Inhibiting fibroblast aggregation in skin wounds unlocks developmental pathway to regeneration

Seifert, Ashley W.; Cook, Adam B.; Shaw, Douglas

doi:10.1016/j.ydbio.2019.07.001

Cited by 7 publications

(5 citation statements)

References 48 publications

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“…While regeneration shares mechanisms with embryonic development, the molecules involved are often different and expression changes after mammalian spinal cord injury generally do not closely recapitulate development (Harty et al, 2003;Nacu and Tanaka, 2011;Seifert et al, 2019). However, a study of expression changes in cortical neurons regenerating their axons into spinal embryonic grafts found a partial recapitulation of the embryonic gene expression pattern (Poplawski et al, 2020).…”

Section: Comparison With Gene Expression During Developmentmentioning

confidence: 99%

“…a9 integrin-kindlin-1-driven axon regeneration does not recapitulate embryonic development The issue of whether integrin-kindlin-driven regeneration represents a return to an embryonic pattern of expression is of obvious interest. In general, repair does not accurately recapitulate development (Harty et al, 2003;Nacu and Tanaka, 2011;Seifert et al, 2019), although basic mechanisms of cell movement are shared. In previous studies, embryonic recapitulation was marginally significant in peripheral nerve regeneration (Renthal et al, 2020).…”

Section: Control Of the Pns And Cns Regeneration Programsmentioning

confidence: 99%

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Integrin-Driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program

et al. 2023

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The peripheral branch of sensory dorsal root ganglion (DRG) neurons regenerates readily after injury unlike their central branch in the spinal cord. However, extensive regeneration and reconnection of sensory axons in the spinal cord can be driven by the expression of α9 integrin and its activator kindlin-1 (α9k1), which enable axons to interact with tenascin-C. To elucidate the mechanisms and downstream pathways affected by activated integrin expression and central regeneration, we conducted transcriptomic analyses of adult male rat DRG sensory neurons transduced with α9k1, and controls, with and without axotomy of the central branch. Expression of α9k1 without the central axotomy led to upregulation of a known PNS regeneration program, including many genes associated with peripheral nerve regeneration. Coupling α9k1 treatment with dorsal root axotomy led to extensive central axonal regeneration. In addition to the program upregulated by α9k1 expression, regeneration in the spinal cord led to expression of a distinctive CNS regeneration program, including genes associated with ubiquitination, autophagy, endoplasmic reticulum, trafficking, and signalling. Pharmacological inhibition of these processes blocked the regeneration of axons from DRGs and human iPSC-derived sensory neurons, validating their causal contributions to sensory regeneration. This CNS regeneration-associated program showed little correlation with either embryonic development or PNS regeneration programs. Potential transcriptional drivers of this CNS program coupled to regeneration include Mef2a, Runx3, E2f4 and Yy1. Signalling from integrins primes sensory neurons for regeneration, but their axon growth in the CNS is associated with an additional distinctive program that differs from that involved in PNS regeneration.SIGNIFICANCE STATEMENT:Restoration of neurological function after spinal cord injury is has yet to be achieved in human patients. To accomplish this, severed nerve fibres must be made to regenerate. Reconstruction of nerve pathways has not been possible, but recently a method for stimulating long-distance axon regeneration of sensory fibres in rodents has been developed. This research uses profiling of messenger RNAs in the regenerating sensory neurons to discover which mechanisms are activated. This study shows that the regenerating neurons initiate a novel CNS regeneration programme which includes molecular transport, autophagy, ubiquitination, and modulation of the endoplasmic reticulum. The study identifies mechanisms that neurons need to activate to regenerate their nerve fibres.

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Section: Comparison With Gene Expression During Developmentmentioning

confidence: 99%

Section: Control Of the Pns And Cns Regeneration Programsmentioning

confidence: 99%

Integrin-Driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program

et al. 2023

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“…Seifert et al. have performed research on the reactivation mechanism of developmental genes, which promote skin regeneration ( Seifert et al., 2019 ). The remaining questions are whether the developmental program is activated in the event of skin damage and what the specific gene flow of the skin developmental program is.…”

Section: Discussionmentioning

confidence: 99%

“…Amphibians have skin structures that are comparable to those of other vertebrates. Axolotls— Ambystoma mexicanum— have epidermis and dermis in the skin as in mammals ( Seifert et al., 2019 ). The epidermis consists of keratinocytes and the dermis contains collagen-synthesizing fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Lattice-patterned collagen fibers and their dynamics in axolotl skin regeneration

et al. 2022

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“…If and how this heterogeneity and structural complexity influence the WE formation will be important to decipher. Indeed, during metamorphosis, amphibian skin goes through specialization and extensive changes ( Schreiber and Brown, 2003 ; Seifert et al, 2012 , 2019 ). In a parallel, unlike premetamorphic axolotl, postmetamorphic axolotl regenerates at a slower rate with a reduced regeneration ability ( Monaghan et al, 2014 ), and a comparison between premetamorphic and postmetamorphic axolotl showed that the wound closure is slower in postmetamorphic animals ( Seifert et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Tissues and Cell Types of Appendage Regeneration: A Detailed Look at the Wound Epidermis and Its Specialized Forms

Aztekin

2021

Front. Physiol.

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Therapeutic implementation of human limb regeneration is a daring aim. Studying species that can regrow their lost appendages provides clues on how such a feat can be achieved in mammals. One of the unique features of regeneration-competent species lies in their ability to seal the amputation plane with a scar-free wound epithelium. Subsequently, this wound epithelium advances and becomes a specialized wound epidermis (WE) which is hypothesized to be the essential component of regenerative success. Recently, the WE and specialized WE terminologies have been used interchangeably. However, these tissues were historically separated, and contemporary limb regeneration studies have provided critical new information which allows us to distinguish them. Here, I will summarize tissue-level observations and recently identified cell types of WE and their specialized forms in different regeneration models.

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Inhibiting fibroblast aggregation in skin wounds unlocks developmental pathway to regeneration

Cited by 7 publications

References 48 publications

Integrin-Driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program

Integrin-Driven Axon Regeneration in the Spinal Cord Activates a Distinctive CNS Regeneration Program

Lattice-patterned collagen fibers and their dynamics in axolotl skin regeneration

Tissues and Cell Types of Appendage Regeneration: A Detailed Look at the Wound Epidermis and Its Specialized Forms

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