The future of diabetic wound healing: unveiling the potential of mesenchymal stem cell and exosomes therapy.

Am J Stem Cells 2024;13(2):87-100 www.AJSC.us /ISSN:2160-4150/AJSC0155352 Review Article The future of diabetic wound healing: unveiling the potential of mesenchymal stem cell and exosomes therapy Sara Memarpour1, Ramin Raoufinia1,2, Ehsan Saburi1, Masoud Sharifian Razavi3, Matin Attaran4, Farhad Fakoor5, Hamid Reza Rahimi6,7 Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; 2Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran; 3Department of Internal Medicine, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran; 4Department of Obstetrics and Gynecology, Mashhad University of Medical Sciences, Mashhad, Iran; 5Department of Paramedical Sciences, Iran University of Medical Sciences, Tehran, Iran; 6Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; 7Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 1 Received January 9, 2024; Accepted March 18, 2024; Epub April 25, 2024; Published April 30, 2024 Abstract: Diabetes mellitus (DM) is a significant public health problem and is one of the most challenging medical conditions worldwide. It is the severe complications that make this disease more intricate. A diabetic wound is one of these complications. Patients with diabetes are at higher risk of developing diabetic foot ulcers (DFU). Due to the ineffectiveness of Conventional treatments, growth in limb amputation, morbidity, and mortality have been recognized, which indicates the need for additional treatment. Mesenchymal stem cells (MSCs) can significantly improve wound healing. However, there are some risks related to stem cell therapy. Exosome therapy is a new treatment option for diabetic wounds that has shown promising results. However, an even more advanced form called cellfree therapy using exosomes has emerged. This upgraded version of stem cell therapy offers improved efficacy and eliminates the risk of cancer progression. Exosome therapy promotes wound healing from multiple angles, unlike traditional methods that primarily rely on the body’s self-healing ability and only provide wound protection. Therefore, exosome therapy has the potential to replace conventional treatments effectively. However, further research is necessary to distinguish the optimal type of stem cells for therapy, ensure their safety, establish appropriate dosing, and identify the best management trail. The present study focused on the current literature on diabetic wound ulcers, their treatment, and mesenchymal stem cell and exosome therapy potential in DFU. Keywords: Diabetes mellitus, diabetic foot ulcers, mesenchymal stem cell, exosome therapy Introduction The economy has grown noticeably in recent decades, so dietary habits have changed. Thereby, the number of patients dealing with diabetes has increased [1, 2]. Epidemiological calculations projected that there will be approximately 700 million by 2045 [3]. Furthermore, the treatment and care of DM force a significant economic burden on the patients and society [4, 5]. Diabetes can cause much harm, primarily through its complications. One of the most significant complications is diabetic wounds, and it is known that patients who have diabetes are very vulnerable to developing foot ulcers [6]. Statistics show that this disease consumes 20-40% of medical resources yearly [7]. Approximately 15% of diabetic patients are dealing with DFU complications, and this condition is responsible for about 84% of lower limb amputations [8]. Diabetic foot ulcer prognosis is often poor, and the mortality rates are unpromising (60% reduction in their five-year overall survival) [9, 10]. However, the healing of DFUs can be predicted by several factors, some of which can be modified. For instance, better control of diabetes, https://doi.org/10.62347/OVBK9820 Mesenchymal stem cell and exosomes therapy in diabetic wound healing treatment of neuropathy, and early management of ulcers can improve the healing process. Therefore, patients’ diagnosis and prompt treatment measures are vital to enhance their chances of healing [6]. There are several traditional treatments for foot ulcers resulting from diabetes, such as offloading the wound, wound dressings to provide a moist wound environment, debridement, and using antibiotics and surgical intervention. Stem cell transplantation has recently become important in curing various diseases, including DFU. Previous investigations have shown that MSCs can significantly improve wound healing [6]. Moreover, in multiple studies, exosome therapy has shown promising results as a new treatment option for DFUs [11]. Regulating recipient cells and managing cellular crosstalk among macrophages, endothelial cells (ECs), and fibroblasts are done by exosomes derived from MSC via genetic material and transcription factors transportation. More importantly, compared to stem cell therapy alone, it has a lower risk of cancer, making it a safer option for diabetic wound treatment [11]. Therefore, it has become a popular choice for diabetic wound healing. This paper reviews the current literature on the Potential of Mesenchymal Stem Cell and Exosomes Therapy in DFU. The pathogenesis and features of foot ulcers in diabetic patients The etiology and progression of DFU are intricate and influenced by various intrinsic and extrinsic factors. Considering both aspects is essential to realize responsible mechanisms for raising this issue. Neuropathy Neuropathy in DFU cases causes sensory and motor nerve impairment. Likewise, the autonomic nervous system may be damaged. Therefore, an increased risk of skin ulcers, muscle atrophy, and motor dysfunction in the lower extremities may arise [12, 13]. Additionally, abnormalities in sweat gland secretion resulting from neuropathy can cause overheating skin and elevate the danger of foot ulcers. Combining sensory and motor neuropathies can result in rough foot pressure, eventually leading to difficult healing ulcers [14]. 88 Vascular lesions dominated by atherosclerosis Vascular lesions can cause endothelial damage, inflammation, and blood hypercoagulability. Thus, it promotes the formation of atherosclerotic lesions [15, 16]. This angiopathy is the underlying factor behind DFU, amputation, and death [17]. Atherosclerotic plaque rupture can lead to arterial thrombosis, leading to lower limb ischemia and the formation of DFUs [18]. Wound infections As a result of poor blood supply and nerve damage, diabetic foot infection can arise in diabetic patients. These chronic infections may result from multiple microorganisms like Candida albicans as fungi [19]. Also, continual diseases are related to immune cellular disorders, impairing resistant characteristics [20]. Numerous growth elements have also been identified to play a pivotal role in developing DM and its complications. 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