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

Dang Z, Maselli D, Spinetti G, Sangalli E, Carnelli F, Rosa F, Seganfreddo E, Canal F, Furlan A, Paccagnella A, Paiola E, Lorusso B, Specchia C, Albiero M, Cappellari R, Avogaro A, Falco A, Quaini F, Ou K, Rodriguez-Arabaolaza I, Emanueli C, Sambataro M, Fadini GP, Madeddu P - Diabetologia (2015)

Bottom Line: 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.Nociceptors may represent a new target for treatment of diabetic complications.

View Article: PubMed Central - PubMed

Affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Street, Bristol, BS2 8HW, UK.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

CD34+ cell mobilisation induced by G-CSF administration correlates with pain score in non-diabetic individuals. (a) Changes (mean ± SEM) in PB CD34+ cells of individuals given placebo (white bar, n = 10) or given G-CSF and classified as reporting no/mild bone/back pain (light grey bar, n = 15) or moderate/severe pain (dark grey bar, n = 15); *p < 0.05 for indicated comparison. (b) A pain score was computed as described in the Methods section and plotted; *p < 0.05 for indicated comparison. (c) Linear correlation between the pain score and the degree of CD34+ cell mobilisation in individuals who received G-CSF (r = 0.36; p = 0.016); dashed lines represent the 95% CI and dotted line shows the grid line at y = 0
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Fig6: CD34+ cell mobilisation induced by G-CSF administration correlates with pain score in non-diabetic individuals. (a) Changes (mean ± SEM) in PB CD34+ cells of individuals given placebo (white bar, n = 10) or given G-CSF and classified as reporting no/mild bone/back pain (light grey bar, n = 15) or moderate/severe pain (dark grey bar, n = 15); *p < 0.05 for indicated comparison. (b) A pain score was computed as described in the Methods section and plotted; *p < 0.05 for indicated comparison. (c) Linear correlation between the pain score and the degree of CD34+ cell mobilisation in individuals who received G-CSF (r = 0.36; p = 0.016); dashed lines represent the 95% CI and dotted line shows the grid line at y = 0

Mentions: A cohort of healthy volunteers received placebo or recombinant human G-CSF. Those receiving G-CSF were grouped according to the level of pain (graded as pain score) induced by the growth factor. Interestingly, individuals who experienced moderate to severe bone or back pain showed a significantly greater increase in PB CD34+ HSPC counts than those who reported no pain or mild pain (Fig. 6a, b). There was a significant direct correlation between the pain score and the increase in the number of CD34+ HSPCs induced by G-CSF (r = 0.36, p < 0.02; Fig. 6c).Fig. 6


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

Dang Z, Maselli D, Spinetti G, Sangalli E, Carnelli F, Rosa F, Seganfreddo E, Canal F, Furlan A, Paccagnella A, Paiola E, Lorusso B, Specchia C, Albiero M, Cappellari R, Avogaro A, Falco A, Quaini F, Ou K, Rodriguez-Arabaolaza I, Emanueli C, Sambataro M, Fadini GP, Madeddu P - Diabetologia (2015)

CD34+ cell mobilisation induced by G-CSF administration correlates with pain score in non-diabetic individuals. (a) Changes (mean ± SEM) in PB CD34+ cells of individuals given placebo (white bar, n = 10) or given G-CSF and classified as reporting no/mild bone/back pain (light grey bar, n = 15) or moderate/severe pain (dark grey bar, n = 15); *p < 0.05 for indicated comparison. (b) A pain score was computed as described in the Methods section and plotted; *p < 0.05 for indicated comparison. (c) Linear correlation between the pain score and the degree of CD34+ cell mobilisation in individuals who received G-CSF (r = 0.36; p = 0.016); dashed lines represent the 95% CI and dotted line shows the grid line at y = 0
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Related In: Results  -  Collection

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Fig6: CD34+ cell mobilisation induced by G-CSF administration correlates with pain score in non-diabetic individuals. (a) Changes (mean ± SEM) in PB CD34+ cells of individuals given placebo (white bar, n = 10) or given G-CSF and classified as reporting no/mild bone/back pain (light grey bar, n = 15) or moderate/severe pain (dark grey bar, n = 15); *p < 0.05 for indicated comparison. (b) A pain score was computed as described in the Methods section and plotted; *p < 0.05 for indicated comparison. (c) Linear correlation between the pain score and the degree of CD34+ cell mobilisation in individuals who received G-CSF (r = 0.36; p = 0.016); dashed lines represent the 95% CI and dotted line shows the grid line at y = 0
Mentions: A cohort of healthy volunteers received placebo or recombinant human G-CSF. Those receiving G-CSF were grouped according to the level of pain (graded as pain score) induced by the growth factor. Interestingly, individuals who experienced moderate to severe bone or back pain showed a significantly greater increase in PB CD34+ HSPC counts than those who reported no pain or mild pain (Fig. 6a, b). There was a significant direct correlation between the pain score and the increase in the number of CD34+ HSPCs induced by G-CSF (r = 0.36, p < 0.02; Fig. 6c).Fig. 6

Bottom Line: 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.Nociceptors may represent a new target for treatment of diabetic complications.

View Article: PubMed Central - PubMed

Affiliation: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Upper Maudlin Street, Bristol, BS2 8HW, UK.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus