Sensory neuropathy hampers nociception-mediated bone marrow stem cell release in mice and patients with diabetes

Zexu Dang, Davide Maselli, Gaia Spinetti, Elena Sangalli, Franco Carnelli, Francesco Rosa, Elena Seganfreddo, Fabio Canal, Anna Furlan, Agostino Paccagnella, Emanuela Paiola, Bruno Lorusso, Claudia Specchia, Mattia Albiero, Roberta Cappellari, Angelo Avogaro, Angela Falco, Federico Quaini, Kepeng Ou, Iker Rodriguez-Arabaolaza, Costanza Emanueli, Maria Sambataro, Gian Paolo Fadini, Paolo Madeddu
Diabetologia 2015, 58 (11): 2653-62

AIMS/HYPOTHESIS: 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/INTERPRETATION: Sensory neuropathy translates into defective liberation and homing of reparative HSPCs. Nociceptors may represent a new target for treatment of diabetic complications.

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