INTRODUCTION:

Wound healing is described as a process in which inflammation and remodelling go hand in hand to reconstruct the dermal and epidermal layers of the skin. The usual wound healing process falls short of fully restoring skin function in pathological conditions such as diabetes or severe burns, raising the risk of life-threatening infections or ulcers¹. The healing process typically begins with haemostasis, which serves to control blood loss and prevent microbes from invading the wounded area.

This is swiftly followed by an inflammatory phase, where neutrophils, which are pro-inflammatory cells, are initially up-regulated and later followed by macrophages that remove debris and pathogens, as well as growth factors and other cytokines and cells. The proliferative phase overlaps with the inflammatory phase, during which the formation of new tissue, blood vessels (angiogenesis), and matrix construction is initiated to fill the wound area.

Finally, the remodelling phase increases the tensile strength of the extracellular matrix and reduces blood supply to the damaged region². People with diabetes experience delayed healing due to a variety of causes which can include lower peripheral blood flow and local (decreased) angiogenesis as well as impaired cell and growth factor responsiveness. In diabetic patients, restricted oxygen supply to the wound is caused by vascular dysfunction and neuropathy. Additionally, wound cells in inflammation consume oxygen at a high rate, further contributing to hypoxia. In diabetic patients, an imbalance may occur between angiogenic factors (including TGF-β, FGF2, VEGF, angiopoietins) and angiostatic factors (such as thrombospondins, endostatin, angiostatin), which can exacerbate wound hypoxia. Furthermore, hypoxia can amplify the inflammatory response, leading to increased oxygen radicals and an extended healing period³. Stem Cell Therapies stands as a huge potential to aid in wound healing using living cells as a regenerative therapy. Stem cells can be extracted from any tissue, however the most common type is the mesenchymal stem cells.However other sources of stem cells like epithelial stem cells may also improve soft tissue regeneration and wound healing ⁴.Stem cells have a huge potential to improve tissue regeneration and repair after injury especially for diabetic patients⁵. Mesenchymal stem cells play a significant function in accelerating the repair of ulcer ⁶. Additionally, MSC’s are known to produce anti-fibrotic consequences by suppressing inflammation ⁷.While embryonic stem cell (ESC)-derived MSC are more potent than those derived from adults, their use is limited due to ethical considerations, invasive harvesting techniques, immunogenicity, and limited cell survival in vivo^8.The focus of this article is to analyse both traditional and contemporary techniques for treating diabetic wounds, as well as the roles of stem cells in wound care management. Moreover, the article highlights the crucial molecular characteristics and factors that influence the molecular mechanisms of stem cells involved in the process of wound healing.

CONVENTIONAL THERAPY:

Wound care is one of the most important elements for diabetic wounds’ management. As for the choice of wound management for diabetic patients as of now, there is no established standard⁹. Debridement is the process of removing dead, damaged, or contaminated tissue, which enhances the ability of the remaining healthy tissues to heal. After debridement, the usage of antibiotics and several different types of dressings help reduce the chances of further infection. Topical antibiotics are less harmful and provide broad-spectrum antibacterial protection. The use of antibiotics must be directed by the proper cultures. Antibiotic misuse may result in resistance and negative outcomes. Wet-to-dry dressing also known as mechanical debridement is one of the least expensive dressings in use worldwide. It is very absorbent and adherent, but depending on the severity of the wound, it must be changed frequently. Tulle dressings are made of gauze that has been treated with paraffin. The paraffin reduces dressing adherence, but if the dressing dries out, the paraffin virtue is gone. Earlier research that evaluated the rates of re-epithelialization between moist environment dressings and conventional dry dressings provided strong support for the use of Tulle’s dressing. Additionally the application of many medicinal plants and herbs in wound healing therapy has demonstrated notable advantages, whether utilized in isolation ^{10, 11, 12}, or in formulation ^13,14. The primary mechanism of these plants' or herbs' in wound-healing qualities is their potent anti-inflammatory and antioxidant actions, which speed up the healing process¹¹, diminished characteristics of epithelialization ¹² as well as angiogenic and mitogenic potentials¹⁴.

MSC-Derived, Administrationand Mechanism (Angiogenesis/SCAR Formation):

Administration:

The method of delivery of MSCs for therapeutic applications is a major concern. The two traditional modes of MSC delivery are intravenous and topical administration. A study done to study the efficacy of IV and topical MSC administration to treat diabetic wounds in mice indicated that rats that were treated with IV MSCs showed better perfusion and lower blood glucose¹⁵. According to another comparative study of the efficacy of intravenous and topical administration, while intravenous administration may yield faster results, topical administration is preferred as there is a lesser risk of adverse reaction¹⁶. Furthermore, the intravenous injection could rapidly accumulate in the liver and spleen, further reducing its therapeutic effect. Another phenomenon associated with systemic administration is called “Lung Entrapment” where MSCs get trapped in the lungs without effectively reaching the target tissue¹⁵.Another research which used MSCs to accelerate the wound healing in Wistar rats with streptozotocin-induced diabetes used immunohistochemical analysis and flow cytometry to find that after topical subcutaneous injection of MSCs, the MSCs remained in the bloodstream for about 4 weeks¹⁷. This delivery method unfortunately carries the risk of causing further injury to the wound site. A better option is to administer the MSCs or MSC-derived extracellular vesicles (MSC-EV) along with the dressing to prevent further injury to the wound site and increase retention in the wound area¹⁸.

Mechanism:

The process of wound healing has 4 different phases, namely, haemostasis, inflammation, proliferation, and maturation.

Haemostasis:

Studies have shown that the surface of MSCs, as well as MSC-EVs, have a high content of tissue factor (TF) and phosphatidylserine which is responsible for triggering coagulation. A study involving the addition of MSCs to platelet-free plasma still triggered fibrin clot formation, suggesting that platelets are not required for clot formation by MSCs¹⁹.

Inflammation:

MSCs have several anti-inflammatory mechanisms that can improve tissue regeneration. It has been shown that MSCs could polarise inflammatory M1 macrophages to anti-inflammatory M2 acrophages thus suppressing TNF-α release from the M1 macrophages²⁰. Additionally, it also increases TGF-β which induces myofibroblast-driven wound contraction. Furthermore, it modulates Th1-Th2 cytokine balance which increases the production of several anti-inflammatory cytokines such as IL-4, IL-6, IL-10 etc. and decreases the production of proinflammatory cytokines like IL-1 &IFNy which are also involved in pathological pain. MSCs also suppress Natural Killer cells which in turn suppresses cytotoxicity. MSCs have also been shown to upregulate antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) which aids in reducing oxidative stress by reactive oxygen species²¹. MSC-EVs have also shown the capability to reduce myeloperoxidase (MPO) and caspases (caspase-3, caspase-8 and caspase-9), thus further reducing oxidative stress and apoptosis respectively²².

Proliferation:

MSC treatment enhances the migration of fibroblasts and keratinocytes which are crucial for the proliferative stage of wound healing. MSC-EVs have also been proven to increase the expression of Proliferating Cell Nuclear Antigen (PCNA, Cytokeratin 19 (CK19) and collagen type I (as opposed to collagen type III)²³. PCNA helps to regulate the cell cycle and is crucial for DNA replication. It has also been shown that MSCs also play a role in maintaining the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). MMPs are responsible for the degradation of the extracellular matrix(ECM). TIMPs bind to MMPs and prevent ECM degradation. Essentially MSCs saturate the site of the wound with both MMPs and TIMPs. MMPs and TIMPs interact with each other so the end result is that MMP activities will be highly regulated, and collagen and elastin production happen smoothly, thus further enhancing ECM remodelling.

Maturation:

During this phase, MSCs release hepatocyte growth factor (HGF) which is necessary to prevent fibrosis. It also secretes adrenomedullin which is a peptide with angiogenic and antimicrobial properties. Some MSCs that migrate into the wound will secrete prostaglandin E2 (PGE2) which inhibits myofibroblast differentiation. Nearby cells are also signalled by the MSCs to produce ECM in the correct orientation to resemble the dermal tissue by upregulation of integrin alpha-7 and downregulation of ICAM1 and VCAM1. The aforementioned regulation is crucial for proper cell-matrix interaction. Most importantly MSCs secrete several proangiogenic factors such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). This promotes neovascularisation which is very important to complete healing of the wound as well as maintain perfusion in the area²⁴.

Molecular Pathway:

While all the molecular pathways followed by MSCs are not fully understood, there is evidence showing that MSCs can regulate the TGF-β/Smad signalling pathway to improve cutaneous wound healing and restore skin function and perfusion. The TGF-β/Smad signalling pathway plays a vital role in promoting wound healing. Smad is a transcription factor which is known to induce fibroblast differentiation. In this pathway, TGF-β activates the downstream mediators Smad2 and Smad3 to induce the expression of α-SMA. Moreover, when Smad2/Smad3 are phosphorylated, they induce Smad7 which causes negative feedback regulation of TGF-β1. A study used Western blotting and RT-qPCR to analyse the expression of TGF-β1(fibrotic isoform), TGF-β3 (anti-fibrotic isoform), Smad2, Smad3, Smad4, and Smad7. It was found that in the trial group treated with MSCs, MSCs upregulated TGF-β3 by inhibiting Smad7 which led to the increased expression of α-SMA via the TGF-β/Smad signalling pathway²⁵. This increased expression of α-SMA leads to a significant improvement in cutaneous wound healing by playing a role in dermal fibroblast proliferation and neovascularization. Tissue regeneration by reducing tissue fibrosis and enhanced resident stem cell proliferation are the ultimate outcomes of MSCs'²⁶.

Figure 1: Illustration of MSCs regulating the TGF-β/Smad signalling pathway. MSC’s activate TGF-β3 and inhibit TGF-β1, which upregulates the phosphorylation of Smad2 and Smad3. This leads to the transcription and expression of α-SMA, which plays a role in dermal fibroblast proliferation and neovascularization. Inhibitory Smad7 is also stimulated which leads to negative feedback regulation of TGF-β1.

COMPARATIVE STUDY ON STEM CELLS:

Efforts have been focused on untying the features of a mesenchymal stem cell population ever since its discovery and separation. International Society of Cellular Therapy (ISCT) has documented certain cell surface markers which have to be expressed or unexpressed for a population of cells to be identified as mesenchymal stem cells. CD29, CD44, CD90, CD49a-f, CD51, CD73 (SH3), CD105 (SH2), CD106, CD166, and Stro-1 are markers that are required to be expressed while cells should lack expression of CD45, CD34, CD14 or CD11b, CD79a orCD19 and HLA-DR surface molecules²⁷.

One of the studies categorized the currently known 40 surface markers of cancer stem cells (CSC) into three distinct groups based on their expression in human embryonic stem cells (hESCs), adult stem cells, and normal tissue cells. They observed that almost 73% of the known CSC surface markers are found to be existing on embryonic or adult stem cells, while they are hardly noticed on normal tissue cells. Conversely, the remaining CSC surface markers are expressed to a large extent in normal tissue cells, and several research groups have extensively validated them as CSC surface markers. For instance, cell surface markers such as CD271, CD33, CD56, CD105, CD54, CXCR1, and CXCR2 are mainly expressed in adult mesenchymal stem cells and CSC of melanoma, liver, lung, and other cancers, but their expression is rare in normal stem cells. Conversely, markers like CD9, CD166, CD29, and CD144 are expressed in both mesenchymal stem cells and normal cells, besides in certain cancer stem cells. SSEA3, SSEA4, CD90, POPXL-1, CD146, CD10, and CD117 are supplementary surface markers detected in mesenchymal stem cells and some cancer stem cells, but they are seldom detected in normal cells²⁸.

The influence of high blood sugar levels on the ability of aging MSCs to differentiate and express cell markers is still very ambiguous. Existing research indicates that hyperglycaemia negatively affects the differentiation of bone and cartilage cells and to a limited extent affects adipose cell differentiation²⁹. Studies indicate that the expression levels of stem cell markers in MSCs from both diabetic and non-diabetic donors are typically comparable. However, certain research suggests that elevated blood sugar levels might decrease the expression of stemness-related markers specifically in MSCs derived from sources like umbilical cord³⁰. Extensive downregulation of MSC markers in the subcutaneous adipose tissue of diabetic rats was observed by another study using systems biology approach³¹. In contrast to the aforementioned reports, some studies suggest that stemness markers are present at similar levels in both normal cells and cells growing under hyperglycemic conditions³². These contradictory results point to the fact that hyperglycemia may reduce the stemness of MScs however more research needs to be done to safely conclude their effect on identification markers of MScs.

SURVIVAL:

Diabetic wounds have a significant amount of hypoxia/ischemia which is why the wounds struggle to heal in the first place. A valid concern is how MSCs can survive in these conditions. Studies have shown that MSCs primarily rely on anaerobic respiration rather than mitochondrial aerobic respiration to tolerate short-term ischemia³³. Keeping this theory in mind, further studies have proved that over 90% of MSCs remained viable after a long-term ischemic condition provided that there was an adequate supply of glucose³⁴.

LIMITATIONS:

Treating chronic wounds efficiently still presents problems, despite breakthroughs in stem cell therapy. Mesenchymal stem cells, or MSCs, carry several hazards, including the possibility of cancer and thrombotic episodes brought on by TF and phosphatidylserine activity³⁵. Whether perinatal or adult, the best source of MSCs is still unknown. The variability of stem cells makes standardization challenging, and their erratic capacities for proliferation and differentiation make matters worse. Immunogenicity can be minimized by removing MSCs from patients, although older or diabetic patients may experience a decrease in MSC efficacy³⁶. Amplification techniques are expensive and time-consuming, yet they can produce vast amounts of stem cells. The functional diversity of MSCs poses obstacles to their widespread application and commercialization.

Studies on different MSC sources, such as bone marrow and adipose tissue, show notable variations that impact their therapeutic potential. Techniques for MSC growth, isolation, and classification must be standardized⁵. Despite encouraging results from clinical trials, additional investigation is required to fully comprehend MSC-derived signals and in vivo responses in wound healing.

ADVANCEMENTS IN STEM CELL THERAPY:

The prospect of finding an effective cure for chronic wounds as in diabetes has received a boost with the development of Induced pluripotent stem cells (iPSCs). Despite the tremendous progress made in tissue engineering there is still some dearth in scrutiny and projecting beneficial outcomes of tissues derived from cells generated from iPSC. No significant extrapolative data has been gathered with regard to their effectiveness. It has been shown that reengineered iPSC-derived cells can be arranged in 3D tissues to form extracellular matrix (ECM) which can then be transported and made to persist in the wound inflicted on the skin of diabetes demonstrating their ability to serve as cellularized scaffold biomaterials. Apart from this, to accelerate chronic wound healing iPSC-generated 3D tissues could be looked into as an ideal source for the delivery of cells and growth factors³⁷.

In recent years a lot of interest has developed in secretome engineering which aims to modify the secretome to improve therapeutic outcomes. Given its vital role in diverse areas of various cellular and tissue mechanisms like cell signalling, immune response, and repair of tissue, secretome has become an important target for therapeutic intervention. It has been found that boosting of the secretome released by the interaction between human mesenchymal stem cells(hMSC) and endothelial cells (EC) by adding re-engineered proteins like angiopoietin-1, angiopoietin-2, Fibroblast growth factor, Matrix metallopeptidase -9, and Vascular Endothelial Growth Factor demonstrated improved healing outcomes of diabetic cutaneous wound than by treatment with hMSCsecretome alone³⁸. An appropriate distribution mechanism to target tissue is paramount without which it can be exposed to unwanted exposure to enzyme activity existing at the target tissue and its likely spread to other tissues. It has been found that one of the most promising molecules to carry out a safe, controlled delivery of secretome are natural polymers owing to their biodegradable, biocompatible, and non-immunogenic properties³⁹. Another feasible therapeutic option which has been looked into in recent times for diabetic wounds with reduced blood supply is using the current knowledge regarding the angiogenic properties of Endothelial progenitor cell (EPC) and transplanting them to the chronic wound site to promote the formation of new blood vessels and tissue regeneration, speeding up the healing process. Toensure optimal functioning and enhanced performance of prevailing, but non-functional, EPCs under diabetic conditions various sources and methods have been looked into to generate EPCs. Some of the resources include transcription factors from somatic cells or induced pluripotent cells. Furthermore, chemicals and drugs have also been chosen to generate EPCs from adult stem cells⁴⁰.

Adipose tissue provides a higher yield of stem cells compared to bone marrow, making it one of its most ideal sources. However, the ability of these stem cells to reach the wound site is reduced in diabetic patients resulting in the wound progressing into a severe and prolonged state⁴¹. Moreover, their decreased expression of pro-angiogenic factors can be one of the major obstacles in their use in cellular therapy. Boosting the pro-angiogenic and regenerative abilities of human diabetic ADSCs can be achieved by a gene-activated scaffold making them parity with healthy ADSCs on a gene-free scaffold. Increased expression of SDF-1 α a chemokine, in diabetic ADSCs embedded in gene-activated scaffolds was observed on analysis of gene and protein expression. SDF-1α a chemokine, promotes recruitment of stem cells to the site of wound. The transfected diabetic ADSCs displayed enhanced wound healing properties, by demonstrating the active transformation of the provisional fibronectin matrix and increased representation of the basement membrane protein collagen type IV⁴².By using enriched serum and grown devices, mesenchymal stem cells can proliferate without causing inflammation to flare up again⁴³.The safety and effectiveness of stem cell therapy have improved significantly in recent years, thanks to the successful clinical trials conducted, leading to increased approvals by regulatory bodies like the FDA. With researchers deepening their understanding of stem cell behaviour at the cellular and molecular levels, they are now developing innovative techniques to maximize the therapeutic potential of these cells.All things considered, the ability of stem cells to self-renew and specialize into different types of cells has shown promise for the development of regenerative medicine in the future^44,45.

CONCLUSION:

Despite the many current therapeutic options, chronic wounds remain a major concern. Experiments in animal models, cell cultures, and clinical studies show that properly regulated stem cells have a positive influence on the biochemistry of the healing process. In particular, MSC and its secretions are promising treatments for accelerating wound healing due to their accessibility and well-established research. It is possible to enhance wound healing through the application of various stem cell modifications, co-cultures, and scaffolds. Further research is required to ascertain the molecular workings of stem cells and to raise their therapeutic effectiveness.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

AUTHOR’S CONTRIBUTION:

Data gathering and idea owner of this study: Zaina Nafees.

Study design and data collection: Karthik Nair, Murk Jaipal Paryani, Uvashree Shrinivas.

Editing and approval of final draft: Vijaya Paul Samuel.

Writing assistance and submitting manuscript: Naveen Kumar.

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Received on 27.05.2024 Revised on 09.08.2024

Accepted on 18.10.2024 Published on 24.12.2024

Available online from December 27, 2024

Research J. Pharmacy and Technology. 2024;17(12):6043-6049.

DOI: 10.52711/0974-360X.2024.00917