Characterization of Human Dermal Fibroblasts in Fabry Disease

Lakomá, Jarmila; Donadio, Vincenzo; Liguori, Rocco; Caprini, Marco

doi:10.1002/jcp.25072

Cited by 6 publications

(7 citation statements)

References 109 publications

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“…As a consequence, Gb3 starts to accumulate within lysosomes of several tissues involving blood vessels, kidneys, nervous system and heart, as well as dermal fibroblasts[5–8], accounting for FD’s clinical features[9,10] mainly including small fibre neuropathy (SFN)[11], stroke, and renal and cardiac dysfunctions[12]. SFN is mainly responsible for paraesthesias of extremities, hypohydrosis, abdominal pain and diarrhoea[5,11,12] often beginning in childhood with progressive severity throughout life.…”

Section: Introductionmentioning

confidence: 99%

Skin globotriaosylceramide 3 deposits are specific to Fabry disease with classical mutations and associated with small fibre neuropathy

et al. 2017

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BackgroundFabry Disease (FD) is characterized by globotriaosylceramide-3 (Gb3) accumulation in several tissues and a small fibre neuropathy (SFN), however the underlying mechanisms are poorly known. This study aimed to: 1) ascertain the presence of Gb3 deposits in skin samples, by an immunofluorescence method collected from FD patients with classical GLA mutations or late-onset FD variants or GLA polymorphisms; 2) correlate skin GB3 deposits with skin innervation.Methodswe studied 52 genetically-defined FD patients (32 with classical GLA mutations and 20 with late-onset variants or GLA polymorphisms), 15 patients with SFN associated with a specific cause and 22 healthy controls. Subjects underwent skin biopsy to evaluate Gb3 deposits and epi-dermal innervation.ResultsSkin Gb3 deposits were found in all FD patients with classical GLA mutations but never in FD patients with late-onset variants or GLA polymorphisms or in patients with SFN and healthy controls. Abnormal deposits were found inside different skin structures but never inside axons. FD patients with GB3 deposits showed lower skin innervation than FD patients with late-onset variants or polymorphisms.Conclusions1) Skin Gb3 deposits are specific to FD patients with classical GLA mutations; 2) Gb3 deposits were associated with lower skin innervation but they were not found inside axons, suggesting an indirect damage on peripheral small fibre innervation.

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Section: Introductionmentioning

confidence: 99%

Skin globotriaosylceramide 3 deposits are specific to Fabry disease with classical mutations and associated with small fibre neuropathy

et al. 2017

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“…[10][11][12] Our first hypothesis, at the molecular level, was referred to the role of the Gb3 deposits in the cell bodies of cells as a typical feature of FD patients. 13,14 Specifically, Gb3 accumulations would interfere with the function of cellular membrane proteins and receptors leading to a direct pathological effect on ganglia or axons of small peripheral sensory neurons in pain perception and/or transduction. [14][15][16] In a previous study, we reported that a-GalA null mice displayed neuropathic pain evidenced by thermal hyperalgesia, mechanical allodynia, and histological analyses.…”

Section: Introductionmentioning

confidence: 99%

“…13,14 Specifically, Gb3 accumulations would interfere with the function of cellular membrane proteins and receptors leading to a direct pathological effect on ganglia or axons of small peripheral sensory neurons in pain perception and/or transduction. [14][15][16] In a previous study, we reported that a-GalA null mice displayed neuropathic pain evidenced by thermal hyperalgesia, mechanical allodynia, and histological analyses. 12 These findings suggested that this was a good model to study the peripheral small fiber neuropathy exhibited by FD and provide molecular evidence for the hyperexcitability of small nociceptors in FD.…”

Section: Introductionmentioning

confidence: 99%

Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model

et al. 2016

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Fabry disease is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3) in the endothelium and vascular smooth muscles. A hallmark symptom of Fabry disease patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. The α-GalA gene null mouse model (α-GalA(−/0)) has provided molecular evidence for the molecular alterations in small type-C nociceptors in Fabry disease that may underlie their hyperexcitability, although the specific mechanism remains elusive. Here, we have addressed this question and report that small type-C nociceptors from α-GalA(−/0) mice exhibit a significant increase in the expression and function of the TRPV1 channel, a thermoTRP channel implicated in painful heat sensation. Notably, male α-GalA(−/0) mice displayed a ≈2-fold higher heat sensitivity than wild-type animals, consistent with the augmented expression levels and activity of TRPV1 in α-GalA(−/0) nociceptors. Intriguingly, blockade of neuronal exocytosis with peptide DD04107, a process that inhibits among others the algesic membrane recruitment of TRPV1 channels in peptidergic nociceptors, virtually eliminated the enhanced heat nociception of α-GalA(−/0) mice. Together, these findings suggest that the augmented expression of TRPV1 in α-GalA(−/0) nociceptors may underly at least in part their increased heat sensitivity, and imply that blockade of peripheral neuronal exocytosis may be a valuable pharmacological strategy to reduce pain in Fabry disease patients, increasing their quality of life.

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“…As the main skin cell population, keratinocytes and fibroblasts are in close and active contact with sensory nerve fiber endings, and human and experimental data are pointing toward an intensive interaction between skin cells and nociceptors . This novel concept of skin cell involvement in sensory signaling is supported by the expression of nociception‐associated receptors and the release of pain‐related mediators by fibroblasts and keratinocytes. In addition, keratinocytes release axon guidance cues like netrins and semaphorins, which may act as local pathfinders.…”

Section: Discussionmentioning

confidence: 99%

Patient‐derived in vitro skin models for investigation of small fiber pathology

Karl

Wußmann

Kreß

et al. 2019

Ann Clin Transl Neurol

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Objective To establish individually expandable primary fibroblast and keratinocyte cultures from 3‐mm skin punch biopsies for patient‐derived in vitro skin models to investigate of small fiber pathology. Methods We obtained 6‐mm skin punch biopsies from the calf of two patients with small fiber neuropathy (SFN) and two healthy controls. One half (3 mm) was used for diagnostic intraepidermal nerve fiber density (IENFD). From the second half, we isolated and cultured fibroblasts and keratinocytes. Cells were used to generate patient‐derived full‐thickness three‐dimensional (3D) skin models containing a dermal and epidermal component. Cells and skin models were characterized morphologically, immunocyto‐ and ‐histochemically (vimentin, cytokeratin (CK)‐10, CK 14, ki67, collagen1, and procollagen), and by electrical impedance. Results Distal IENFD was reduced in the SFN patients (2 fibers/mm each), while IENFD was normal in the controls (8 fibers/mm, 7 fibers/mm). Two‐dimensional (2D) cultured skin cells showed normal morphology, adequate viability, and proliferation, and expressed cell‐specific markers without relevant difference between SFN patient and healthy control. Using 2D cultured fibroblasts and keratinocytes, we obtained subject‐derived 3D skin models. Morphology of the 3D model was analogous to the respective skin biopsy specimens. Both, the dermal and the epidermal layer carried cell‐specific markers and showed a homogenous expression of extracellular matrix proteins. Interpretation Our protocol allows the generation of disease‐specific 2D and 3D skin models, which can be used to investigate the cross‐talk between skin cells and sensory neurons in small fiber pathology.

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Characterization of Human Dermal Fibroblasts in Fabry Disease

Cited by 6 publications

References 109 publications

Skin globotriaosylceramide 3 deposits are specific to Fabry disease with classical mutations and associated with small fibre neuropathy

Skin globotriaosylceramide 3 deposits are specific to Fabry disease with classical mutations and associated with small fibre neuropathy

Increased expression of Trpv1 in peripheral terminals mediates thermal nociception in Fabry disease mouse model

Patient‐derived in vitro skin models for investigation of small fiber pathology

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