Amniotic Epithelial Cells Accelerate Diabetic Wound Healing by Modulating Inflammation and Promoting Neovascularization

Abstract

Human amniotic epithelial cells (hAECs) are nontumorigenic, highly abundant, and low immunogenic and possess multipotent differentiation ability, which make them become ideal alternative stem cell source for regenerative medicine. Previous studies have demonstrated the therapeutic potential of hAECs in many tissue repairs. However, the therapeutic effect of hAECs on diabetic wound healing is still unknown. In this study, we injected hAECs intradermally around the full-thickness excisional skin wounds of db/db mice and found that hAECs significantly accelerated diabetic wound healing and granulation tissue formation. To explore the underlying mechanisms, we measured inflammation and neovascularization in diabetic wounds. hAECs could modulate macrophage phenotype toward M2 macrophage, promote switch from proinflammatory status to prohealing status of wounds, and increase capillary density in diabetic wounds. Furthermore, we found that the hAEC-conditioned medium promoted macrophage polarization toward M2 phenotype and facilitated migration, proliferation, and tube formation of endothelial cells through in vitro experiments. Taken together, we first reported that hAECs could promote diabetic wound healing, at least partially, through paracrine effects to regulate inflammation and promote neovascularization.

Potential Mechanism of Dermal Wound Treatment With Preparations From the Skin Gel of Arabian Gulf Catfish: A Unique Furan Fatty Acid (F6) and Cholesta-3,5-Diene (S5) Recruit Neutrophils and Fibroblasts to Promote Wound Healing

“…By contrast, treating wounds with FB promotes acceleration of wound healing with the deposition of increased amounts of collagen and fibronectin, and increased numbers of fibroblasts, macrophages and large capillaries. These are typical features of late stages of wound healing (Raekallio and Viljanto, 1983;Pettet et al, 1996;Templin et al, 2009;Suhaeri et al, 2018;Zheng et al, 2018;Opneja et al, 2019). These in vivo wound healing data suggested the presence of healing stimulatory component(s) in the FB preparations, as we have described previously in other wound healing models (Al-Hassan and Criddle, 1982;Al-Hassan et al, 1983;Al-Hassan JM et al, 1985;Al-Hassan et al, 1986;Al-Hassan et al, 1987;Al-Hassan et al, 1991).…”

“…Our recent study showed that pure F6 effectively induces neutrophil extracellular trap (NET) formation in human neutrophils (Khan et al, 2018). NETs promote recruitment of neutrophils (Pettet et al, 1996;Templin et al, 2009;Zheng et al, 2018). Although detection of NET formation in zebrafish has not been clearly established, increased local NET formation in the presence of F6 could lead to increased neutrophil recruitment to wound sites.…”

“…These lipids (Ft, F6, and S5) may play essential roles in wound healing processes together with the other components identified in PCEGS such as the hemagglutinating factor (Al-Lahham et al, 1987;Al-Hassan et al, 1991), the hemolytic factor, the platelet aggregating factors with their platelet derived growth factors (Al-Hassan, 1990;Lam et al, 2015;Rodrigues et al, 2019;Opneja et al, 2019), and the vasoactive components (Suhaeri et al, 2018;Paganelli et al, 2020). It can be envisaged that the total aggregate effects of all these active components are unique and may act in synergism to accelerate wound and diabetic ulcer healing processes (Al-Hassan, 1990;Zheng et al, 2018). The current study paves the way for making potent therapeutic formulations with minimal number of stable active ingredients for wound healing (Gomes et al, 2017;Tan et al, 2019)or wound dressing applications (Zhao et al, 2017;Qu et al, 2018;.…”

Evaluation of different routes of administration and biodistribution of human amnion epithelial cells in mice

“…It has been reported, that when a patient with type I Diabetes mellitus was treated with amniotic cells, the patient remained independent of insulin intake for 6.2 months and later, insulin requirements were readjusted to 8 IU/day post-transplantation compared to 38 IU/day, pre-transplant (73). It was also reported, that hAEC have the potential for wound healing (74), and the correction of heart disease (75), stroke (76) multiple sclerosis (40) and many other diseases (Figure 9).…”

Human Amniotic Epithelial Stem Cells: A Promising Seed Cell for Clinical Applications

“…Based on their plasticity and immunomodulatory properties, hAESCs have been considered for treatment of a broad variety of conditions, including lung fibrosis [ 40 , 115 , 131 , 149 , 151 , 152 , 153 , 154 ], spinal cord injuries [ 60 ], Parkinson’s disease [ 64 ], Alzheimer’s disease [ 155 ], diabetes [ 69 ], wound healing [ 147 , 148 , 156 ], liver fibrosis [ 75 , 157 , 158 , 159 ], autoimmune uveitis [ 135 ], Hashimoto’s thyroiditis and systemic lupus erythematosus [ 134 ], and intrauterine adhesions [ 160 , 161 , 162 ]. Among these preclinical trials involving hAESCs, autoimmune diseases make up a large proportion, presumably because of the tremendous effect of immunomodulation.…”