|Year : 2018 | Volume
| Issue : 1 | Page : 1-5
Mesenchymal stem cell therapy for diabetic foot ulcer
Ying Liu1, Yongquan Gu2
1 The Key Tissue Engineering of Jilin Province, Siping Hospital of China Medical University, Siping, Jilin, China
2 Department of Vascular Surgery, Xuanwu Hospital of the Capital Medical University, Beijing, China
|Date of Web Publication||10-Jul-2018|
Department of Vascular Surgery, Xuanwu Hospital of the Capital Medical University, Beijing 100053
Source of Support: None, Conflict of Interest: None
Diabetic foot (DF) disease continues to be a major cause of mortality and disability. The pathophysiology of DF is multifactorial and includes neuropathy, infection, ischemia, and abnormal foot structure and biomechanics. Current therapies are limited; however, based on recent research efforts, there is rising hope for promising and more effective stem cell therapeutic approaches for these patients. In this review, we discuss mesenchymal stem cells as tools for cell/scaffold-based therapies for nonhealing wounds. We have reviewed the main clinical trials dividing them based on their clinical applications and taken into account the ethical issue associated with the stem cell therapy.
Keywords: Critical limb ischemia, diabetic foot, mesenchymal stem cells
|How to cite this article:|
Liu Y, Gu Y. Mesenchymal stem cell therapy for diabetic foot ulcer. Vasc Invest Ther 2018;1:1-5
| Introduction|| |
Diabetic foot ulcer (DFU) is a common complication and the main cause of amputation of diabetes mellitus (DM). According to epidemiological studies, approximately 15% of diabetic patients experience DFUs during their lifetime. Thus, the probability of these patients requiring an amputation is 40 times the rate in nondiabetic patients, and the total financial burden associated with this condition is very high., Neuropathy, peripheral vascular disease, and reduced resistance to infection are the recognized risk factors leading to the development of DFUs, which have all the characteristics of a chronic wound., As diabetes has shown a growing trend and becomes a global public health threat over the past two decades,, DFU is becoming a worldwide threat to public health. Traditional therapies, including local wound care, treatment for infection, and ischemia, do not change the fundamental pathology underlying DFU, and their therapeutic effects are limited.
Over the last two decades, cell therapy had shown great promise for the treatment of a lot of clinical diseases, which was conceived as an innovative way to improve pathophysiological condition and the prognosis of DFU. Even a variety type of stem and progenitor cells have been evaluated, mesenchymal stem cells (MSCs) were considered as the best therapeutic potential cells, owing to their greater ease of isolation and capacity for proliferation and differentiation in vivo and in vitro. Here, we focus on the current status of research into MSCs as a stem cell-based therapy for DFU and the unique challenges to their successful application toward a standard clinical therapy.
Pathophysiology of diabetic foot ulcer
Three underlying major pathologies, mutually interacting for the DFU, are as follows: ischemia, neuropathy, and infection.,,,
Neuropathy is the most common etiology underlying DFU, with a prevalence ranging >60%. About 10%–18% of patients appear to be already affected by peripheral neuropathy at the time of DM diagnosis, and distal sensorimotor polyneuropathy is usually present in about 42% of diabetic patients after 20 years. The distal neuropathy of diabetes frequently involves sensory, motor, and autonomic, each of which contributes to foot ulcer development. There are several hypotheses that are thought to responsible for these abnormalities, which include deficiencies in sorbitol metabolism via the polyol pathway resulting from chronic hyperglycemia., The loss of protective sensation in the neuropathic patient lets foot wounds go undetected in tissue breakdown and ulceration.
Motor nerve involvement
Motor neuropathy is related to the damage of demyelination and motor endplate. The distal motor nerves are most commonly affected, which led to small intrinsic muscles atrophy of the foot, and produce an imbalance of the long flexor and extensor tendons. This pathological phenomenon is mainly related to two abnormalities. First, it results in collapse of the arch and induces the classic high-arched foot and claw toe deformity., Thus, pressures are gradually abnormally distributed on the plantar aspect of the foot, and some plantar sites become prone to ulceration under high pressures.,,,, Second, loss of stability of the metatarsophalangeal joints during midstance of the gait is observed. The distal metatarsal fat pads displaces resulting in hyperextension of the toes and the natural cushioning of the metatarsal heads reducing. These abnormal changes that increase plantar pressures led to callus formation and potential skin breakdown. Due to loss of internal muscles and the disruption of the normal bony relationships of the distal foot, eventually leading to a wider and thicker foot than normal. Furthermore, the primary shoes do not fit any longer, which in turn cause areas of local trauma. Anyway, overcompensation by extrinsic muscles can lead to musculoskeletal deformities.
Autonomic neuropathy changes are manifested as reduced sweating at the epidermal level and arteriovenous shunting at the subcutaneous and dermal level. Hypohidrosis leads to dry skin and callus formation. Arteriovenous shunting reduced the delivery of nutrients and oxygen to the tissues led them susceptible to break down. Furthermore, distal arterial flow and pressure are increased due to the loss of peripheral sympathetic vascular tone in the lower limb, which might contribute to peripheral edema by damaging the capillary basement membrane. Increased edema might be another element of minor trauma caused by wearing shoes that not fit anymore. Skin cracks may become gateways to bacterial invasion and increase the likelihood of infection.
The effects of motor and autonomic neural abnormalities are much less than the loss of sensory neural function on foot protection. When these fibers are affected, protective sensation is lost which manifests as a distal, symmetric loss of sensation described as a “glove and stocking” distribution. In this condition, patients are unable to detect increased loads, repeated trauma, pain from shearing forces, or injuries such as fractures, ulceration, and foot deformities. This sequence of events allows patients walk with a false sense of security and repeated trauma to the foot.,
| Etiology of Diabetic Foot Ulceration|| |
The other major underlying cause of DFU is peripheral vascular disease. Purely ischemic DFUs are uncommon, representing only 10%–20% of ulcers in diabetic patients, and another 15%–33% have a mixed neuropathic-vascular etiology., Overall, the incidence of peripheral arterial disease (PAD) is estimated to be 2–4 times more common in diabetic patients than in others.
PAD in diabetic patients often occurs in numerous vessels, especially in anterior tibial, posterior tibial, and peroneal arteries.,,, Its hallmark occurs in the tibioperoneal vessels while relative sparing of the pedal vessels. Characteristically, occlusive lesions that spare the arteries are usually above the knee in diabetic patients, while the calcific infrapopliteal arteries in single- or multiple-level disease. One or more of the large vessels at the ankle and in the foot are spared. Basically, the peroneal artery in the calf is the last one to occlude [Review in 31]. Thus, it has the potential to provide good blood flow via its terminal tributary to a single tibial artery, peroneal artery, or a pedal bypass to the foot.
Of note, in DFU, microangiopathy induces capillary basement membrane thickening, reducing the supply of oxygen and nutrients, and microcirculating ischemia. Lack of perfusion reduces tissue elasticity, leads to rapid tissue death, and delays wound healing. Once an ulcer is formed, microangiopathy might aggravate chronic ulcer development.
Finally, autonomic neural abnormalities reduce the normal vasoconstriction in the lower leg arteries withstanding, which led to an increase in the intraluminal flow and pressure. Reduced vasoconstrictive ability in turn reduces vessels' capacity to respond to systolic blood pressure expansion. The association of high flow and reduced wall motion promotes the formation of plaque in calf arteries.
It is reported that 40%–80% of DFU has evidence of infection. Several factors increase the risk of development of DFU, including diabetic neuropathy, peripheral arterial disease, and immunologic impairment, especially of the peripheral neuropathy effect. As described above, due to loss of neural protection, diabetic patients are prone to occur repeated trauma and ulcer.
Diabetic-related infection has two characteristics. First, the host immune function is impaired, which is manifested in the function of defects in leukocyte function with serum glucose levels ≥150 ml/dl. The capability of leukocyte is decreased in migration and phagocytosis, intracellular activity is related to hyperglycemia, and impaired cellular immune response is neither spared., These abnormal changes cause a prolonged inflammatory state, a catabolic state in an open wound, gluconeogenesis from protein breakdown. This metabolic dysfunction further impairs the synthesis of proteins, fibroblasts, and collagen at the lesion. Infection is poorly tolerated in diabetic patients and aggravates blood glucose control, which further affects the host's response to infection. Second, the types of bacteria infected with DFU are different in contrast to nondiabetic individuals. An average of five to eight different organisms ,,, is related to diabetic-related infection, which causes complex infections of DFU. The most prevalent organisms identified were Staphylococcus aureus, coagulase-negative Staphylococcus, group B Streptococcus, Proteus, Escherichia More Details coli, Pseudomonas, and Bacteroides. Methicillin-resistant S. aureus (MRSA) is the major infected source in DFUs and prolonged time to healing.,,,
DF infection can be classified into two kinds. One is often mild infections associated with a superficial ulcer, <2 cm of surrounding cellulitis, and no signs of systemic toxicity. In this lesion, the most notable organisms are aerobic Gram-positive cocci, such as S. aureus, coagulase-negative S. aureus, and streptococci. The other one is more severe; the lesion is usually >2 cm of surrounding cellulitis, deeper ulceration, or an undrained abscess, gangrene, or necrotizing fasciitis, which is life- or limb-threatening, and commonly caused by MRSA infection.,,
Mesenchymal stem cells
MSCs were first found in bone marrow in 1966, which are isolated later from various other tissue types, including bone marrow, umbilical cord blood, adipose tissue, and amniotic membrane. It has been recommended that MSCs must fulfill the following cell surface marker expression criteria: ≥95% of the population must express CD105, CD73, and CD90, and ≤2% of the population must not express CD45, CD34, CD14 or CD11b, CD79a or CD19, and HLA class II MSCs must be able to differentiate into osteoblasts, adipocytes, and chondroblasts in vitro.
Recent studies reported that MSCs have the capability of multidirectional differentiation and weak immunogenicity. As MSCs are easy collected, these cells are widely used in the field of regenerative medicine research.
Mesenchymal stem cells in diabetic foot ulcer tissue repair
MSCs are believed to have an important role in tissue repair. MSCs can recruit and differentiate at the lesion after intravenous and local injection. MSCs could affect tissue healing and regeneration through many different routes. One of the most intriguing properties is the capability of ex vivo differentiation. A greating study suggests that MSCs can migrate toward injured sites in response to inflammation and differentiate into multiple cells to repair damaged tissues. Sasaki et al. revealed that MSCs can differentiate into a variety of skin cell types, and Wu et al. reported that MSCs enhance wound healing not only through differentiation but also angiogenesis. Several studies revealed that MSCs could differentiate into endothelial cells in anti-angiogenic environments. Furthermore, a subpopulation of MSCs, which participates to stabilize vessel walls and promote vessel maturation during angiogenesis, known as pericytes, has been proved to be derived from bone marrow following injury. Thus, MSCs have the potential to support new vessel growth in a DFU and to overcome the critical aspect of barriers to current therapies.
The other intriguing role in MSCs is secreting trophic factors to influence the microenvironment in the wound bed. Stimulated by hypoxia and local inflammation, MSCs can release many factors at the wound margin to support epidermal cells proliferate and new blood capillaries grow, such as epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor-β, insulin growth factor-1, and angiopoietin-1.,,, Furthermore, MSCs stimulate endothelial cell recruitment through the secretion of vascular endothelial growth factor, modulate scar formation through prostaglandin E2 secretion, regulate interleukin (IL-10), IL-6, and IL-8, and reduce of collagen production.,, Taken together, MSCs participate in the whole process and promotes tissue regeneration and repair.
Mesenchymal stem cells as immune modulators
Finally, MSCs have immunomodulatory properties through the production of soluble factors.,,,, MSCs can regulate IL-10 production to alter the activity of dendritic cells. MSCs can inhibit T-cell production, such as CD4+ and CD+ 8 T-cells, and increase the number of CD4+CD25+FoxP3+ T-regulatory cells to suppress the immune response., MSCs can inhibit B-cells and NK cells proliferation and IgG secretion of B-cells. Based on these characteristics and their potential immunoprivileged status, MSC therapy represents a method to treat conditions that currently result in generally poor outcomes.
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Conflicts of interest
There are no conflicts of interest.
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