慢性创面不但影响患者生活质量，也给社会带来了沉重负担。创面修复是一个复杂过程涉及多种成分共同参与，因此如何引导创面内各细胞组分的可塑性，形成结构和功能兼备的组织替代物是慢性创面修复研究面临的难题之一。本项目基于我们前期关于神经-分泌通过调控表皮角质细胞（HEK）发生EMT样改变促进创面愈合、并调控HEK可塑性的工作基础，以β2-AR/PKA/STAT3为介入点，在研究β2-AR通路诱导HEK表型变化及命运转归相关分子机制的同时，构建纳米组装控释系统实现药物的靶向投递，客观地评价β2-AR通路在促进创面愈合及修复质量过程中的作用。在此基础上通过β2-AR通路干预HEK的可塑性使其获得干性，并联合基因编辑手段上调EDA的表达，诱导驯化HEK重编程为汗腺样细胞。本项目抓住了当前学科领域的关键问题，研究结果在理论及技术上的突破为促进慢性创面的功能性修复、实现多种组织原位同步再生奠定实验基础。

Chronic wounds, including diabetic foot ulcers, venous leg ulcers, and pressure ulcers, often lead to tissue and organ defects that reduce quality of life. It has been estimated that 1 to 2% of the population in developed countries will experience a chronic wound in their lifetime. In China, the situation is more serious. An anticipated risk of diabetes and age-associated healing impairments dramatically contribute to the increased prevalence of chronic wounds. Not only are chronic wounds incredibly painful for patients, but they also require long-term treatment which present a substantial economic burden to the healthcare system. Wound healing is an intricate tissue remodeling process that is arbitrarily divided into three, overlapping phases, such as inflammation, tissue growth (proliferation) and tissue remodeling (maturation), and requires a coordinated interplay among cells, growth factors, and extracellular matrix proteins. Although healing is a consistent and regulated process, poor healing, however, increases the risk for wound infections or complications, lengthens hospital stays, magnifies patient discomfort, and slows return to activities of daily living. In this regard,, how to promote the regenerative capacity of surviving cells at the wound area and lead to functional recovery of wounded skin involved with sweat gland regeneration poses a great challenge for physicians and medical specialists. Converging evidence from different research paradigms suggest that neuroendocrine factors and their receptors participate in a complex network that modulates chronic wound healing. Described as the body's largest organ, the skin is strategically located at the interface with the external environment where it has evolved to detect, integrate and respond to a diverse range of stressors. The skin also functions as an important peripheral (neuro) endocrine organ that is tightly networked to central stress axes. In our previous study, we found an involvement of β2-AR signaling in the induction of EMT-like alterations in human keratinocytes in vitro. β2-AR signaling also affected HaCaT cell migration, resulting in faster closure on the wound gap as measured by in vitro scratch wound healing assay. Given the process of EMT portrays similar characteristics with “stemness” acquisition, the β2-AR/PKA/STAT3 cascade was therefore designed as an intervention to explore the mechanisms that regulate keratinocytes’ plasticity and cell-fate determination in this study, which will help to more clearly elucidate the pathways linking neuroendocrine factors and healing processes. Importantly, we constructed nanoparticles in targeted drug delivery by combining β2-AR agonist-PLGA microspheres with collagen sponge. Aiming at controlled release of the drug in the targeting wound, we tried to evaluate the role of β2-AR signaling on the healing outcome of chronic wounds. Based on these results, we further regulated the the plasticity of keratinocytes and promoted stemness via interactions of β2-AR signaling, which induced the reprogramming of keratinoctyes to sweat gland-like cells coupling with upregulation of ectodysplasin (EDA) expression levels in human epidermal keratinoctyes. Our results might shed new insight on precise control of the’ plasticity and fate determination of the surviving cells during chronic wound healing. Meanwhile, our study regarding to the neuroendocrine-controlled cell-fate modulation network also provides a novel target for therapeutic interventions during skin wound healing to rebulid the histological architecture and kinetics in reconstructed tissues, to restore normal function to damaged tissues, and ultimately reach the goal of perfect skin regeneration.