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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

Impairment of the nociceptive mechanism is associated with reduced liberation and homing of stem cells in diabetic mice submitted to unilateral LI. (a–h) Flow cytometry analyses showing the abundance of LSK and LSK-NK1R cells in the BM (a–d) and PB (e–h) of diabetic (white bars) and non-diabetic (black bars) mice, before and after induction of unilateral LI. Data expressed as percentage of mononuclear cells (MNCs) *p < 0.05, **p < 0.01 and ***p < 0.001 vs time 0; ††p < 0.01 and †††p < 0.001 vs non-diabetic control; n = 5 per group. (i–l) Flow cytometry analyses showing the abundance of LSK (i, j) and LSK-NK1R (k, l) cells in ischaemic and contralateral limb muscles of non-diabetic (black boxes) and diabetic (white boxes) mice at 3 days post-LI compared with pre-LI. ***p < 0.001 vs pre-LI; ††p < 0.01 vs non-diabetic control; ‡‡p < 0.01 vs contralateral; n = 5 per group. The gating strategy is shown in (i) and (k). (m–o) Levels of SP in the BM (m), PB (n) and ischaemic muscles (o) of non-diabetic (black boxes) and diabetic (white boxes) mice before and after induction of LI. *p < 0.05, **p < 0.01 and ***p < 0.001 vs pre-LI; †p < 0.05, ††p < 0.01 and †††p < 0.001 vs non-diabetic control; n = 5 per group
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Fig5: Impairment of the nociceptive mechanism is associated with reduced liberation and homing of stem cells in diabetic mice submitted to unilateral LI. (a–h) Flow cytometry analyses showing the abundance of LSK and LSK-NK1R cells in the BM (a–d) and PB (e–h) of diabetic (white bars) and non-diabetic (black bars) mice, before and after induction of unilateral LI. Data expressed as percentage of mononuclear cells (MNCs) *p < 0.05, **p < 0.01 and ***p < 0.001 vs time 0; ††p < 0.01 and †††p < 0.001 vs non-diabetic control; n = 5 per group. (i–l) Flow cytometry analyses showing the abundance of LSK (i, j) and LSK-NK1R (k, l) cells in ischaemic and contralateral limb muscles of non-diabetic (black boxes) and diabetic (white boxes) mice at 3 days post-LI compared with pre-LI. ***p < 0.001 vs pre-LI; ††p < 0.01 vs non-diabetic control; ‡‡p < 0.01 vs contralateral; n = 5 per group. The gating strategy is shown in (i) and (k). (m–o) Levels of SP in the BM (m), PB (n) and ischaemic muscles (o) of non-diabetic (black boxes) and diabetic (white boxes) mice before and after induction of LI. *p < 0.05, **p < 0.01 and ***p < 0.001 vs pre-LI; †p < 0.05, ††p < 0.01 and †††p < 0.001 vs non-diabetic control; n = 5 per group

Mentions: Remarkable differences were observed in the tissue redistribution of HSPC populations following LI in non-diabetic mice compared with diabetic mice. In both groups, LI caused an initial expansion of LSK-HSPCs in the BM, and this was followed by a return to basal levels at 3–7 days post-LI and then a second peak at 14 days (Fig. 5a, b). The subpopulation of LSK-NK1R-HSPCs was reduced in the BM of non-diabetic mice during the acute phase of LI, returning to basal levels by day 7. In contrast, no change was observed in diabetic mice before and after LI (Fig. 5c, d). When looking at cellular changes in PB, we observed a striking increase in LSK-HSPCs and LSK-NK1R-HSPCs from day 1 to day 14 post-LI in non-diabetic mice, with this response being remarkably attenuated and delayed in diabetic mice (Fig. 5e–h, p < 0.01 vs non-diabetic mice). Additionally, the diabetic mice manifested a reduction in the homing of LSK-HSPCs and LSK-NK1R-HSPCs at the level of the ischaemic limb muscle, whereas no difference between groups was seen in the contralateral muscle (Fig. 5i–l, p < 0.01 vs non-diabetic mice).Fig. 5


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)

Impairment of the nociceptive mechanism is associated with reduced liberation and homing of stem cells in diabetic mice submitted to unilateral LI. (a–h) Flow cytometry analyses showing the abundance of LSK and LSK-NK1R cells in the BM (a–d) and PB (e–h) of diabetic (white bars) and non-diabetic (black bars) mice, before and after induction of unilateral LI. Data expressed as percentage of mononuclear cells (MNCs) *p < 0.05, **p < 0.01 and ***p < 0.001 vs time 0; ††p < 0.01 and †††p < 0.001 vs non-diabetic control; n = 5 per group. (i–l) Flow cytometry analyses showing the abundance of LSK (i, j) and LSK-NK1R (k, l) cells in ischaemic and contralateral limb muscles of non-diabetic (black boxes) and diabetic (white boxes) mice at 3 days post-LI compared with pre-LI. ***p < 0.001 vs pre-LI; ††p < 0.01 vs non-diabetic control; ‡‡p < 0.01 vs contralateral; n = 5 per group. The gating strategy is shown in (i) and (k). (m–o) Levels of SP in the BM (m), PB (n) and ischaemic muscles (o) of non-diabetic (black boxes) and diabetic (white boxes) mice before and after induction of LI. *p < 0.05, **p < 0.01 and ***p < 0.001 vs pre-LI; †p < 0.05, ††p < 0.01 and †††p < 0.001 vs non-diabetic control; n = 5 per group
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Fig5: Impairment of the nociceptive mechanism is associated with reduced liberation and homing of stem cells in diabetic mice submitted to unilateral LI. (a–h) Flow cytometry analyses showing the abundance of LSK and LSK-NK1R cells in the BM (a–d) and PB (e–h) of diabetic (white bars) and non-diabetic (black bars) mice, before and after induction of unilateral LI. Data expressed as percentage of mononuclear cells (MNCs) *p < 0.05, **p < 0.01 and ***p < 0.001 vs time 0; ††p < 0.01 and †††p < 0.001 vs non-diabetic control; n = 5 per group. (i–l) Flow cytometry analyses showing the abundance of LSK (i, j) and LSK-NK1R (k, l) cells in ischaemic and contralateral limb muscles of non-diabetic (black boxes) and diabetic (white boxes) mice at 3 days post-LI compared with pre-LI. ***p < 0.001 vs pre-LI; ††p < 0.01 vs non-diabetic control; ‡‡p < 0.01 vs contralateral; n = 5 per group. The gating strategy is shown in (i) and (k). (m–o) Levels of SP in the BM (m), PB (n) and ischaemic muscles (o) of non-diabetic (black boxes) and diabetic (white boxes) mice before and after induction of LI. *p < 0.05, **p < 0.01 and ***p < 0.001 vs pre-LI; †p < 0.05, ††p < 0.01 and †††p < 0.001 vs non-diabetic control; n = 5 per group
Mentions: Remarkable differences were observed in the tissue redistribution of HSPC populations following LI in non-diabetic mice compared with diabetic mice. In both groups, LI caused an initial expansion of LSK-HSPCs in the BM, and this was followed by a return to basal levels at 3–7 days post-LI and then a second peak at 14 days (Fig. 5a, b). The subpopulation of LSK-NK1R-HSPCs was reduced in the BM of non-diabetic mice during the acute phase of LI, returning to basal levels by day 7. In contrast, no change was observed in diabetic mice before and after LI (Fig. 5c, d). When looking at cellular changes in PB, we observed a striking increase in LSK-HSPCs and LSK-NK1R-HSPCs from day 1 to day 14 post-LI in non-diabetic mice, with this response being remarkably attenuated and delayed in diabetic mice (Fig. 5e–h, p < 0.01 vs non-diabetic mice). Additionally, the diabetic mice manifested a reduction in the homing of LSK-HSPCs and LSK-NK1R-HSPCs at the level of the ischaemic limb muscle, whereas no difference between groups was seen in the contralateral muscle (Fig. 5i–l, p < 0.01 vs non-diabetic mice).Fig. 5

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