Transcriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response

Abstract

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients’ quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.

Notoginsenoside R1 Facilitated Wound Healing in High-Fat Diet/Streptozotocin-Induced Diabetic Rats

“…Numerous studies have indicated that wound healing in diabetes is due to apoptosis [32] and insufficient angiogenesis [5,13]. In our study, we showed that NR1 decreased cleaved caspase-3 and increased CD31 expression in diabetic wounds, which indicated that topical NR1 treatment Oxidative Medicine and Cellular Longevity attenuated apoptosis, increased angiogenesis, and consequently enhanced wound healing in diabetic rats.…”

Mechanism and application of β‐adrenoceptor blockers in soft tissue wound healing

“…Prolonged inflammatory response is a typical feature of impaired wound healing 37 . Both neutrophils and macrophages express β‐AR and secrete corresponding catecholamine ligands 38 .…”

“…36 Prolonged inflammatory response is a typical feature of impaired wound healing. 37 Both neutrophils and macrophages express β-AR and secrete corresponding catecholamine ligands. 38 β-AR activation not only increases the number of inflammatory cells in the wound, but also prolongs their presence, thus slowing down healing speed, while the treatment of β-blockers restored the healing time to the normal level.…”

miR‐186‐5p targets TGFβR2 to inhibit RAW264.7 cell migration and proliferation during mouse skin wound healing

“…Skin is the first barrier of the body against the external environment, and its integrity helps maintain health and homeostasis. 1 However, external stimuli can cause skin damage, tissue loss, and structural and functional impairment. 2 The healing of skin wounds primarily involves hemostasis, inflammation, proliferation, and remodeling.…”