Cason Dudney

Background:  Burn wounds represent a significant clinical challenge due to their complexity, high morbidity, and long-term disability. Traditional therapies often fall short in addressing the extensive tissue loss and impaired healing in severe burns. Recent advances in regenerative medicine have highlighted the potential of stem cell-based therapies in promoting skin repair, with a particular focus on the PI3K/AKT signaling pathway, which plays a central role in cell survival, angiogenesis, proliferation, and immune modulation. Additionally, the integration of stem cells with hydrogel-based delivery systems is transforming therapeutic approaches by improving cellular retention and targeted healing effects. This review explores the translational potential of these combined strategies in advancing burn wound care.

Objective:  To evaluate the efficacy and mechanisms of stem cell therapies, particularly those activating the PI3K/AKT pathway, in enhancing skin regeneration after burn injuries, and to examine the role of hydrogel-based technologies in optimizing therapeutic delivery and outcomes.

Search Methods:   A literature search was conducted using PubMed from 2017 to the current date. Search terms included the terms and keywords: “burn wounds,” “stem cell therapy,” “PI3K/AKT pathway,” “skin regeneration,” “hydrogel wound dressing,” and “wound healing signaling.” Articles selected included in vitro, in vivo, and translational studies focusing on stem cell mechanisms in burn wound repair.

Results:  Li et al demonstrated that human amniotic mesenchymal stem cells (hAMSCs) significantly enhanced re-epithelialization in thermally injured skin by inhibiting apoptosis and promoting proliferation via the PI3K/AKT signaling cascade.¹ Shi et al found that exosomes from human amniotic epithelial cells activated PI3K-AKT-mTOR signaling to stimulate angiogenesis and fibroblast function in diabetic wounds.² Similarly, HGF released from cancer-associated fibroblasts promoted vascularization through PI3K/AKT and ERK1/2 activation, emphasizing the pathway’s angiogenic potential.³ Zhang et al provided evidence of crosstalk between PI3K/AKT and Wnt/β-catenin signaling in tissue regeneration, suggesting a synergistic mechanism in stem cell-mediated repair.⁴ Lastly, Hsu et al introduced a hydrogel wound dressing embedded with adipose-derived stem cells that enhanced wound healing and maintained AKT activation, providing a viable platform for targeted stem cell therapy.⁵

Conclusion:  Stem cell-based therapies, particularly those leveraging PI3K/AKT signaling, hold great promise in advancing the healing of complex burn wounds. These therapies promote critical regenerative processes such as anti-apoptosis, angiogenesis, cell proliferation, and immune regulation. The incorporation of hydrogel technologies further enhances their therapeutic value by facilitating localized delivery and sustained cellular activity. Together, these approaches represent a significant step forward in the translation of molecular and cellular insights into clinically effective burn wound treatments.  Continued research is needed to standardize stem cell sources, optimize delivery methods, and assess long-term safety and efficacy in human trials. Future directions should explore the combinatorial use of biomaterials, gene editing, and signaling modulation to create highly personalized and effective therapies for burn patients.

Works Cited

1. Li JY, Ren KK, Zhang WJ, et al. Human amniotic mesenchymal stem cells and their paracrine factors promote wound healing by inhibiting heat stress-induced skin cell apoptosis and enhancing their proliferation through activating PI3K/AKT signaling pathway. Stem Cell Res Ther. 2019;10(1):247. doi:10.1186/s13287-019-1366-y
2. Shi Q, Qian Z, Liu D, et al. Exosomes derived from human amniotic epithelial cells accelerate diabetic wound healing via PI3K-AKT-mTOR-mediated promotion in angiogenesis and fibroblast function. Burns Trauma. 2020;8:tkaa020. doi:10.1093/burnst/tkaa020
3. Wang Y, Liu S, Fu Y, Wang H, Li Y, Yan M. HGF derived from cancer-associated fibroblasts promotes vascularization in gastric cancer via PI3K/AKT and ERK1/2 signaling. Oncol Rep. 2018;40(2):1045-1053. doi:10.3892/or.2018.6500
4. Zhang X, Liu L, Liu Y, et al. The PI3K/AKT pathway promotes fracture healing through its crosstalk with Wnt/β-catenin. Exp Cell Res. 2020;396(2):112137. doi:10.1016/j.yexcr.2020.112137
5. Hsu LC, Peng BY, Chen MS, et al. The potential of the stem cells composite hydrogel wound dressings for promoting wound healing and skin regeneration: In vitro and in vivo evaluation. J Biomed Mater Res B Appl Biomater. 2019;107(2):278-285. doi:10.1002/jbm.b.34118