Delayed wound healing is
commonly associated with diabetes. It may lead to amputation and death if not
treated timely. Limited treatments are available partially due to the poor understanding
of the complex disease pathophysiology. Here, we investigated the role of
Leucine-rich alpha-2-glycoprotein1 (LRG1) in normal and diabetic wound healing.
Firstly, our data showed that LRG1 was significantly increased at the
inflammation stage of murine wound healing, and bone marrow-derived cells served
as a major source of LRG1. LRG1 deletion causes impaired immune cell
infiltration, re-epithelialization and angiogenesis. As a consequence, there is
a significant delay in wound closure. On the other hand, LRG1 was markedly
induced in diabetic wounds in both humans and mice. LRG1-deficient mice were
resistant to diabetes-induced delay in wound repair. We further demonstrated
that this could be explained by the mitigation of increased neutrophil
extracellular traps (NETs) in diabetic wounds. Mechanistically, LRG1 mediates
NETosis in an Akt-dependent manner through TGF-beta type I receptor kinase ALK5.
Taken together, our studies demonstrated that LRG1 derived from bone marrow
cells is required for normal wound healing, revealing a physiological role for
this glycoprotein, but that excess LRG1 expression in diabetes is pathogenic
and contributes to chronic wound formation.
The Role of a Combination of Autogenous Fresh Bone Marrow and Omental Free Graft in the Cervical Esophageal Wound Healing in Dogs