With the development of economies around the world, the global incidence and prevalence of diabetes is growing rapidly. As of 2011, there are about 366 million people with diabetes, accounting for 7% of the global population. 80% of these patients live in developing countries, and diabetes has become the third most serious chronic disease threatening human health after tumor and cardiovascular disease.
China, the world’s largest developing country, has the highest number of diabetics in the world at 92 million as of 2011. The complications caused by diabetes involve all organs of the human body, among which skin damage and prolonged wounds seriously affect the quality of life of diabetic patients. Traditional medication and surgical treatment can heal the difficult-to-heal skin wounds of diabetic patients, but the recurrence rate is as high as 50%.
Mechanisms that contribute to the difficulty in healing skin injuries in diabetic patients include microvascular damage, altered growth factors and accumulation of glycosylation end products (AGEs). Increased blood viscosity and hemoglobin glycosylation caused by hyperglycemia can lead to local tissue hypoxia, which further causes vascular endothelial cell damage, resulting in local microcirculatory disorders that exacerbate hypoxia, forming a vicious cycle. This condition results in decreased cell proliferation and increased apoptosis, leading to slow granulation tissue formation, bacterial infection, and difficult wound healing.
In addition to this, microcirculatory disorders due to microvascular injury may cause changes in the stem cell microenvironment and a decrease in stem cell function, resulting in difficulty in wound healing. The altered secretion of growth factors at the wound site leads to reduced neointima formation, further aggravating the hypoxic state and causing impaired collagen matrix formation, which further delays the healing of skin wounds in diabetic patients.
The increase of AGEs under continuous high glucose conditions, the accumulation of AGEs in local skin tissues leads to glycosylation of other proteins, the modification of LDL glycosylation leads to atherosclerosis and causes local blood supply deficiency; the glycosylation of growth factors and their receptors reduces functionally active growth factors and their receptors, which in turn affects the proliferation and migration of repair cells, thus affecting trauma repair.
However, with the rise of biological cell therapy, the use of stem cell transplantation can heal ulcers by improving the blood flow around the ulcer and restoring the normal cellular microenvironment.
I. Progress of stem cell treatment for skin damage in diabetic patients
1. Mesenchymal stem cells: (1) bone marrow mesenchymal stem cells (BMSC): BMSC are a group of mesenchymal stem cells originated from bone marrow, with characteristics of self-renewal, high expansion potential in vitro and easy to purify, which can differentiate into cartilage under certain conditions.
It has been shown that local or systemic injection of BMSC can promote the healing of skin injury in diabetic rats, while significantly enhancing the collagen level in the skin defects of diabetic rats.Kuo et al. in their study found that the application of BMSC can clearly shorten the wound healing time in diabetic rats, and also demonstrated the ability of BMSC to promote skin wound healing in diabetic rats.Inoue et al. applied Bioimage technique confirmed the involvement of BMSC in the whole process of wound healing and repair.
(2) Adipose mesenchymal stem cells (AD-MSC): AD-MSC are a group of mesenchymal stem cells with self-renewal ability in adipose and can differentiate into epidermis, adipose, bone, cartilage and nerve tissues. It was found that the application of AD-MSC could promote skin injury healing in diabetic rats.
In a study on the mechanism of AD-MSC to promote wound healing, Kim et al. found that AD-MSC promoted the formation of neovascularization in periwound tissue by paracrine secretion of vascular endothelial growth factor (VEGF), improved the hypoxic microenvironment caused by diabetic microvascular injury, and promoted cell proliferation, which in turn promoted the healing of skin defects in diabetic patients. a study by Nie et al. confirmed that AD- MSC increased the concentration of VEGF by secretion and stimulated the formation of blood vessels, thus achieving the promotion of healing of skin lesions.
(3) Human umbilical cord blood MSCs: In addition to MSCs of bone marrow and adipose tissue origin, MSCs isolated from fetal umbilical cord blood also have the ability to promote the healing of skin lesions in diabetic patients.
Tark et al. applied human umbilical cord blood MSCs isolated from human umbilical cord blood to treat delayed healing wounds in diabetic model mice by local and systemic injection, and found that both local and systemic injection groups played a positive role in promoting wound healing; in the assay of cytokines, it was found that the content of β-transforming growth factor (TGF-β) was increased in the injection group, and the reason for its promotion of wound healing might is that the increase of TGF-β promotes the proliferation of cells, thus accelerating the wound healing.
2, vascular endothelial precursor cells: (1) bone marrow negative lineage vascular precursor cells: bone marrow negative lineage precursor cells are a group of stem cells extracted from bone marrow with the ability to differentiate into vascular endothelial cells, improve blood flow and thus promote wound healing. lin et al. injected the bone marrow extracted negative lineage precursor cells into the skin defect of diabetic mouse model and found that the bone marrow negative lineage vascular precursor cells significantly increased vascularization of the wound and accelerated the healing of the skin defect.
(2) Mononuclear cells: In a study using bone marrow-derived mononuclear cells (BMMNCs) to promote diabetic foot revascularization, it was found that patients treated with mononuclear cells were superior in wound oxygen partial pressure and pain-free walking time compared to patients who did not take mononuclear cell therapy, suggesting a role for the cells in improving the quality of life of diabetic foot patients.
Rehman et al. reported that peripheral blood circulation-derived mononuclear cells (PBMNCs) produced more angiogenic factors and cytokines than BMMNCs. Thus Hoshino et al. reduced the symptoms of pain and lower limb ischemia associated with severe atherosclerotic vasculitis by autologous transplantation of PBMNCs, and improved the quality of life of diabetic patients who were dependent on hemodialysis for survival.
Broqueres-You et al. found in a diabetic murine model that EFNB2-activated PBMNCs increased the number of circulating vascular precursor cells, enhanced the ability of endogenous BMMNCs to differentiate into endothelial cells and restored the potential for blood vessel formation, resulting in more neovascularization in the treatment group than in the control group, ultimately promoting faster healing of skin wounds than in the control group.
(3) Embryonic stem cells: Embryonic stem cells are a group of specialized cells with unlimited proliferation, self-renewal and multidirectional differentiation in in vitro culture. In both in vitro and in vivo environments, embryonic stem cells can be induced to differentiate into all types of cells.
However, there are not many studies on embryonic stem cells for skin injury in diabetic patients because the study of embryonic stem cells is still a controversial field, but the study by Lee et al. found that the expression of VEGF and epithelial growth factor (EGF) was significantly increased after local injection of embryonic stem cells into the wound site, which effectively promoted the healing of skin wounds in diabetic patients.
II. Cytokine therapy for skin injury in diabetic patients
1, human epidermal growth factor (bEGF): hEGF has the role of promoting and regulating epidermal growth and proliferation. hardwicke et al. accelerated the closure of skin defects and the formation of new dermal tissue in diabetic rats after local application of hEGF in a diabetic rat model.
2, platelet-derived factor (PDGF): PDGF is a cytokine synthesized by monocytes/macrophages and stored in platelets, with the ability to promote specific cell mitosis and collagen secretion by fibroblasts to promote fibrosis. It was found that the expression of PDGF and receptors at the trauma site was severely decreased in diabetic injuries, suggesting that the expression levels of PGDF and its receptors are critical for normal defect repair.
In a study by Li et al. in which PDGF-BB gel was used to treat refractory wounds in diabetic patients, it was found that increased vascularization, active cell proliferation and epidermal regeneration promoted the healing of skin injuries in diabetic patients.
3. VEGF: VEGF is the main factor that stimulates angiogenesis during normal wound healing, but it cannot regulate angiogenesis normally during wound healing in diabetic patients. kirchner et al. found that VEGF significantly shortened the time of skin defect closure after applying VEGF to skin defects in a diabetic mouse model.
Meanwhile, Kwon et al. and Ko et al. used genetic engineering techniques to combine VEGF and EGF genes with plasmids, then introduced seed cells and implanted back into skin wounds to increase the expression of VEGF and EGF factors around the wounds, thus improving the speed and quality of skin defect healing in diabetic patients.
In summary, current research on the treatment of refractory skin defects in diabetic patients has focused on improving the blood circulation around the wounds, thereby promoting the healing of skin defects.
A part of the research has proven its effectiveness in clinical application, such as autologous bone marrow mononuclear cell transplantation can promote vascularization of foot ulcers in diabetic patients, thus improving diabetic foot symptoms; another part of the research has proven to be effective in promoting healing of skin defects in diabetic patients in the laboratory, but is still a long way from clinical application due to ethical and medical safety restrictions, such as embryonic stem cells.
In conclusion, diabetes is a long-term chronic disease, and current treatments lack long-term follow-up results, and long-term effects remain to be proven.