SA/G hydrogel containing NRF2-engineered HEK-293-derived CM improves wound healing efficacy of WJ-MSCs in a rat model of excision injury.

AIM OF THE STUDY: Skin wounds are a major public health issue due to the lack of real effective remedies. Mesenchymal stem cells (MSCs) are considered as a promising therapeutic strategy for wound injuries; however, low survival rate following transplantation limited their application. In an attempt to introduce a novel potential wound dressing and improve wound healing properties, the current study was conducted. MATERIAL AND METHODS: we prepared conditioned medium (CM) harvested from HEK-293 cells overexpressing nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of antioxidant genes expression. Then, the CM was loaded in a biodegradable hydrogel. Next, in an animal model of full-thickness excision wound, wharton's jelly derived-mesenchymal stem cells (WJ-MSCs) were transplanted at the margins of the wound followed by application of the hydrogel on injury site. Finally, wound healing characteristics were evaluated by proper methods. RESULTS: Our findings revealed that, the NRF2-CM protected the WJ-MSCs against H2O2-induced toxicity in vitro. Furthermore, in vivo results showed that, SA/G hydrogel containing NRF2-CM significantly (P < 0.01) promoted WJ-MSCs survival, increased angiogenesis, accelerated wound contraction, and promoted wound healing compared to other groups. CONCLUSION: Though further preclinical and clinical studies regarding mechanisms behind the protection and also safety of the strategy are needed, our findings strongly suggest that the prepared wound dressing enhanced the efficacy of therapeutic potential of WJ-MSCs by providing an enriched/antioxidant niche support.

Conditioned medium harvested from Hif1α engineered mesenchymal stem cells ameliorates LAD-occlusion -induced injury in rat acute myocardial ischemia model.

Acute myocardial infarction (AMI) is the most common type of ischemic heart diseases with a high mortality rate. Although recent advances in medical cares and therapies have increased the patient's outcomes, but, still there is no real and effective therapeutic modality for AMI. Hence, development of novel therapeutic strategies is under focus of investigations. MSCs-based therapy has been proposed for AMI, though its efficacy is controversial yet. It is believed that MSCs exert their healing effects via secretion of growth factors/cytokines. However, these cells produce a very minute amount of the factors under normal cultivation. Here, in an attempt to improve the potential therapeutic effect of MSCs-derived conditioned medium (CM) on AMI, we transfected the cells with a recombinant plasmid encoding Hif1α-3A (a mutant form of Hif1α stable under normoxic condition), so Hif1α expression and secretion into CM (MSCs-Hif1α-CM) could be up-regulated under normoxic condition. The therapeutic potential of the MSCs-Hif1α-3A-CM was investigated in a rat model of AMI and compared to the CM harvested from non-manipulated MSCs. Our results showed that the MSCs-Hif1α-3A-CM mitigated MI-induced tissues injury, decreased fibrosis, reduced apoptosis, and limited infarct area size. These findings propose a potential therapeutic strategy for treatment of AMI. However, further preclinical and clinical investigations in this regard are still needed.

Transplantation of Umbilical Cord-Derived Mesenchymal Stem Cells Overexpressing Lipocalin 2 Ameliorates Ischemia-Induced Injury and Reduces Apoptotic Death in a Rat Acute Myocardial Infarction Model.

Myocardial infarction (MI) is a leading cause of death worldwide and requires development of efficient therapeutic strategies . Mesenchymal stem cells (MSCs) -based therapy of MI has been promising but inefficient due to undesirable microenvironment of the infarct tissue. Hence, the current study was conducted to fortify MSCs against the unfavorable microenvironment of infarct tissue via overexpression of Lipocalin 2 (Lcn2) as a cytoprotective factor. The engineered cells (Lcn2-MSCs) were transplanted to infarcted heart of a rat model of MI. According to our findings, Lcn2 overexpression resulted in increased MSCs survival in the MI tissue (p < 0.05) compared to non-engineered cells. Furthermore, the infusion of Lcn2-MSCs mitigated Left ventricle (LV) remodeling, decreased fibrosis (p < 0.0001), and reduced apoptotic death of the LVs' cells (p < 0.0001) compared to the control. Our findings suggest a potential novel therapeutic strategy for MI, however, further investigations such as safety and efficacy assessments in large animals followed by clinical trials are required.