Stem Cell Therapy: 3D Skin Regeneration

Abstract

Wound treatment today has minimal efficiency and is economically unfeasible. As a result, regenerative medicine has emerged as a viable option for improving healing outcomes while potentially lowering long-term costs. Regenerative treatment focuses primarily on stem cells, which have the potential to self-renew and differentiate into a variety of cell types and are essential for physiologic tissue renewal and damage repair. Human stem cells may provide significant potential for gene therapy, drug discovery, and regenerative medicine by supplying undifferentiated and differentiated cells. The primary clinical goal of stem cell therapy in wound care is to improve wound healing quality. Embryonic stem cells, iPSCs, mesenchymal stem cells, and hematopoietic stem cells are only a few of the cell types that are currently being studied. According to new research, Autologous MSC treatment in cutaneous healing has shown significant potential as a therapeutic agent in clinical practice. The following review will elucidate the significance of utilizing stem cells for tissue regeneration.

Introduction

 

The skin, the body's biggest organ, has various purposes, including serving as a barrier for protection and dehydration prevention, as a sensory and thermoregulatory organ, and as a location for vitamin D production and immunological surveillance (1). The epidermis and dermis are the two primary layers of skin. The epidermis is arranged morphologically into distinct layers that reflect the sequential differentiation of keratinocytes as they migrate from the basal layer, where they have lost their ability to proliferate, to the outermost cornified layers where they are sloughed off (2).

An open wound is a form of injury in which the skin is ripped, sliced, or pierced, causing normal anatomic structure and function to be disrupted (3). Normal wound healing is made up of a well-coordinated process of cell migration, proliferation, and extracellular matrix deposition that goes through three separate but overlapping phases of inflammation, proliferation, and maturation (4) and is considered an extremely crucial factor for survival. In situations like diabetes, infection, or radiation exposure, cellular and molecular signaling disruption can lead to ineffective recovery. Surgical to unintentional lacerations, burns, pressure ulcers, diabetic ulcers, and venous ulcers are just some of the skin wounds that can occur. Selecting suitable dressings to maintain a favourable wound-healing environment, manage infection, debride the tissue, and address underlying causes such as ischemia and diabetes are common wound care procedures. In today's medical practice, chronic cutaneous wound healing frequently requires substantial, long-term medical treatment and costs a significant amount of money (5).

Traditional or usual chronic wound healing methods involve debridement. Doctors and nurses frequently remove dead or inflammatory tissue while treating chronic wounds. Debridement is the term for this procedure. Tweezers, a sharp spoon-like device known as a curette or a scalpel, are used to remove the tissue. In some instances, an enzyme-based gel is used to assist in cleaning the wound. A high-pressure water jet can also be used to clean the wound. Another method of debridement is to employ a specific type of maggot (fly larvae) that has been carefully developed for medicinal use. The maggots are applied directly to the incision or in a pouch. They clean the wound of dead tissue and fluid. Debridement is typically unpleasant; thus, a topical anesthetic is given to alleviate the discomfort. Using an ointment, for example. Painkillers might also be administered before treatment if more severe pain is predicted. Larger wounds may require general anesthesia to be cleansed. Unfortunately, there is insufficient information on the benefits and drawbacks of different debridement methods to determine their effectiveness.

Wound treatment today has minimal efficiency and is economically unfeasible. As a result, regenerative medicine has emerged as a viable option for improving healing outcomes while potentially lowering long-term costs. Regenerative treatment focuses primarily on stem cells, which have the potential to self-renew and differentiate into a variety of cell types and are essential for physiologic tissue renewal and damage repair. Stem cell-based treatments are becoming more common in translational medicine as fundamental research, particularly preclinical models, improves our understanding of stem cell biology. The current review focuses on the involvement of several endogenous and adult stem cells in cutaneous wound healing.

Wound healing using cells

Human stem cells may provide significant potential for gene therapy, drug discovery, and regenerative medicine by supplying undifferentiated and differentiated cells (6). The primary clinical goal of stem cell therapy in wound care is to improve wound healing quality. The medical practitioner uses stem cells to achieve faster healing, avoid wound contracture and scar formation, close wounds sooner, and, ideally, regenerate the skin and its appendages using stem cells (7). Furthermore, stem cells could be transduced ex vivo, and modified cells could be reintroduced back into the host. Manipulated stem cells may potentially provide novel treatment options for specific illnesses. Wound healing is a complicated process regulated by various secreted substances such as cytokines, chemokines, and growth factors. In principle, using stem cells to treat wounds is better than using a single medication because stem cells have the unique ability to interact with the wound environment and control their activity to release numerous substances that aid wound healing.

Embryonic Stem Cells (ESCs)

Embryonic stem cells (ESCs) are pluripotent cells that live inside the blastocyst and are pluripotent in nature. These cells have the ability to develop into one of three germ layers: endoderm, mesoderm, or ectoderm (8). In addition, ES cells can develop into brain cells, blood cells, adipocytes, chondrocytes, muscle cells, and skin cells, among other cell types (9).

Induced Pluripotent Stem Cells (IPSCs)

iPSCs are multipotent cells with self-renewal capabilities that are generated from differentiated adult somatic cells, such as fibroblasts and keratinocytes, employing transcription factors (e.g., Oct-3/4, Sox2, c-Myc, and KLF4) [54–56]. iPSCs, unlike ESCs, not only eliminate ethical concerns and minimise the risk of immunological rejection when used therapeutically (10). In 2006, Yamanaka et al. (11). The injection of four genes (Oct-3/4, Sox2, c- Myc, and KLF4) into cells from the mouse tail might convert the cell back to an embryonic stage, according to researchers at Kyoto University in Japan. In 2007, human cells were used to create iPS cells. In terms of shape, proliferation potential, gene expression pattern, pluripotency, and telomerase activity, these induced pluripotent stem cells were found to be very comparable to ESCs.

Mesenchymal Stem Cells

MSCs are defined by their ability to adhere to a plastic surface, their expression of the surface markers CD73, CD90, and CD105, their lack of expression of hematopoietic markers CD14, CD34, CD45, CD11b/CD79, and CD19/HLA-DR, and their ability to differentiate along osteoblastic, adipocytic, and chondrocyte pathways, according to the International Society of Cellular Therapy (ISCT) (13). MSCs with phenotypic variability may be produced from bone marrow and other tissues such as adipose tissue, nerve tissue, umbilical cord blood, and dermis. Unlike embryonic stem cells, the use of mesenchymal stem cells in regenerative medicine might sidestep ethical concerns.

Hematopoietic Stem Cells

Surface markers can be used to separate HSC from the bone marrow (BM), umbilical cord blood, and peripheral blood. After clinical HSC transplantations such as BM or peripheral blood mononuclear cells (PBMC), skin "chimerism" (identifying of epithelial cells of donor genotype) has been seen on many occasions (14). In addition, research found that human umbilical cord blood stem cells had the ability to differentiate into keratinocytes in vitro (15). Aside from plasticity, the role of HSC in angiogenesis is also seen in a myocardial infarction model, which is essential and might be linked to the complete and functional regeneration of skin tissue (16).

Clinical applications

In this expanding area, adult stem cells are gaining traction. Many have been isolated to date, including BMSCs, bone marrow-derived mononuclear stem cells, umbilical cord-derived mesenchymal stem cells (UC-MSCs), adipose-derived stem cells (ASCs), peripheral blood mononuclear cells, placenta-derived stem cells, human foetal aorta-derived progenitor cells, and mesenchymal stem cells (MSCs), the last of these being well described and most commonly used in preclinical and clinical studies (17). Rodriguez-Menocal et al. (18) recently showed that, compared to cultured bone marrow cells or BM-derived MSCs, cells from entire bone marrow had the highest beneficial impact on wound healing both in vivo and in vitro. By speeding wound healing, increasing re-epithelialization, boosting angiogenesis, displaying flexibility, and releasing paracrine signalling molecules. (19) These cells can be sprayed, injected, or administered systemically to the wounds or given through skin scaffolds. (20)

Conclusion

It is clear that stem cells have a great deal of promise for cutaneous tissue regeneration, as they can replace damaged tissue and stimulate wound healing via a paracrine mechanism. Embryonic stem cells, iPSCs, mesenchymal stem cells, and hematopoietic stem cells are only a few of the cell types that are currently being studied. According to new research, Autologous MSC treatment in cutaneous healing has shown significant potential as a therapeutic agent in clinical practice. Adult stem cells and iPS cells are available in the patient, allowing for the generation of these structures without the danger of immunological rejection. Even though progress in the field of hiPSCs has been exponential, much remains to be learned and improved upon in terms of the reprogramming process itself, cell differentiation potential, the difference between iPSCs and ESCs, the "dark side" of induced pluripotency, and their potential use in clinical therapy.

By: Areesha Ameem 

References

1. Lee S.H., Jeong S.K., Ahn S.K. An update of the defensive barrier function of the skin. Yonsei Med. J. 2006;47:293–306. DOI: 10.3349/ymj.2006.47.3.293.
2.  Bouwstra J.A., Ponec M. The skin barrier in healthy and diseased state. Biochim. Biophys. Acta. 2006;1758:2080–2095. doi: 10.1016/j.bbamem.2006.06.021.
3. B. S. Atiyeh, J. Ioannovich, C. A. Al-Amm, and K. A. El-Musa, "Management of acute and chronic open wounds: the importance of moist environment in optimal wound healing," Current Pharmaceutical Biotechnology, vol. 3, no. 3, pp. 179–195, 2002.
4. B. S. Atiyeh, J. Ioannovich, C. A. Al-Amm, and K. A. El-Musa, "Management of acute and chronic open wounds: the importance of moist environment in optimal wound healing," Current Pharmaceutical Biotechnology, vol. 3, no. 3, pp. 179–195, 2002.
5. B. S. Atiyeh, J. Ioannovich, C. A. Al-Amm, and K. A. El-Musa, "Management of acute and chronic open wounds: the importance of moist environment in optimal wound healing," Current Pharmaceutical Biotechnology, vol. 3, no. 3, pp. 179–195, 2002.
6. C. Roh, Q. Tao, C. Photopoulos, and S. Lyle, "In vitro differences between keratinocyte stem cells and transit-amplifying cells of the human hair follicle," The Journal of Investigative Dermatology, vol. 125, no. 6, pp. 1099–1105, 2005.
7. Butler KL, Goverman J, Ma H, Fischman A, Yu Y-M, Bilodeau M, Rad AM, Bonab AA, Tompkins RG, Fagan SP. Stem cells and burns: review and therapeutic implications. J Burn Care Res. 2010;31:874–81.
8. J. A. Thomson, J. Itskovitz-Eldor, S. S. Shapiro et al., "Embryonic stem cell lines derived from human blastocysts," Science, vol. 282, no. 5391, pp. 1145–1147, 1998.
9. Gauglitz GG, Jeschke MG. Combined gene and stem cell therapy for cutaneous wound healing. Mol Pharm. 2011;8:1471–9.
10. P. Guha, J. W. Morgan, G. Mostoslavsky, N. P. Rodrigues, and A. S. Boyd, "Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells," Cell Stem Cell, vol. 21, no. 1, pp. 144–148, 2017
11. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.
12. Yamanaka S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell. 2007;1:39–49.
13. Dominici M, et al: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315-317.
14. M. Korbling, R. L. Katz, A. Khanna et al., "Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells," The New England Journal of Medicine, vol. 346, no. 10, pp. 738–746, 2002.
15. L. P. Kamolz, A. Kolbus, N. Wick et al., "Cultured human epithelium: human umbilical cord blood stem cells differentiate into keratinocytes under in vitro conditions," Burns, vol. 32, no. 1, pp. 16–19, 2006
16. L. P. Kamolz, A. Kolbus, N. Wick et al., "Cultured human epithelium: human umbilical cord blood stem cells differentiate into keratinocytes under in vitro conditions," Burns, vol. 32, no. 1, pp. 16–19, 2006
17. Shabbir A., Cox A., Rodriguez-Menocal L., Salgado M., van Badiavas E. Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells Dev. 2015;24:1635–1647. doi: 10.1089/scd.2014.0316.
18. Rodriguez-Menocal L., Shareef S., Salgado M., Shabbir A., van Badiavas E. Role of whole bone marrow, whole bone marrow cultured cells, and mesenchymal stem cells in chronic wound healing. Stem Cell Res. Ther. 2015;6 doi: 10.1186/s13287-015-0001-9.
19. Teng M., Huang Y., Zhang H. Application of stems cells in wound healing—an update. Wound Repair Regen. 2014;22:151–160. doi: 10.1111/wrr.12152
20. Falanga V., Iwamoto S., Chartier M., Yufit T., Butmarc J., Kouttab N., Shrayer D., Carson P. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 2007;13:1299–1312.