Vertebrate Epidermal Cells Are Broad-Specificity Phagocytes That Clear Sensory Axon Debris

Rasmussen, Jeffrey P.; Sack, Georgeann S.; Martin, Seanna M.; Sagasti, Alvaro

doi:10.1523/jneurosci.3613-14.2015

Cited by 72 publications

(99 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4D). Because lack of growth could also relate to defects mediated within the epidermis due to keratinocyte damage, we next assessed paclitaxel's effects on Wallerian degeneration (WD), for which it was shown in Drosophila and zebrafish that axon debris clearance depends on keratinocytes acting as "nonprofessional" phagocytes (28,29). Similar to mammals, zebrafish cutaneous axons degenerate by WD when severed (30), a process that is defined by a lag phase during which the severed axons remain intact, an axon fragmentation phase, and a clearance phase during which axon debris is phagocytosed.…”

Section: Resultsmentioning

confidence: 99%

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

Lisse

Middleton

Pellegrini

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in cancer treatment and in a number of curative and palliative regimens. Despite its beneficial effects on cancer, paclitaxel also damages healthy tissues, most prominently the peripheral sensory nervous system. The mechanisms leading to paclitaxelinduced peripheral neuropathy remain elusive, and therapies that prevent or alleviate this condition are not available. We established a zebrafish in vivo model to study the underlying mechanisms and to identify pharmacological agents that may be developed into therapeutics. Both adult and larval zebrafish displayed signs of paclitaxel neurotoxicity, including sensory axon degeneration and the loss of touch response in the distal caudal fin. Intriguingly, studies in zebrafish larvae showed that paclitaxel rapidly promotes epithelial damage and decreased mechanical stress resistance of the skin before induction of axon degeneration. Moreover, injured paclitaxel-treated zebrafish skin and scratch-wounded human keratinocytes (HEK001) display reduced healing capacity. Epithelial damage correlated with rapid accumulation of fluorescein-conjugated paclitaxel in epidermal basal keratinocytes, but not axons, and upregulation of matrix-metalloproteinase 13 (MMP-13, collagenase 3) in the skin. Pharmacological inhibition of MMP-13, in contrast, largely rescued paclitaxel-induced epithelial damage and neurotoxicity, whereas MMP-13 overexpression in zebrafish embryos rendered the skin vulnerable to injury under mechanical stress conditions. Thus, our studies provide evidence that the epidermis plays a critical role in this condition, and we provide a previously unidentified candidate for therapeutic interventions.aclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in the treatment of common cancers, including breast, ovarian, and lung cancer. Despite its promising anticancerous properties, paclitaxel also damages healthy tissues, most prominently peripheral axons of somatosensory neurons (reviewed in ref. 1). Paclitaxel-induced peripheral neuropathy initiates in the distal extremities and presents as neuropathic pain syndrome, temperature sensitivity, and paresthesia (tingling and numbness). Nerve biopsies from patients suggest that axon degeneration is the primary manifestation of this condition, followed by secondary demyelination and nerve fiber loss in severely affected patients (1, 2). Certain drugs have been shown in vitro and in vivo to protect against paclitaxel-induced nerve damage, including acetyl-L-carnitine, erythropoietin, alpha-lipoic acid, olesoxime, amifostine, nerve growth factor, and glutamate (reviewed in ref.3). However, so far, these agents have either not successfully passed clinical trials or merely alleviate symptoms such as pain without prevention (1). Thus, a better understanding of the underlying causes of paclitaxel-induced peripheral neuropathy is necessary and may help identify new candidate drugs with which to treat this condition.A widely...

show abstract

Section: Resultsmentioning

confidence: 99%

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

Lisse

Middleton

Pellegrini

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

show abstract

“…Inset in panel J, trigeminal sensory axons over the eye to confirm presence of transgene. Transgenes: (A) keratinocytes [ Tg(krt4:EGFP) ] (Rasmussen et al, 2015) and osteoblasts [ Tg(sp7:mCherry-nfsB) ] (Singh et al, 2012); (C) keratinocytes [ Tg(actb2:BswitchR) ] (Kobayashi et al, 2014); (C,E,G) somatosensory neurons [ Tg(p2rx3b:EGFP) ] (Kucenas et al, 2006); (D,F,H) Tg(−28.5Sox10:Cre);Tg(ubb:GswitchR) (Kague et al, 2012; Mosimann et al, 2011) ; (I-K) somatosensory axons Tg(p2rx3a>mCherry) (Palanca et al, 2013) . Staining: (E,F) nuclei (DAPI).…”

Section: Figurementioning

confidence: 99%

Fish Scales Dictate the Pattern of Adult Skin Innervation and Vascularization

Rasmussen

Sagasti

2018

Developmental Cell

Self Cite

View full text Add to dashboard Cite

As animals mature from embryonic to adult stages, the skin grows and acquires specialized appendages, like hairs, feathers, and scales. How cutaneous blood vessels and sensory axons adapt to these dramatic changes is poorly understood. By characterizing skin maturation in zebrafish, we discovered that sensory axons are delivered to the adult epidermis in organized nerves patterned by features in bony scales. These nerves associate with blood vessels and osteoblasts above scales. Osteoblasts create paths in scales that independently guide nerves and blood vessels during both development and regeneration. By preventing scale regeneration and examining mutants lacking scales, we found that scales recruit, organize, and polarize axons and blood vessels to evenly distribute them in the skin. These studies uncover mechanisms for achieving comprehensive innervation and vascularization of the adult skin and suggest that scales coordinate a metamorphosis-like transformation of the skin with sensory axon and vascular remodeling.

show abstract

“…It is well admitted that macrophages and Schwann cells are actors in the clearance of debris. Surprisingly, it has been shown in Zebrafish skin that epidermal cells also phagocytose debris generated after injury to peripheral axons (64). Schwann cells that surround the axon of the fiber ending certainly play a major role to promote and to guide axon sprout.…”

Section: Mechanisms Of Nerve Regeneration During Cutaneous Healingmentioning

confidence: 99%

Biotechnological Management of Skin Burn Injuries: Challenges and Perspectives in Wound Healing and Sensory Recovery

Girard

LaverdetBetty

BuhéVirginie

et al. 2017

Tissue Engineering Part B: Reviews

View full text Add to dashboard Cite

Many wound management protocols have been developed to improve wound healing after burn with the primordial aim to restore the barrier function of the skin and also provide a better esthetic outcome. Autologous skin grafts remain the gold standard in the treatment of skin burn, but this treatment has its limitation especially for patients presenting limited donor sites due to extensive burn areas. Deep burn injuries also alter the integrity of skin-sensitive innervation and have an impact on patient's quality of life by compromising perceptions of touch, temperature, and pain. Thus, patients can suffer from long-term disabilities ranging from cutaneous sensibility loss to chronic pain. The cellular mechanisms involved in skin reinnervation following injury are not elucidated yet. Depending on the depth of the burn, nerve sprouting can occur from the wound bed or the surrounding healthy tissue, but somehow this process fails to provide correct reinnervation of the wound during scarring. In addition, several clinical observations indicate that damage to the peripheral nervous system influences wound healing, resulting in delayed wound healing or chronic wounds, underlining the role of innervation and neuromediators for normal cutaneous tissue repair development. Promising tissue engineering strategies, including the use of biomaterials, skin substitutes, and stem cells, could provide novel alternative treatments in wound healing and help in improving patient's sensory recovery.

show abstract

Vertebrate Epidermal Cells Are Broad-Specificity Phagocytes That Clear Sensory Axon Debris

Cited by 72 publications

References 73 publications

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

Fish Scales Dictate the Pattern of Adult Skin Innervation and Vascularization

Biotechnological Management of Skin Burn Injuries: Challenges and Perspectives in Wound Healing and Sensory Recovery

Contact Info

Product

Resources

About