effect on joint shape. To link TRPV4 desensitization with impaired mechanosensitivity, we developed a finite element model of a regenerating humerus. Local tissue growth was the sum of a biological contribution proportional to chondrocyte density, which was constant, and a mechanical contribution proportional to fluid pressure. Computational predictions of growth agreed with experimental outcomes of joint shape, suggesting that interstitial pressure driven from cyclic mechanical stimuli promotes local tissue growth. Predictive computational models informed by experimental findings allow us to explore potential physical mechanisms involved in tissue growth to advance our understanding of the mechanobiology of joint morphogenesis.

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Section: Discussionmentioning

confidence: 99%

Local mechanical stimuli correlate with tissue growth in axolotl salamander joint morphogenesis

et al. 2022

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“…To understand the molecular pathways involved in CT regeneration, we used a high-transcriptomecoverage scRNA-seq method (Fluidigm C1) to analyze mCherry-positive (mCherry + ) cells isolated by FACS (Prrx1:Cre-ER;Caggs:lp-Cherry) along a dense time course that captures the major transitions during regeneration. Time points were determined on the basis of the average blastema cell cycle length (53 to 103 hours) (13,14) and previous bulk transcriptional dynamics (15) and therefore included the uninjured upper forelimbs (108 cells), as well as blastema stages (3 dpa, 108 cells; 5 dpa, 167 cells; 8 dpa, 121 cells; 11 dpa, 163 cells; and 18 dpa, 135 cells) and a fully regenerated upper forelimb (3 to 12 months postamputation, 128 cells) (Fig. 2A, fig.…”

Section: Blastema Formation From Axolotl Upper Arm Ct Cells Involves ...mentioning

confidence: 99%

Single-cell analysis uncovers convergence of cell identities during axolotl limb regeneration

Gerber

Murawala

Knapp

et al. 2018

Science

320

435

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Amputation of the axolotl forelimb results in the formation of a blastema, a transient tissue where progenitor cells accumulate prior to limb regeneration. Connective tissue (CT) – skeleton, periskeleton, tendon, dermis, interstitial fibroblasts – contributes the vast majority of cells that populate the blastema, however, it is unclear how individual CT cells may reprogram their fate in order to rebuild the tetrapod limb. Here we use a combination of Cre-loxP reporter lineage tracking and single-cell (sc) RNA-seq to molecularly track, for the first time, adult CT cell heterogeneity and its transition to a limb blastema state. We uncover a multi-phasic molecular program where CT cell types found in the uninjured adult limb revert to a relatively homogenous progenitor state that participates in inflammation and extracellular matrix disassembly prior to proliferation, establishment of positional information, and ultimately re-differentiation. While the early regeneration transcriptome states are unique to the blastema, the later stages recapitulate embryonic limb development. Notably, we do not find evidence of a pre-existing blastema-like precursor nor limb bud-like progenitors in the uninjured adult tissue. However, we find that distinct CT subpopulations in the adult limb differentially contribute to extending bone at the amputation plane versus regenerating new segments. Together, our data illuminates molecular and cellular reprogramming during complex organ regeneration in a vertebrate.

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“…This apparent discrepancy between amount of cell proliferation and humeri size could be due to the axolotl long cell cycles, which have been recorded to be up to 88 hours in regenerating tissues [65,66]. Then, throughout the 10 day experimental treatment, few complete cycles would have occurred.…”

Section: Discussionmentioning

confidence: 99%

Local mechanical stimuli shape tissue growth in vertebrate joint morphogenesis

Comellas

Farkas

Kleinberg

et al. 2021

Preprint

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The correct formation of synovial joints is essential for proper motion throughout life. Movement-induced forces are critical to creating correctly shaped joints, but it is unclear how cells sense and respond to these mechanical cues. To determine how mechanical stimuli drive joint morphogenesis, we combined experiments on regenerating axolotl forelimbs with a poroelastic model of bone rudiment growth. Animals either regrew forelimbs normally (control) or were injected with a TRPV4 agonist to impair chondrocyte mechanosensitivity during joint morphogenesis. We quantified growth and shape in regrown humeri from whole mount light sheet fluorescence images of the regenerated limbs. Results revealed statistically significant differences in morphology and cell proliferation between the two groups, indicating that mechanical stimuli play a role in the shaping of the joint. Local tissue growth in our finite element model was dictated by a biological contribution, proportional to chondrocyte density, and a mechanical one, driven by fluid pore pressure dynamics. Computational predictions agreed with experimental outcomes, suggesting that interstitial pressure might promote local tissue growth. Predictive computational models informed by experimental findings allow us to explore potential physical mechanisms and regulatory dynamics involved in tissue growth to advance our understanding of the mechanobiology of joint morphogenesis.

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The cell cycle during amphibian limb regeneration

Cited by 44 publications

References 17 publications

Local mechanical stimuli correlate with tissue growth in axolotl salamander joint morphogenesis

Local mechanical stimuli correlate with tissue growth in axolotl salamander joint morphogenesis

Single-cell analysis uncovers convergence of cell identities during axolotl limb regeneration

Local mechanical stimuli shape tissue growth in vertebrate joint morphogenesis

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