Limits...
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

Complicated diabetes inhibits CD34+ cell mobilisation induced by G-CSF. (a) Changes (mean ± SEM) in the PB levels of CD34+ cells in patients grouped according to the presence (DM) or absence (Ctrl) of diabetes and the presence (black bars) or absence (white bars) of pain after G-CSF stimulation. **p < 0.01, pain vs no pain; in non-diabetic individuals p = 0.07 for pain vs no pain. (b) Changes in the PB levels of CD34+ cells before and after G-CSF stimulation in patients grouped according to diabetes complications (white bar, no complications; light grey bar, neuropathy; dark grey bar neuroischaemia). **p < 0.01 and ****p < 0.0001, vs non-diabetic (black bar). (c) Changes in SP concentrations induced by G-CSF stimulation in diabetic (DM) patients and non-diabetic individuals (ND). *p < 0.05 ND vs DM. (d) Changes in SP concentrations induced by G-CSF stimulation in diabetic patients grouped according to complications (see [b] for key). *p < 0.05 and **p < 0.01, for indicated comparisons. (e) Changes in the levels of CD34+ cells after G-CSF stimulation in individuals showing stable or reduced SP levels vs those showing an increase in SP levels (*p < 0.05)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4589553&req=5

Fig7: Complicated diabetes inhibits CD34+ cell mobilisation induced by G-CSF. (a) Changes (mean ± SEM) in the PB levels of CD34+ cells in patients grouped according to the presence (DM) or absence (Ctrl) of diabetes and the presence (black bars) or absence (white bars) of pain after G-CSF stimulation. **p < 0.01, pain vs no pain; in non-diabetic individuals p = 0.07 for pain vs no pain. (b) Changes in the PB levels of CD34+ cells before and after G-CSF stimulation in patients grouped according to diabetes complications (white bar, no complications; light grey bar, neuropathy; dark grey bar neuroischaemia). **p < 0.01 and ****p < 0.0001, vs non-diabetic (black bar). (c) Changes in SP concentrations induced by G-CSF stimulation in diabetic (DM) patients and non-diabetic individuals (ND). *p < 0.05 ND vs DM. (d) Changes in SP concentrations induced by G-CSF stimulation in diabetic patients grouped according to complications (see [b] for key). *p < 0.05 and **p < 0.01, for indicated comparisons. (e) Changes in the levels of CD34+ cells after G-CSF stimulation in individuals showing stable or reduced SP levels vs those showing an increase in SP levels (*p < 0.05)

Mentions: We also re-analysed data from a trial of BM stimulation with human recombinant G-CSF in diabetic and non-diabetic individuals. Specifically, here we investigated the association of HSPC mobilisation and pain perception. In the whole cohort, the individuals who reported back or bone pain after G-CSF administration showed a significantly higher increase in PB CD34+ HSPCs than those reporting no pain (p < 0.01, Fig. 7a). Two-way ANOVA detected an inhibitory effect of diabetes (p < 0.0001) and an enhancing effect of pain (p < 0.01) on G-CSF-induced mobilisation, with no interaction between factors. Furthermore, in diabetic patients, mobilisation was completely abrogated in the absence of pain (Fig. 7a) and there was no incremental effect of vascular complications on mobilisation in comparison with diabetic patients without vascular disease (Fig. 7b). To determine whether depressed nociceptive signals may account for the reduced mobilisation of HSPCs in diabetic patients, we measured PB SP concentrations before and 24 h after G-CSF injection. Interestingly, G-CSF administration caused an increase in SP levels in non-diabetic individuals (p < 0.05), with this response being abrogated in diabetic patients (Fig. 7c). Additionally, in diabetic patients with neuropathy and vascular complications, G-CSF stimulation resulted in a decrease in PB SP levels (Fig. 7d, p < 0.01 vs non-diabetic individuals, p < 0.05 vs diabetes without complications). We also found an association between changes in SP concentrations and the degree of CD34+ HSPC mobilisation in response to G-CSF. In fact, CD34+ HSPC mobilisation was significantly higher in individuals showing an increase in SP concentrations compared with those showing unchanged or decreased SP levels (Fig. 7e, p < 0.05).Fig. 7


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)

Complicated diabetes inhibits CD34+ cell mobilisation induced by G-CSF. (a) Changes (mean ± SEM) in the PB levels of CD34+ cells in patients grouped according to the presence (DM) or absence (Ctrl) of diabetes and the presence (black bars) or absence (white bars) of pain after G-CSF stimulation. **p < 0.01, pain vs no pain; in non-diabetic individuals p = 0.07 for pain vs no pain. (b) Changes in the PB levels of CD34+ cells before and after G-CSF stimulation in patients grouped according to diabetes complications (white bar, no complications; light grey bar, neuropathy; dark grey bar neuroischaemia). **p < 0.01 and ****p < 0.0001, vs non-diabetic (black bar). (c) Changes in SP concentrations induced by G-CSF stimulation in diabetic (DM) patients and non-diabetic individuals (ND). *p < 0.05 ND vs DM. (d) Changes in SP concentrations induced by G-CSF stimulation in diabetic patients grouped according to complications (see [b] for key). *p < 0.05 and **p < 0.01, for indicated comparisons. (e) Changes in the levels of CD34+ cells after G-CSF stimulation in individuals showing stable or reduced SP levels vs those showing an increase in SP levels (*p < 0.05)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4589553&req=5

Fig7: Complicated diabetes inhibits CD34+ cell mobilisation induced by G-CSF. (a) Changes (mean ± SEM) in the PB levels of CD34+ cells in patients grouped according to the presence (DM) or absence (Ctrl) of diabetes and the presence (black bars) or absence (white bars) of pain after G-CSF stimulation. **p < 0.01, pain vs no pain; in non-diabetic individuals p = 0.07 for pain vs no pain. (b) Changes in the PB levels of CD34+ cells before and after G-CSF stimulation in patients grouped according to diabetes complications (white bar, no complications; light grey bar, neuropathy; dark grey bar neuroischaemia). **p < 0.01 and ****p < 0.0001, vs non-diabetic (black bar). (c) Changes in SP concentrations induced by G-CSF stimulation in diabetic (DM) patients and non-diabetic individuals (ND). *p < 0.05 ND vs DM. (d) Changes in SP concentrations induced by G-CSF stimulation in diabetic patients grouped according to complications (see [b] for key). *p < 0.05 and **p < 0.01, for indicated comparisons. (e) Changes in the levels of CD34+ cells after G-CSF stimulation in individuals showing stable or reduced SP levels vs those showing an increase in SP levels (*p < 0.05)
Mentions: We also re-analysed data from a trial of BM stimulation with human recombinant G-CSF in diabetic and non-diabetic individuals. Specifically, here we investigated the association of HSPC mobilisation and pain perception. In the whole cohort, the individuals who reported back or bone pain after G-CSF administration showed a significantly higher increase in PB CD34+ HSPCs than those reporting no pain (p < 0.01, Fig. 7a). Two-way ANOVA detected an inhibitory effect of diabetes (p < 0.0001) and an enhancing effect of pain (p < 0.01) on G-CSF-induced mobilisation, with no interaction between factors. Furthermore, in diabetic patients, mobilisation was completely abrogated in the absence of pain (Fig. 7a) and there was no incremental effect of vascular complications on mobilisation in comparison with diabetic patients without vascular disease (Fig. 7b). To determine whether depressed nociceptive signals may account for the reduced mobilisation of HSPCs in diabetic patients, we measured PB SP concentrations before and 24 h after G-CSF injection. Interestingly, G-CSF administration caused an increase in SP levels in non-diabetic individuals (p < 0.05), with this response being abrogated in diabetic patients (Fig. 7c). Additionally, in diabetic patients with neuropathy and vascular complications, G-CSF stimulation resulted in a decrease in PB SP levels (Fig. 7d, p < 0.01 vs non-diabetic individuals, p < 0.05 vs diabetes without complications). We also found an association between changes in SP concentrations and the degree of CD34+ HSPC mobilisation in response to G-CSF. In fact, CD34+ HSPC mobilisation was significantly higher in individuals showing an increase in SP concentrations compared with those showing unchanged or decreased SP levels (Fig. 7e, p < 0.05).Fig. 7

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