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Sun, D.; Ma, J.; Fang, Y.; Lin, B.; Lei, P.; Wang, L.; Qu, L.; Wu, W.; Jin, L. Zebrafish for Diabetes Mellitus with Wound Model. Encyclopedia. Available online: https://encyclopedia.pub/entry/44096 (accessed on 08 May 2024).
Sun D, Ma J, Fang Y, Lin B, Lei P, Wang L, et al. Zebrafish for Diabetes Mellitus with Wound Model. Encyclopedia. Available at: https://encyclopedia.pub/entry/44096. Accessed May 08, 2024.
Sun, Da, Jiahui Ma, Yimeng Fang, Bangchang Lin, Pengyu Lei, Lei Wang, Linkai Qu, Wei Wu, Libo Jin. "Zebrafish for Diabetes Mellitus with Wound Model" Encyclopedia, https://encyclopedia.pub/entry/44096 (accessed May 08, 2024).
Sun, D., Ma, J., Fang, Y., Lin, B., Lei, P., Wang, L., Qu, L., Wu, W., & Jin, L. (2023, May 10). Zebrafish for Diabetes Mellitus with Wound Model. In Encyclopedia. https://encyclopedia.pub/entry/44096
Sun, Da, et al. "Zebrafish for Diabetes Mellitus with Wound Model." Encyclopedia. Web. 10 May, 2023.
Zebrafish for Diabetes Mellitus with Wound Model
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This entry is adapted from the peer-reviewed paper 10.3390/bioengineering10030330

Diabetic foot ulcers cause great suffering and are costly for the healthcare system. Normal wound healing involves hemostasis, inflammation, proliferation, and remodeling. However, the negative factors associated with diabetes, such as bacterial biofilms, persistent inflammation, impaired angiogenesis, inhibited cell proliferation, and pathological scarring, greatly interfere with the smooth progress of the entire healing process. It is this impaired wound healing that leads to diabetic foot ulcers and even amputations. Therefore, drug screening is challenging due to the complexity of damaged healing mechanisms. The establishment of a scientific and reasonable animal experimental model contributes significantly to the in-depth research of diabetic wound pathology, prevention, diagnosis, and treatment. In addition to the low cost and transparency of the embryo (for imaging transgene applications), zebrafish have a discrete wound healing process for the separate study of each stage, resulting in their potential as the ideal model animal for diabetic wound healing in the future. 

zebrafish diabetic wound delayed wound healing model animal

1. Introduction

Diabetes is a debilitating disease that has a significant economic impact on global health systems [1]. According to the International Diabetes Federation, 463 million adults had diabetes in 2019 and this number is expected to reach 700 million by 2045 [2][3]. The healing of a normal wound generally happens in four stages: hemostasis, inflammation, proliferation, and remodeling [4]. However, diabetic hyperglycemia leads to various systemic complications, resulting in a series of local lesions in the wound microenvironment, including chronic inflammation, angiogenesis, hypoxia-induced oxidative stress, neuropathy, impaired signal transduction of advanced glycation end products (AGEs) and neuropeptides. Eventually, diabetic wounds are characterized by impaired healing, prolonged inflammation, and reduced epithelialization dynamics [5][6][7][8][9][10].
For preclinical studies of diabetic wound therapy, appropriate animal models are essential; after all, studies in vitro cannot fully capture the complexity of the diabetic wound environment [11]. In recent years, zebrafish (Danio rerio) have become increasingly popular as animal models in biomedical, toxicological, and pharmacological research [12][13], much of which has to do with the highly conserved nature of pathways and genes, good genetic susceptibility, low cost, and rapid passage [14][15][16][17]. As opposed to other wound healing models listed above, zebrafish and mammals utilize a very similar principle to close their epidermis; their caudal fin wounds re-epithelialize rapidly, making them an ideal model for studying wound healing—the healing process of caudal fin injury is shown in Figure 1.
/media/item_content/202305/645b63555af3bbioengineering-10-00330-g001.png
Figure 1. The role of participating in a zebrafish caudal fin regenerative wound healing model. Within 1–3 h-post-amputation (hpa), epithelial cells migrate to cover and close the wound. By 18–24 hpa, an apical epidermal cap is formed, and a mass of undifferentiated mesenchymal cells called the blastema accumulates underneath the apical epidermal cap. At 24 hpa the blastema cells segregate into two morphologically indistinct compartments: a slowly proliferating distal blastema and a rapidly proliferating proximal blastema. After 48 hpa the regeneration program is installed and the regenerative outgrowth continues until the original tissue architecture is reconstituted.

2. Mechanism of Delayed Healing of Diabetic Wounds

Usually, the healing process begins with hemostasis to prevent blood loss and microbial invasion of the wound. This phase follows and overlaps with the inflammatory stage, in which proinflammatory neutrophils are up-regulated initially, and then macrophages clean up fragments and pathogens as well as growth factors, other cytokines, and cells. The proliferative phase overlaps with the inflammatory phase, during which new tissues, new blood vessels (angiogenesis), and matrix structures are activated to fill the wound [18][19]. The final remodeling stage increases the tensile strength of the extracellular matrix (ECM) and reduces the blood supply to the damaged area [20][21][22].
Diabetes is the most common heterogeneous metabolic disorder, which is associated with disorders of glucose, lipid, and protein metabolism [23], characterized by elevated blood glucose or insulin response to tissue, which can lead to many complications, including diabetic skin wounds or ulcers [24]. Diabetic skin ulcers are characterized by painful ulcers with disintegration of dermis (including epidermis, dermis and, in many cases, subcutaneous tissue) [25]. At present, the research on the pathology of DFU is mainly focused on immune dysfunction, microbial invasion, impaired cell proliferation, angiogenesis, and pathological scar [26][27][28][29][30]. The molecular and cellular mechanisms in delayed diabetic skin wound healing are shown in Figure 2.
/media/item_content/202305/645b636d8db9fbioengineering-10-00330-g002.png
Figure 2. The molecular and cellular mechanisms in delayed diabetic skin wound healing.

2.1. Immune Dysfunction

The inflammatory phase of the wound can last for weeks or even months under the influence of diabetes [31][32]. The repair process (bacterial defense, cell proliferation, and collagen synthesis) requires energy, and the strictly oxygen-dependent NADPH-linked oxygenase will produce ROS during this period. Many pathways (polyol pathway, hexosamine pathway, etc.) related to oxidative stress of AGEs are maladjusted, resulting in NADPH depletion, decreased glutathione production, activation of protein kinase C and NADPH oxidases, and excessive production of oxygen free radicals and ROS, which further magnify the inflammatory response under high glucose conditions [7][33]. The functional impairment of neutrophils and macrophages was manifested in the continuous activation of citrulline histone H3, NETosis, and irregular release of NETs in diabetic wounds. Macrophages were affected by increased secretion of prostaglandin E2/D2 and excessive accumulation of AGEs, resulting in weakening of burial and phagocytosis of polymorphonuclear leukocytes such as apoptotic neutrophils, which remained in the M1 phenotype for a long time [20][34][35]. 

2.2. Microbial Invasion

The ability of diabetic patients to stimulate immune response is limited, and toll-like receptors (TLRs) are down-regulated in diabetic wounds, which can damage the innate immune system and inflammatory response, decrease the number of CD4+ T cells, and reduce chemotaxis. This delays the recruitment and immune response of various inflammatory cells, resulting in bacterial susceptibility, bacterial connection, and biofilm formation in the wound. These biofilms protect microorganisms from antimicrobial agents and immune systems, and disrupt the healing process [20][36]. The minimum inhibitory concentration and minimum bactericidal concentration of bacteria in biofilm may be as high as 10–1000 times compared with planktonic bacteria [37]. The pH of the wound becomes alkaline under persistent infection, inhibiting physiological processes such as angiogenesis, epithelial hyperplasia, oxygen release, and bacteriostasis [38]. It is the most common cause of lower limb amputation in diabetic wounds.

2.3. Impaired Cell Proliferation and Angiogenesis

In the proliferative stage, the cascade mediated by different matrix metalloproteinases, cytokines, inflammatory cells, keratinocytes, fibroblasts, and endothelial cells is the basis of successful wound healing [39][40][41][42]. On the one hand, keratinocyte and fibroblast proliferation and migration provide basic conditions for ECM and re-epithelialization [43][44][45]. On the other hand, a continuous supply of blood provides adequate oxygen and cytokines, which are necessary for tissue regeneration. Wound areas with active proliferating fibroblasts can only be seen when pO2 is above 15 mm Hg [7][46]. Further, keratinocyte, fibroblast proliferation and migration provide basic conditions for ECM and re-epithelialization of ECM [47]. Decreased levels of heat shock proteins (HSPs) (HSP90, HSP70, HSP47, and HSP27) and their downstream molecules TLR4 and p38-mitogen-activated protein kinases affect procollagen synthesis and protein homeostasis [20][48]. Irregular pro-inflammatory response can activate the irrational upregulation of activating transcription factor-3 and inducible nitric oxide synthase (iNOS), accompanied by the increasing level of free radicals and the upgradulating activities of caspase-3, -8 and -9. High oxidative stress results in the down-regulation of nuclear factor E2-related factor 2 (affecting the expression of MMP-9, transforming growth factor-beta (TGF-β), migration and proliferation-related genes). Impaired cell differentiation and remodeling are associated with abnormal Bcl2, keratin K16, notch junction protein 43, and platelet reactive protein- 1 expression. In addition, the expression of angiopoietin-like 4, one of the stromal cell proteins, is difficult to up-regulate in diabetic wounds as occurs in normal wounds. The activation of the JAK1/STAT3/iNOS signaling pathway is blocked, and the production of NO is inhibited, hinting to angiogenesis and re-epithelialization [20]23

2.4. Pathological Scar

The remodeling phase requires the synthesis of new collagen and concurrent collagen degradation, a process mediated by MMPs. Type III collagen is gradually replaced by type I collagen with greater tensile strength. The presence of myofibroblasts also causes wound contraction, contributing to potential scar formation [46]. However, premature senescence of fibroblasts occurs under high glucose conditions, which is associated with persistent oxidative stress and inflammation [18]. At the same time, pathological skin scarring exhibits excessive accumulation of fibroblasts and ECM (mainly type I collagen). The vertical growth of pathological scars generally subsides after a few years; however, the joint site can lead to contracture, severely limiting function, requiring surgical treatment, and seriously affecting appearance and normal life [18]. Several lines of evidence suggest that inflammatory bodies in local fibroblasts are involved in skin fibrosis by inducing these normally stationary cells to differentiate into pathogenic myofibroblasts, resulting in high levels of ECM. This inflammasome activation in these non-immune cells triggers skin fibrosis, and subsequent inflammasome activation in immune cells amplifies the local inflammatory response [49].

3. The Advantages of Zebrafish for Diabetic Wound Healing

Zebrafish as a model for studying diabetic wound healing has many unique advantages (Figure 3): Zebrafish larvae are only subject to animal experimentation regulations upon reaching 120 h post fertilization and starting to live free, as stipulated by the directive of the European Union on the Protection of Animals used for scientific purposes. As the volume is small, whole-organism imaging can be performed in a multiwell plate; the cost is low; the reproduction ability is strong (about 200 eggs per female per week) [50]; the generation time is short, generally 3–4 months. Thus, selection experiments can be conducted; larvae developed rapidly, and fully developed juveniles can be obtained 48 h after hatching. The embryonic and juvenile stages are transparent throughout the body, making real-time imaging of target organs possible, giving ease of embryonic manipulation, and the possibility of screening therapeutic agents at a low cost [51][52][53]. All of the above contribute to their increasing popularity for high-throughput and high-content assays. On the other hand, as a result of the zebrafish genome sequence, 71% of human proteins and 82% of disease-causing human proteins have been found to be orthologous in zebrafish, with significant homology to human proteins. The mechanisms of infection and inflammation caused by innate immune responses can be isolated and studied in the early stages of development without the complications associated with adaptive immune responses. It is suitable for the study of gene expression regulation by gene specific knockout technique or by mRNA or plasmid overexpression of protein. There is good genetic control and in the embryonic and larval stages, the skin of zebrafish is already composed of a superficial peritrind, a middle epidermal double layer, and a basal layer attached to the basal membrane, while its multilayer epidermis is formed during the metamorphosis on the 25th day after fertilization. At the same time, fibroblasts penetrate the dermis, take over the collagen produced by keratinocytes in the basal layer, form locally thickened dermal papillae, and begin to scale. In short, the skin structure of zebrafish is very similar to that of human beings, and the basic principle of the wound healing mechanism is conservative between human and zebrafish: there are discrete stages of healing, allowing specific processes to be studied separately; a remarkable ability to regenerate new fin tissue after amputation is retained, and its caudal fin has a relatively simple but symmetrical structure, including epidermis, blood vessels, nerves, pigment cells, and fibroblasts [54][55][56][57][58][59].
/media/item_content/202305/645b6397df82dbioengineering-10-00330-g003.png
Figure 3. Advantages of zebrafish for diabetes mellitus with wound model.

4. Construction and Application of Zebrafish Diabetic Wound Model

Zebrafish have been applied as ideal model animals for diabetic wound studies. These construction and application are described in Figure 4.
https://www.mdpi.com/bioengineering/bioengineering-10-00330/article_deploy/html/images/bioengineering-10-00330-g004.png
Figure 4. Application of zebrafish and their larvae in diabetic wounds.

4.1. STZ-Induced Caudal Fin Regeneration Model of Zebrafish with Type 1 Diabetes

Zebrafish respond efficiently and rapidly to streptozotocin (STZ) injection induced diabetes, and hypercholesterolemia caused by high cholesterol diet (HCD)—associated with a high risk of DFUs) Cho et al. [60] injected 30 μL 5 mM citrate buffer containing 0.3% STZ into the subcutaneous tissue adjacent to the abdomen for eight consecutive days utilizing a 26-needle micro-syringe. Prior to that, they were given a 4% cholesterol high cholesterol diet (HCD) for 4 weeks, consisting of normal diet (ND) alone group, ND+STZ group, HCD alone group. and HCD+STZ group. Finally, patients were treated with Heberprot-P75®, Easyef® (two commercial epidermal growth factor (EGF) products, intraperitoneal injection of 10 μL, 50 μg/mL) and PBS on day 3, 5 and 7, respectively. As a result of treatment with PBS in the ND+STZ and HCD+STZ groups, adult fish showed serious delays in healing, as well as multiple cracks which is the typical damage pattern induced by STZ injection in diabetic zebrafish on their caudal fins. However, no cracks appeared in the HCD alone group [61]. Heberprot-P75® showed caudal fin regeneration activity 2.1 times higher than Easyef® (ND+STZ group) and 1.7 and 1.5 times higher than the Easyef® group and PBS group (HCD+STZ group) under the same injection and amputation regimen, with more distinct and clean regeneration modes [61]. Intine et al. injected 0.35 mg/g of STZ intraperitoneally for 1, 3, and 5 days and maintained the injection weekly with the tank temperature maintained at 22–24 °C, as well as amputating the caudal fin in a straight line using a sterile size 10 scalpel, proximal to the first lepidotrichia branching point to obtain an adult zebrafish wound model of type I diabetes bearing an average blood glucose of more than 300 mg/dL, impaired caudal fin regeneration, accumulation of AGEs, and epigenetic changes including genome-wide demethylation. At 21 days to stop the injection of STZ, and restore normal blood insulin and glucose control through pancreas regeneration, and obtain the metabolic memory (MM) fish, whose limb regeneration was still the same as the state of acute diabetes damage, even at 30, 60, 90 days, and this affects the genetic to daughter cells [62], as well as bnormal DNA methylation was also retained, but AGEs did not accumulate and ROS induced stress signals did not increase. In conclusion, restoring physiologically normal glycemic control may not save altered target tissue from diabetes-induced changes [63].

4.2. Caudal Fin Model of Type II Diabetes in Adult Zebrafish Induced by Alloxan and Glucose Combined with Aqueous Solution Exposure

Aquaporin (AQP) and GLUT1, both present in the gill and skin epithelium, are thought to be responsible for the production of HG zebrafish following the application of alloxan and glucose in water. Wibowo et al. combined 0.4% Alloxan and glucose (E-Merck) % solution, and placed adult zebrafish aged from 3 to 6 months in 100 mL Alloxan solution for 1 h a day for 5 days, and then transferred 2L 2% glucose solution for 24 h for 6 days, as well as amputating using a lancet (Aesculap Scalpel Handle No. 3 and Aesculap Scalpel Blade No. 10 of B BRAUN) at the first or the second segment below the level of the first ray bifurcation. The expressions of shha, igf2a, bmp2b, and col1a2 were down-regulated in the experimental group, which may be related to the glucose metabolism inducing the generation of superoxide or ROS, the inhibition of GAPDH, the accumulation of methyl glyoxal, and the disruption of hypoxia inducible factor-1α transcription factor stability, leading to the transcriptional inhibition of some of the above target genes. The percentage of caudal fin regeneration and the expression of shha, igf2a, bmp2b, and col1a2 were increased after treatment with 15 ppm propolis ethanol extract [64].

4.3. Caudal Fin Regeneration Model of Zebrafish Juvenile Type II Diabetes Induced by Single Immersion or Injection of Glucose

With zebrafish, each process can be studied separately, which allows us to observe wound healing more directly. Morris et al. studied the wound model of hyperglycemic transgenic Tg (mfap4:turquoise)xt27 induced by immersion (5% glucose) and injection (15 nmol). Macrophages of transgenic Tg (mfap4:turquoise)xt27 juveniles were labeled with turquoise fluorescent protein, neutrophils of Tg (lyzC:DsRed)nz50 juveniles were labeled with DsRed fluorescent protein, and reduced neutrophils were found in the juveniles injected with glucose. That is, innate immune cell development is affected. Tg (itga2b:gfp)LA2 juvenile tail fin transection was observed to stop bleeding, while injection and immersion showed reduced platelet accumulation. At the same time, the accumulation of fibrin was reduced by using Tg (fabp10a:fgb-gfp)mi4001, which expresses fluorescently tagged fibrinogen and allows visualization of clots. Finally, the infusion of glucose at 0 day post fertilization (dpf) and the feeding of a HFD at 5 dpf found a significant acceleration of lipid accumulation after only one day of feeding, providing a more rapid model for studying lipid accumulation [65].

4.4. Skin Wound Model of Adult Zebrafish Type I Diabetes Induced by STZ Injection

The full-layer wound healing mechanism of zebrafish is very similar to that of humans. On the one hand, in the embryonic and larval stages, the skin of zebrafish is already composed of the outer layer of peritrind, the middle layer of epidermis, and the basal layer attached to the basal membrane. In the process of metamorphosis on the 25th day after fertilization, multiple layers of epidermis are formed. At the same time, fibroblasts penetrate the dermis and take over collagen produced by basal keratinocytes to form locally thickened dermal papilla and scale, which is very similar to human skin structure. On the other hand, skin healing of zebrafish involves activation of signal transduction pathways downstream of hydrogen peroxide, including epidermal growth factor EGF, forkhead box-1, and IkappaB kinase-alpha. EGF regulates TGF-β through ERK1/2 and EGFR signal transduction. Damaged cells bind to EGFR to trigger cascades (such as TGF-β/integrin and ROCK/JNK pathways) to induce DNA synthesis and cell proliferation at the wound site.

5. Conclusions

Delayed wound healing induced by diabetes results in a heavy burden on patients physically, mentally, and economically. To discover specific drugs with excellent efficacy, it is essential to investigate the specific mechanism behind the delayed feature utilizing appropriate preclinical research models. Zebrafish are characterized by high throughput, small ethical disputes, larval body transparency, quick development, fast and efficient establishment of a model of diabetes, convenient caudal fin regeneration of wound repair evaluation, and are the height of human gene homology, etc. In addition, quantitative gavage and feeding shrimp with high glucose can solve restrictions such as water-soluble exposure and potential damage by injection. Zebrafish will become an ideal model for diabetic wound model organisms in the future, bringing a new dawn for the screening of rapid healing treatment for diabetic wounds and the exploration of the underlying mechanism.

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Subjects: Others
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Da Sun
,
Jiahui Ma
,
Yimeng Fang
,
Bangchang Lin
,
Pengyu Lei
,
Lei Wang
,
Linkai Qu
,
Wei Wu
,
Libo Jin
View Times: 354
Revisions: 2 times (View History)
Update Date: 10 May 2023
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