Endothelial βII Spectrin Deletion Exacerbates Inflammation and Impairs Tissue Regeneration in Ischemic-Diabetic Skin Wound Healing

Authors

Ruchi Gupta, Department of Surgery, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Paula O. Cooper, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Weidong Chai, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Pritham Mulagura, Department of Surgery, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Sean M. Lee, Office of Clinical Research, The George Washington University, Washington, DC, USA.
Georgios Theocharidis, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Anton N. Sidawy, Department of Surgery, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Brett A. Shook, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Bao-Ngoc Nguyen, Department of Surgery, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.

Document Type

Journal Article

Publication Date

1-1-2025

Journal

Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society

Volume

33

Issue

6

DOI

10.1111/wrr.70103

Keywords

SPTBN1; TGFβ‐SMAD signalling; angiogenesis; endothelial cells; inflammation; ischemic‐diabetic wound healing; myeloid cells; βII spectrin

Abstract

Impaired lower extremity wound healing due to diabetes presents a significant societal burden, as 25% of diabetic wounds lead to major amputations. While TGF-β has been extensively studied in diabetic wound healing, the role of βII spectrin (SPTBN1), a known adapter of SMAD3 in the canonical TGF-β signalling pathway, remains unexplored. Single-cell RNA sequencing analysis revealed an increase in SPTBN1 expression in endothelial cells from non-diabetic skin to diabetic skin and ulcers. We found that silencing SPTBN1 in human umbilical vein endothelial cells (HUVECs) suppressed endothelial sprouting and tube formation. Based on these findings, we hypothesised that SPTBN1 regulates diabetic wound healing by modulating angiogenesis. To test this, we created Sptbn1 endothelial-specific conditional knockout (Sptbn1) mice and used the well-established streptozocin-induced diabetic excisional dorsal wound model. Interestingly, while Sptbn1 mice showed delayed wound healing, the delay was not due to impaired angiogenesis, but rather due to excessive inflammation. Inflammation persisted in Sptbn1 mice when it resolved in controls, as evidenced by higher numbers of neutrophils, inflammatory monocytes and greater iNOS staining intensity in the wound beds. Additionally, Sptbn1 wounds had significantly less granulation tissue and fewer fibroblasts in the regenerative phase. Collectively, these findings suggest that βII spectrin in endothelial cells is a potential therapeutic target in chronic diabetic wound healing.

APA Citation

Gupta, Ruchi; Cooper, Paula O.; Chai, Weidong; Mulagura, Pritham; Lee, Sean M.; Theocharidis, Georgios; Sidawy, Anton N.; Shook, Brett A.; and Nguyen, Bao-Ngoc, "Endothelial βII Spectrin Deletion Exacerbates Inflammation and Impairs Tissue Regeneration in Ischemic-Diabetic Skin Wound Healing" (2025). GW Authored Works. Paper 8179.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8179

Department

Surgery