Dual CXCR4/IL-10 Gene-Edited Human Amniotic Mesenchymal Stem Cells Exhibit Robust Therapeutic Properties in Chronic Wound Healing

Abstract

Although stem cells have attracted attention as a novel therapeutic solution for tissue regeneration, their minimal efficacy remains controversial. In the present study, we aimed to investigate the enhanced therapeutic property of CXCR4/IL-10 dual angiogenic/anti-inflammatory gene knock-in amniotic mesenchymal stem cells (AMM) in a wound-healing model. Dual CXCR4 and IL-10 genes were inserted into the AMM genome using transcription-activator-like effector nuclease (TALEN). Matrigel tube formation and anti-inflammatory effects were assessed in vitro, and efficacy was tested in vivo in a diabetic wound-healing model. CXCR4/IL-10-expressing amniotic MSCs (AMM/CI) strongly expressed CXCR4 and IL-10 genes and robustly promoted tube formation and anti-inflammatory potential. AMM/CI transplantation resulted in accelerated wound healing, as well as high engraftment and re-epithelialization potential. Transplanted AMM/CI also exhibited high angiogenic and decreased pro-inflammatory gene expression in the wound tissue, indicating direct therapeutic effects on wound healing. Taken together, these data indicate that dual angiogenic/anti-inflammatory gene knock-in may be a novel approach to enhance the therapeutic effects of stem cells, and transplantation of AMM/CI can be an alternative therapeutic option in chronic wound healing.

Bioengineered MSCCxcr2 transdifferentiated keratinocyte-like cell-derived organoid potentiates skin regeneration through ERK1/2 and STAT3 signaling in diabetic wound

“…Our previous study reported an enhanced migration of the intravenously transplanted Cxcr6 bioengineered MSCs in response to the increased level of its cognate ligand CXCL16 at the wound area [ 16 ]. The overexpression of Cxcr4 , a potent angiogenic factor, also enhanced the migration of MSCs and angiogenesis at the injury site via its cognate ligand CXCL12 [ 29 ]. Similarly, CCR2 overexpressed MSCs exhibited increased homing toward the injury site in response to the increased level of CCL2 in diabetic db/db mice wounds [ 10 ].…”

Therapeutic gene delivery by mesenchymal stem cell for brain ischemia damage: Focus on molecular mechanisms in ischemic stroke

“…Overexpressing pro‐survival, proangiogenic, or antiapoptotic genes, such as protein kinase B (Akt1), adrenomedullin, B‐cell lymphoma‐2 (Bcl‐2), and heme oxygenase‐1 (HO‐1), has significantly increased the survival of MSC in vivo 126–128 . Viral alteration has also enhanced MSC migration to areas of damage, inflammation, and malignancy by overexpressing homing receptors such C‐C chemokine receptor type‐1 (CCR‐1) 129,130 and chemokine (C‐X‐C motif) receptor 4 (CXCR4) 131,132 . In the myocardium's injured infarct area, more MSC than normal MSC overexpress CXCR4 home.…”

Effect of amniotic membrane/collagen scaffolds on laryngeal cartilage repair

“…Investigations have shown that cells release some growth factors 15,16 and cytokines, 17,18 such as epithelial growth factor, fibroblast growth factor, transforming growth factor, keratinocyte growth factor, IL‐6, and IL‐10. These mediators promote cellular proliferation, migration, and differentiation and reduce tissue inflammation and infection 19,20 …”

“…These mediators promote cellular proliferation, migration, and differentiation and reduce tissue inflammation and infection. 19 , 20 …”

“…These mediators promote cellular proliferation, migration, and differentiation and reduce tissue inflammation and infection. 19,20 In this study, we investigated the efficacy of collagen-based scaffolds enveloped by amniotic membrane (AM/C) on regeneration of cartilaginous laryngeal defects in an experimental model in rabbits.…”