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Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs.

Authors :
Huerta, Carlos Theodore
Ortiz, Yulexi Y.
Li, Yan
Ribieras, Antoine J.
Voza, Francesca
Le, Nga
Dodson, Caroline
Wang, Gaofeng
Vazquez-Padron, Roberto I.
Liu, Zhao-Jun
Velazquez, Omaida C.
Source :
Annals of Surgery; Sep2023, Vol. 278 Issue 3, p383-395, 13p
Publication Year :
2023

Abstract

Objective: Here, we report a new method to increase the therapeutic potential of mesenchymal stem/stromal cells (MSCs) for ischemic wound healing. We tested biological effects of MSCs modified with E-selectin, a cell adhesion molecule capable of inducing postnatal neovascularization, on a translational murine model. Background: Tissue loss significantly worsens the risk of extremity amputation for patients with chronic limb-threatening ischemia. MSC-based therapeutics hold major promise for wound healing and therapeutic angiogenesis, but unmodified MSCs demonstrate only modest benefits. Methods: Bone marrow cells harvested from FVB/ROSA26Sor<superscript>mTmG</superscript> donor mice were transduced with E-selectin-green fluorescent protein (GFP)/AAV-DJ or GFP/AAV-DJ (control). Ischemic wounds were created via a 4 mm punch biopsy in the ipsilateral limb after femoral artery ligation in recipient FVB mice and subsequently injected with phosphate-buffered saline or 1×10<superscript>6</superscript> donor MSC<superscript>GFP</superscript> or MSC<superscript>E-selectin-GFP</superscript>. Wound closure was monitored daily for 7 postoperative days, and tissues were harvested for molecular and histologic analysis and immunofluorescence. Whole-body DiI perfusion and confocal microscopy were utilized to evaluate wound angiogenesis. Results: Unmodified MSCs do not express E-selectin, and MSC<superscript>E-selectin-GFP</superscript> gain stronger MSC phenotype yet maintain trilineage differentiation and colony-forming capability. MSC<superscript>E-selectin-GFP</superscript> therapy accelerates wound healing compared with MSC<superscript>GFP</superscript> and phosphate-buffered saline treatment. Engrafted MSC<superscript>E-selectin-GFP</superscript> manifest stronger survival and viability in wounds at postoperative day 7. Ischemic wounds treated with MSC<superscript>E-selectin-GFP</superscript> exhibit more abundant collagen deposition and enhanced angiogenic response. Conclusions: We establish a novel method to potentiate regenerative and proangiogenic capability of MSCs by modification with E-selectin/adeno-associated virus. This innovative therapy carries the potential as a platform worthy of future clinical studies. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00034932
Volume :
278
Issue :
3
Database :
Supplemental Index
Journal :
Annals of Surgery
Publication Type :
Academic Journal
Accession number :
170751009
Full Text :
https://doi.org/10.1097/SLA.0000000000005949