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Sensory Reinnervation of Human Skin by Human Neural Stem Cell‒Derived Peripheral Neurons Ex Vivo

      Although the use of full-thickness human skin organ culture in preclinical research has many advantages compared with the use of reconstructed so-called three-dimensional skin equivalents, it is usually denervated (
      • Zhou L.
      • Zhang X.
      • Paus R.
      • Lu Z.
      The renaissance of human skin organ culture: a critical reappraisal.
      ). Reinnervation of human skin ex vivo by sensory neurons derived from rat dorsal root ganglia (
      • Chéret J.
      • Lebonvallet N.
      • Buhé V.
      • Carre J.L.
      • Misery L.
      • Le Gall-Ianotto C.
      Influence of sensory neuropeptides on human cutaneous wound healing process.
      ;
      • Lebonvallet N.
      • Pennec J.P.
      • Le Gall-Ianotto C.
      • Chéret J.
      • Jeanmaire C.
      • Carré J.L.
      • et al.
      Activation of primary sensory neurons by the topical application of capsaicin on the epidermis of a re-innervated organotypic human skin model.
      ,
      • Lebonvallet N.
      • Boulais N.
      • Le Gall C.
      • Pereira U.
      • Gauché D.
      • Gobin E.
      • et al.
      Effects of the re-innervation of organotypic skin explants on the epidermis.
      ) combines cells/tissues from two very different species and requires that rat nerve fibers (NFs), neuropeptides, neurotransmitters, and neurotrophins communicate with cognate human receptors. This interspecies design creates complications and data interpretation challenges (see Supplementary Text S1).

      Abbreviations:

      KC (keratinocyte), NF (nerve fiber), NGF (nerve GF), nSC (neural stem cell)
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      References

        • Aloe L.
        • Rocco M.L.
        • Bianchi P.
        • Manni L.
        Nerve growth factor: from the early discoveries to the potential clinical use.
        J Transl Med. 2012; 10: 239
        • Ayasse M.T.
        • Buddenkotte J.
        • Alam M.
        • Steinhoff M.
        Role of neuroimmune circuits and pruritus in psoriasis.
        Exp Dermatol. 2020; 29: 414-426
        • Bae J.Y.
        • Kim J.H.
        • Cho Y.S.
        • Mah W.
        • Bae Y.C.
        Quantitative analysis of afferents expressing substance P, calcitonin gene-related peptide, isolectin B4, neurofilament 200, and peripherin in the sensory root of the rat trigeminal ganglion.
        J Comp Neurol. 2015; 523: 126-138
        • Bataille A.
        • Leschiera R.
        • L'Hérondelle K.
        • Pennec J.P.
        • Le Goux N.
        • Mignen O.
        • et al.
        In vitro differentiation of human skin-derived cells into functional sensory neurons-like.
        Cells. 2020; 9: 1000
        • Bernal A.
        • Arranz L.
        Nestin-expressing progenitor cells: function, identity and therapeutic implications.
        Cell Mol Life Sci. 2018; 75: 2177-2195
        • Bertolini M.
        • Pretzlaff M.
        • Sulk M.
        • Bähr M.
        • Gherardini J.
        • Uchida Y.
        • et al.
        Vasoactive intestinal peptide, whose receptor-mediated signalling may be defective in alopecia areata, provides protection from hair follicle immune privilege collapse.
        Br J Dermatol. 2016; 175: 531-541
        • Björklund H.
        • Dalsgaard C.J.
        • Jonsson C.E.
        • Hermansson A.
        Sensory and autonomic innervation of non-hairy and hairy human skin. An immunohistochemical study.
        Cell Tissue Res. 1986; 243: 51-57
        • Buhé V.
        • Trimaille A.
        • Schollhammer M.
        • Morvan F.
        • Hu W.
        • Egles C.
        • et al.
        Heterogeneity of skin re-innervation after burns and factors involved in its regulation: a pilot study.
        Acta Derm Venereol. 2018; 98: 280-281
        • Campiche R.
        • Daniltchenko M.
        • Imfeld D.
        • Peters E.M.J.
        Effects of the selective TrkA agonist gambogic amide on pigmentation and growth of human hair follicles in vitro.
        PLoS One. 2019; 14e0221757
        • Chéret J.
        • Lebonvallet N.
        • Buhé V.
        • Carre J.L.
        • Misery L.
        • Le Gall-Ianotto C.
        Influence of sensory neuropeptides on human cutaneous wound healing process.
        J Dermatol Sci. 2014; 74: 193-203
        • Forsythe P.
        • Bienenstock J.
        The mast cell-nerve functional unit: a key component of physiologic and pathophysiologic responses.
        Chem Immunol Allergy. 2012; 98: 196-221
        • Gonzalez-Martinez T.
        • Perez-Piñera P.
        • Díaz-Esnal B.
        • Vega J.A.
        S-100 proteins in the human peripheral nervous system.
        Microsc Res Tech. 2003; 60: 633-638
        • Groneberg D.A.
        • Serowka F.
        • Peckenschneider N.
        • Artuc M.
        • Grützkau A.
        • Fischer A.
        • et al.
        Gene expression and regulation of nerve growth factor in atopic dermatitis mast cells and the human mast cell line-1.
        J Neuroimmunol. 2005; 161: 87-92
        • Haberberger R.V.
        • Barry C.
        • Dominguez N.
        • Matusica D.
        Human dorsal root ganglia.
        Front Cell Neurosci. 2019; 13: 271
        • Hendrickson M.L.
        • Rao A.J.
        • Demerdash O.N.
        • Kalil R.E.
        Expression of nestin by neural cells in the adult rat and human brain.
        PLoS One. 2011; 6: e18535
        • Hsieh S.T.
        • Chiang H.Y.
        • Lin W.M.
        Pathology of nerve terminal degeneration in the skin.
        J Neuropathol Exp Neurol. 2000; 59: 297-307
        • Hsieh S.T.
        • Lin W.M.
        Modulation of keratinocyte proliferation by skin innervation.
        J Invest Dermatol. 1999; 113: 579-586
        • Jimenez-Andrade J.M.
        • Mantyh W.G.
        • Bloom A.P.
        • Xu H.
        • Ferng A.S.
        • Dussor G.
        • et al.
        A phenotypically restricted set of primary afferent nerve fibers innervate the bone versus skin: therapeutic opportunity for treating skeletal pain [published correction appears in Bone 2010;46:1670–1].
        Bone. 2010; 46: 306-313
        • Lebonvallet N.
        • Boulais N.
        • Le Gall C.
        • Pereira U.
        • Gauché D.
        • Gobin E.
        • et al.
        Effects of the re-innervation of organotypic skin explants on the epidermis.
        Exp Dermatol. 2012; 21: 156-158
        • Lebonvallet N.
        • Pennec J.P.
        • Le Gall-Ianotto C.
        • Chéret J.
        • Jeanmaire C.
        • Carré J.L.
        • et al.
        Activation of primary sensory neurons by the topical application of capsaicin on the epidermis of a re-innervated organotypic human skin model.
        Exp Dermatol. 2014; 23: 73-75
        • Lu Z.
        • Hasse S.
        • Bodo E.
        • Rose C.
        • Funk W.
        • Paus R.
        Towards the development of a simplified long-term organ culture method for human scalp skin and its appendages under serum-free conditions.
        Exp Dermatol. 2007; 16: 37-44
        • Luengas-Martinez A.
        • Hardman-Smart J.
        • Rutkowski D.
        • Purba T.S.
        • Paus R.
        • Young H.S.
        Vascular endothelial growth factor blockade induces dermal endothelial cell apoptosis in a clinically relevant skin organ culture model.
        Skin Pharmacol Physiol. 2020; 33: 110-118
        • Peters E.M.
        • Stieglitz M.G.
        • Liezman C.
        • Overall R.W.
        • Nakamura M.
        • Hagen E.
        • et al.
        P75 neurotrophin receptor-mediated signaling promotes human hair follicle regression (catagen).
        Am J Pathol. 2006; 168: 221-234
        • Roggenkamp D.
        • Köpnick S.
        • Stäb F.
        • Wenck H.
        • Schmelz M.
        • Neufang G.
        Epidermal nerve fibers modulate keratinocyte growth via neuropeptide signaling in an innervated skin model.
        J Invest Dermatol. 2013; 133: 1620-1628
        • Sainath R.
        • Gallo G.
        Cytoskeletal and signaling mechanisms of neurite formation.
        Cell Tissue Res. 2015; 359: 267-278
        • Skaper S.D.
        Nerve growth factor: a neuroimmune crosstalk mediator for all seasons.
        Immunology. 2017; 151: 1-15
        • Talagas M.
        • Lebonvallet N.
        • Berthod F.
        • Misery L.
        Cutaneous nociception: role of keratinocytes.
        Exp Dermatol. 2019; 28: 1466-1469
        • Talagas M.
        • Lebonvallet N.
        • Leschiera R.
        • Elies P.
        • Marcorelles P.
        • Misery L.
        Intra-epidermal nerve endings progress within keratinocyte cytoplasmic tunnels in normal human skin.
        Exp Dermatol. 2020; 29: 387-392
        • Tiede S.
        • Kloepper J.E.
        • Ernst N.
        • Poeggeler B.
        • Kruse C.
        • Paus R.
        Nestin in human skin: exclusive expression in intramesenchymal skin compartments and regulation by leptin.
        J Invest Dermatol. 2009; 129: 2711-2720
        • Yuan A.
        • Sasaki T.
        • Kumar A.
        • Peterhoff C.M.
        • Rao M.V.
        • Liem R.K.
        • et al.
        Peripherin is a subunit of peripheral nerve neurofilaments: implications for differential vulnerability of CNS and peripheral nervous system axons.
        J Neurosci. 2012; 32: 8501-8508
        • Zhou L.
        • Zhang X.
        • Paus R.
        • Lu Z.
        The renaissance of human skin organ culture: a critical reappraisal.
        Differentiation. 2018; 104: 22-35

      Supplementary References

        • Bertolini M.
        • Pretzlaff M.
        • Sulk M.
        • Bähr M.
        • Gherardini J.
        • Uchida Y.
        • et al.
        Vasoactive intestinal peptide, whose receptor-mediated signalling may be defective in alopecia areata, provides protection from hair follicle immune privilege collapse.
        Br J Dermatol. 2016; 175: 531-541
        • Buhé V.
        • Vié K.
        • Guéré C.
        • Natalizio A.
        • Lhéritier C.
        • Le Gall-Ianotto C.
        • et al.
        Pathophysiological study of sensitive skin.
        Acta Derm Venereol. 2016; 96: 314-318
        • Chéret J.
        • Lebonvallet N.
        • Buhé V.
        • Carre J.L.
        • Misery L.
        • Le Gall-Ianotto C.
        Influence of sensory neuropeptides on human cutaneous wound healing process.
        J Dermatol Sci. 2014; 74: 193-203
        • Dolenšek J.
        • Rupnik M.S.
        • Stožer A.
        Structural similarities and differences between the human and the mouse pancreas.
        Islets. 2015; 7e1024405
        • Haberberger R.V.
        • Barry C.
        • Dominguez N.
        • Matusica D.
        Human dorsal root ganglia.
        Front Cell Neurosci. 2019; 13: 271
        • Hyvärinen T.
        • Hyysalo A.
        • Kapucu F.E.
        • Aarnos L.
        • Vinogradov A.
        • Eglen S.J.
        • et al.
        Functional characterization of human pluripotent stem cell-derived cortical networks differentiated on laminin-521 substrate: comparison to rat cortical cultures.
        Sci Rep. 2019; 9: 17125
        • Lauria G.
        • Hsieh S.T.
        • Johansson O.
        • Kennedy W.R.
        • Leger J.M.
        • Mellgren S.I.
        • et al.
        European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.
        Eur J Neurol. 2010; 17: 903-912.e44–9
        • Liao T.
        • Lehmann J.
        • Sternstein S.
        • Yay A.
        • Zhang G.
        • Matthießen A.E.
        • et al.
        Nestin+ progenitor cells isolated from adult human sweat gland stroma promote reepithelialisation and may stimulate angiogenesis in wounded human skin ex vivo.
        Arch Dermatol Res. 2019; 311: 325-330
        • Livak K.J.
        • Schmittgen T.D.
        Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method.
        Methods. 2001; 25: 402-408
        • Meier N.T.
        • Haslam I.S.
        • Pattwell D.M.
        • Zhang G.Y.
        • Emelianov V.
        • Paredes R.
        • et al.
        Thyrotropin-releasing hormone (TRH) promotes wound re-epithelialisation in frog and human skin.
        PLoS One. 2013; 8: e73596
        • Peters E.M.
        • Michenko A.
        • Kupfer J.
        • Kummer W.
        • Wiegand S.
        • Niemeier V.
        • et al.
        Mental stress in atopic dermatitis--neuronal plasticity and the cholinergic system are affected in atopic dermatitis and in response to acute experimental mental stress in a randomized controlled pilot study.
        PLoS One. 2014; 9e113552
        • Post H.
        • Hundt J.E.
        • Zhang G.
        • Depping R.
        • Rose C.
        • Langan E.A.
        • et al.
        Thyroxine restores severely impaired cutaneous re-epithelialisation and angiogenesis in a novel preclinical assay for studying human skin wound healing under "pathological" conditions ex vivo.
        Arch Dermatol Res. 2021; 313: 181-192
        • Santos D.
        • González-Pérez F.
        • Giudetti G.
        • Micera S.
        • Udina E.
        • Del Valle J.
        • et al.
        Preferential enhancement of sensory and motor axon regeneration by combining extracellular matrix components with neurotrophic factors.
        Int J Mol Sci. 2016; 18: 65
        • Schwarzbauer J.E.
        • Tamkun J.W.
        • Lemischka I.R.
        • Hynes R.O.
        Three different fibronectin mRNAs arise by alternative splicing within the coding region.
        Cell. 1983; 35: 421-431
        • Sugawara K.
        • Bíró T.
        • Tsuruta D.
        • Tóth B.I.
        • Kromminga A.
        • Zákány N.
        • et al.
        Endocannabinoids limit excessive mast cell maturation and activation in human skin.
        J Allergy Clin Immunol. 2012; 129: 726-738.e8
        • Umezawa K.
        • Kornblihtt A.R.
        • Baralle F.E.
        Isolation and characterization of cDNA clones for human liver fibronectin.
        FEBS Lett. 1985; 186: 31-34
        • White E.S.
        • Baralle F.E.
        • Muro A.F.
        New insights into form and function of fibronectin splice variants.
        J Pathol. 2008; 216: 1-14