Loss of Innervation and Axon Plasticity Accompanies Impaired Diabetic Wound Healing

Abstract

Loss of cutaneous innervation from sensory neuropathy is included among mechanisms for impaired healing of diabetic skin wounds. The relationships between cutaneous axons and their local microenvironment during wound healing are challenged in diabetes. Here, we show that secondary wound closure of the hairy dorsal skin of mice is delayed by diabetes and is associated with not only a pre-existing loss of cutaneous axons but substantial retraction of axons around the wound. At 7d following a 3mm punch wound, a critical period of healing and reinnervation, both intact skin nearby the wound and skin directly at the wound margins had over 30-50% fewer axons and a larger deficit of ingrowing axons in diabetics. These findings contrasted with a pre-existing 10-15% deficit in axons. Moreover, new diabetic ingrowing axons had less evidence of plasticity. Unexpectedly, hair follicles adjacent to the wounds had a 70% reduction in their innervation associated with depleted expression of hair follicular stem cell markers. These impairments were associated with the local upregulation of two established axon regenerative ‘roadblocks’: PTEN and RHOA, potential but thus far unexplored mediators of these changes. The overall findings identify striking and unexpected superimposed cutaneous axon loss or retraction beyond that expected of diabetic neuropathy alone, associated with experimental diabetic skin wounding, a finding that prompts new considerations in diabetic wounds.

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

“…S13). This result is consistent with the inability of diabetic mice to regenerate neurons fully (29)(30)(31). There were no significant differences in the vascular density among the groups at day 21 (SI Appendix, Fig.…”

“…S13), it is important to emphasize that robust and full hair regrowth and reinnervation in the wounds of diabetic animals is generally not reported (61,(75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85). The inability of these animals to regenerate nerves fully has also been recognized (29)(30)(31). This failure is in contrast to woundhealing studies in healthy animals, such as burn injury models, that reported hair regrowth (72) and signs of reinnervation as judged by the presence of PgP9.5 in the wound (78).…”

The Role of Neuromediators and Innervation in Cutaneous Wound Healing

“…Animal studies have shown that diabetic mice have slower wound healing compared with controls and have delayed inflammatory cell migration (98). Neuropathy itself hinders the rate of cutaneous nerve regeneration (99) and Cheng et al (100) showed that diabetic mice lack the capabilities to regenerate nerves. Neuropeptide expression and functions are affected in diabetes.…”

PKCδ inhibition normalizes the wound-healing capacity of diabetic human fibroblasts

“…The systemic changes characteristic of diabetes progression, including hyperglycemia (6,7), insulin resistance (8), obesity (9,10), and subsequent microvascular (11)(12)(13)(14) or macrovascular complications (15), as well as localized factors, have been associated with an increased risk of diabetic foot ulcers. Multiple treatment modalities using cytokine replacement (16) and transplantation of keratinocytes or fibroblasts are effective in nondiabetic populations (17)(18)(19), but their efficacy in patients with diabetes is diminished as a result of undetermined mechanisms (17).…”