title: Sensory neuropathy hampers nociception-mediated bone marrow stem cell release in mice and patients with diabetes.
abstract: OBJECTIVE
  Upon tissue injury, peripheral sensory neurons release nociceptive factors (e.g. substance P [SP]), which exert local and systemic actions including the recruitment of bone marrow (BM)-derived haematopoietic stem and progenitor cells (HSPCs) endowed with paracrine pro-angiogenic properties. We herein explore whether diabetic neuropathy interferes with these phenomena.
  
  
  METHODS
  We first investigated the presence of sensory neuropathy in the BM of patients with type 2 diabetes by immunohistochemistry and morphometry analyses of nerve size and density and assessment of SP release by ELISA. We next analysed the association of sensory neuropathy with altered HSPC release under ischaemia or following direct stimulation with granulocyte colony-stimulating factor (G-CSF). BM and circulating HSPCs expressing the neurokinin 1 receptor (NK1R), which is the main SP receptor, were measured by flow cytometry. We finally assessed whether an altered modulation of SP secretion interferes with the mobilisation and homing of NK1R-HSPCs in a mouse model of type 2 diabetes after limb ischaemia (LI).
  
  
  RESULTS
  Nociceptive fibres were reduced in the BM of patients and mice with type 2 diabetes. Patients with neuropathy showed a remarkable reduction in NK1R-HSPC mobilisation under ischaemia or upon G-CSF stimulation. Following LI, diabetic mice manifested an altered SP gradient between BM, peripheral blood and limb muscles, accompanied by a depressed recruitment of NK1R-HSPCs to the ischaemic site.
  
  
  CONCLUSIONS
  Sensory neuropathy translates into defective liberation and homing of reparative HSPCs. Nociceptors may represent a new target for treatment of diabetic complications.
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Street, Bristol, BS2 8HW, UK.
authors.forename: Zexu
authors.initials: Z
authors.lastname: Dang
authors.affiliation: I.R.C.C.S. (Scientific Institute of Medical Research) MultiMedica, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Maselli
authors.affiliation: I.R.C.C.S. (Scientific Institute of Medical Research) MultiMedica, Milan, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Spinetti
authors.affiliation: I.R.C.C.S. (Scientific Institute of Medical Research) MultiMedica, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Sangalli
authors.affiliation: I.R.C.C.S. (Scientific Institute of Medical Research) MultiMedica, Milan, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Carnelli
authors.affiliation: I.R.C.C.S. (Scientific Institute of Medical Research) MultiMedica, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rosa
authors.affiliation: Department of Pathology, Santa Maria of Ca' Foncello Hospital, Treviso, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Seganfreddo
authors.affiliation: Department of Pathology, Santa Maria of Ca' Foncello Hospital, Treviso, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Canal
authors.affiliation: Department of Specialized Medicines, Hematology Unit, Santa Maria of Ca' Foncello Hospital, Treviso, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Furlan
authors.affiliation: Department of Specialized Medicines, Endocrine, Metabolic and Nutrition Diseases Unit, Santa Maria of Ca' Foncello Hospital, 1 Piazza Ospedale, 31100, Treviso, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Paccagnella
authors.affiliation: I.R.C.C.S. (Scientific Institute of Medical Research) MultiMedica, Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Paiola
authors.affiliation: Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lorusso
authors.affiliation: I.R.C.C.S. (Scientific Institute of Medical Research) MultiMedica, Milan, Italy.|Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Specchia
authors.affiliation: Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Albiero
authors.affiliation: Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cappellari
authors.affiliation: Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Avogaro
authors.affiliation: Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Falco
authors.affiliation: Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Quaini
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Street, Bristol, BS2 8HW, UK.
authors.forename: Kepeng
authors.initials: K
authors.lastname: Ou
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Street, Bristol, BS2 8HW, UK.
authors.forename: Iker
authors.initials: I
authors.lastname: Rodriguez-Arabaolaza
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Street, Bristol, BS2 8HW, UK.
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.affiliation: Department of Specialized Medicines, Endocrine, Metabolic and Nutrition Diseases Unit, Santa Maria of Ca' Foncello Hospital, 1 Piazza Ospedale, 31100, Treviso, Italy. msambataro@ulss.tv.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Sambataro
authors.affiliation: Department of Medicine, University of Padova, Padova, Italy.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Fadini
authors.affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Street, Bristol, BS2 8HW, UK. Paolo.Madeddu@bristol.ac.uk.
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000818:Animals; D003430:Cross-Sectional Studies; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D003929:Diabetic Neuropathies / Q000378:metabolism* / Q000473:pathology; D006412:Hematopoietic Stem Cells; D006801:Humans; D051379:Mice; D059225:Nociception / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000473:pathology; D013373:Substance P / Q000378:metabolism*
chemical_list: D013373:Substance P
keywords: Bone marrow; Diabetes mellitus; Nociception