1. What Are the Stages of Wound Healing?

Homeostasis Phase

This phase involves blood vessels’ vasoconstriction (tightening) and platelet aggregation to stop blood loss at the injured site.  Platelet aggregation, also known as coagulation, relies on a primary homeostasis stage and a secondary homeostasis stage [2].

In the first stage, platelets aggregate to form a plug that prevents bleeding, and in the second. In the second stage, intrinsic and extrinsic coagulation pathways are activated through a series of clotting factors.

Intrinsic coagulation factors are activated by the wound-exposed endothelial collagen and include factors I (fibrinogen), II (Prothrombin), IX (Christmas factor), X (Stuart-Prower factor), XI (Plasma Thromboplastin), and XII (Hageman factor).

Extrinsic factors, also named stable factors are activated by tissue factors released by damaged endothelial cells and include factors I, II, VII, and X.

Inflammatory Response Phase

After coagulation, the vasoconstriction that characterizes the homeostasis phase is replaced by vasodilation (opening) that promotes the recruitment of inflammatory cells (neutrophils, monocytes, and endothelial cells) to the site of injury and their binding to the scaffolding that was constructed by the platelets’ aggregation.

Once on-site, neutrophils initiate the phagocytosis and killing of pathogens to decontaminate the wound, while also promoting cell proliferation and angiogenesis.

Besides their direct role in the phagocytosis and killing of pathogens, Monocytes which become macrophages, also remove apoptotic cells and support cell proliferation and tissue restoration following injury.

Endothelial cells are the building blocks for vessels, and during wound healing, these cells generate new vessels (angiogenesis) to satisfy the metabolic demands of the highly proliferative healing tissue. 

 Proliferation Phase

In this phase, keratinocytes, fibroblasts, macrophages, and endothelial cells are extensively activated to contribute to the closure, matrix deposition, and angiogenesis at the wound site [3]. 

keratinocytes in the surroundings of the wound migrate across the wound to reform the epidermal layer through a process known as epithelialization [4]. During this process, hair follicle stem cells are also activated to generate hair on the newly healed skin tissue.

While the epithelialization is ongoing, fibroblasts proceed to the breakdown of the fibrin clot and the deposition of a new extracellular matrix (ECM) and collagen to build structures that support the effective wound-healing effort of the other cells [5].

Although macrophages play a role during the inflammatory response phase, their functions during the proliferation phase are also critical in guiding the proper formation of vessels and in supporting fibroblasts in the breakdown of fibrin [6].

Remodeling Phase

This process is associated with the deposition of collagen by fibroblasts to replace the initial fibrin clot. Although collagen deposition contributes to the scarification of the wound, this deposited collagen is different from the one that was initially present in the unwounded tissue and will only confer for up to 80% of pre-wounding strength [7].

Other components that are required for the remodeling phase include myofibroblasts that secrete alpha-smooth muscle actin (α-SMA), necessary for the generation of strong contractile forces and focal adhesions, and elastin that provide skin elasticity to the healed wound.

2. What Slowdown Wound Healing?

Diabetes and Wound Healing

During the inflammatory response phase, vasodilation of the blood vessels is necessary for the recruitment of inflammatory cells (neutrophils, monocytes, and endothelial cells) to the site of injury.

However, due to the high levels of glucose in the blood of diabetics, the arteries are thickened, resulting in vasoconstriction of the blood vessels which slows down wound healing. 

Another pathological process that can slow down wound healing in diabetics is associated with nerve damage that is caused by high levels of glucose which leads to poor blood circulation.

Malnutrition and wound healing

Micronutrients (minerals and vitamins) and macronutrients (Proteins, lipids, and carbohydrates) are required for effective wound healing. For instance, proteins are necessary for the production of enzymes, collagen, and connective tissue during the remodeling phase of wound healing.  

Neutrophils, monocytes, fibroblasts, endothelial cells, and myofibroblasts require glucose to generate energy for their activity during wound healing. Lipids are necessary for the generation of new cellular membranes.

In addition, vitamin A enhances the early inflammatory response phase and promotes epithelial cell differentiation, and vitamin C promotes the migration of neutrophils and is necessary for the production of collagen.

Finally, zinc is required for DNA and protein synthesis, and cell division during the proliferation stage of wound healing [8].

Smoking and Wound Healing

Clinically, it is well accepted that cigarette smoking delays wound healing as the toxic constituents of cigarette smoke such as nicotine, carbon monoxide, and hydrogen cyanide can affect nutritional blood flow to the skin, which impairs healing of the injured tissue.

Carbon monoxide is known to reduce oxygen transport and metabolism’ while hydrogen cyanide is also a known inhibitor of enzymatic systems required for cellular oxidative metabolism and oxygen transport [9]. 

3. How to Improve Wound Healing?

The consumption of the following foods can improve wound healing:

• – Drinking plenty of water for hydration (if recommended).
• – Proteins (e.g., in lean meat, beans, lentils, and dairy products).
• –  Carbohydrates (e.g., in whole-grain bread and cereals, potatoes, and rice)
• – Vitamins and minerals: vitamin A (e.g., in the liver, milk, eggs, and leafy greens), vitamin C (e.g., in broccoli, strawberries, tomatoes, and kiwi), and Zinc (e.g., in seafood, beans, lentils, and whole-grain bread).

4. Frequently Asked Questions about What Are the Mechanisms of Wound Healing?

What are the stages of wound healing?

Wound healing typically progresses through three main stages: inflammation, proliferation, and remodeling.

What happens during the inflammation stage of wound healing?

During inflammation, the body’s immune response is activated to clear debris and prevent infection. Blood vessels constrict to reduce bleeding, followed by dilation to increase blood flow, bringing white blood cells to the wound site.

What occurs during the proliferation stage of wound healing?

In the proliferation stage, new tissue is formed to repair the wound. This involves the proliferation of fibroblasts, which produce collagen, as well as the formation of new blood vessels (angiogenesis) to supply nutrients to the healing tissue.

What is the role of fibroblasts in wound healing?

Fibroblasts are key cells involved in wound healing. They produce collagen, which provides structural support to the healing tissue, and they also help to contract the wound, reducing its size.

What is angiogenesis and why is it important in wound healing?

Angiogenesis is the formation of new blood vessels. It is crucial in wound healing because it ensures that the healing tissue receives an adequate blood supply, delivering oxygen and nutrients necessary for repair.

How does the remodeling stage contribute to wound healing?

During the remodeling stage, the newly formed tissue undergoes maturation and remodeling. Collagen fibers reorganize to increase tissue strength, and excess scar tissue may be broken down.

This stage can last for months to years, gradually improving the strength and appearance of the healed wound.

What factors can affect the wound healing process?

Various factors, including age, underlying health conditions (such as diabetes or immunodeficiency), nutritional status, medications (such as steroids or chemotherapy), and the presence of infection, can influence the speed and effectiveness of wound healing.

How can I promote optimal wound healing?

To support wound healing, it’s essential to maintain good overall health, including adequate nutrition, hydration, and hygiene.

Following medical advice regarding wound care, avoiding smoking, managing chronic conditions, and protecting the wound from further injury can also facilitate healing.

Conclusion

Wound healing involves the participation of different cells, cytokines, mediators, and the vascular system to repair the damaged tissue. However, to fuel this amazing repair machinery, an appropriate diet that provides proteins, lipids, carbohydrates, vitamins, and minerals is necessary for effective wound healing.

References

[1] Wallace, H.A., Basehore, B.M. and Zito, P.M., 2017. Wound healing phases.

[2] Chaudhry, R., Usama, S.M. and Babiker, H.M., 2018. Physiology, coagulation pathways.

[3] Wilkinson, H.N. and Hardman, M.J., 2020. Wound healing: Cellular mechanisms and pathological outcomes. Open biology, 10(9), p.200223.

[4] Santoro, M.M. and Gaudino, G., 2005. Cellular and molecular facets of keratinocyte reepithelization during wound healing. Experimental cell research, 304(1), pp.274-286.

[5] Driskell, R.R., Lichtenberger, B.M., Hoste, E., Kretzschmar, K., Simons, B.D., Charalambous, M., Ferron, S.R., Herault, Y., Pavlovic, G., Ferguson-Smith, A.C. and Watt, F.M., 2013. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature, 504(7479), pp.277-281.

[6] Willenborg, S., Lucas, T., Van Loo, G., Knipper, J.A., Krieg, T., Haase, I., Brachvogel, B., Hammerschmidt, M., Nagy, A., Ferrara, N. and Pasparakis, M., 2012. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood, The Journal of the American Society of Hematology, 120(3), pp.613-625.

[7] Young, A. and McNaught, C.E., 2011. The physiology of wound healing. Surgery (Oxford), 29(10), pp.475-479.

[8] MacKay, D.J. and Miller, A.L., 2003. Nutritional support for wound healing. Alternative medicine review, 8(4).

[9] Silverstein, P., 1992. Smoking and wound healing. The American journal of medicine, 93(1), pp.S22-S24.

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GDF11 has been proposed as a rejuvenating factor as it was reported that it restores skeletal muscle stem cell function and enhances muscle repair after injury.

In this blog, scientific literature on GDF11 is explored to clarify the potential role of this factor in tissue regeneration and longevity.

I. What Is the Function of GDF11 in the Body?

Before discussing the role of GDF11 in the body, it is important to provide information on its expression in adults and during embryogenesis.

1. Where Is GDF11 Expressed in Humans?

A. Where is GDF11 Expressed in Human Adults?

GDF11In humans, the GDF11 protein is highly expressed in the brain, testis, soft tissue, breast, placenta, prostate, stomach, epididymis, and gallbladder. It is mildly expressed in the intestines, salivary glands, the thyroid, the parathyroid, the adrenal gland, the liver, and the tonsils.

However, it appears that there is no protein expression in the other organs and tissues such as the heart, the skin, skeletal and smooth muscles, or the bone marrow [2].

B. Where is GDF11 Expressed During Human Embryogenesis?

Although based on RNA studies in mice, Gdf11 is mostly expressed in the primitive streak and tailbud regions. The primitive streak is a structure that generates new mesodermal progenitors (stem cells) that migrate and differentiate into the mesoderm germ layer that generates future cells such as cardiac muscle cells, skeletal muscle cells, tubule cells of the kidney, red blood cells, and smooth muscle cells (in the gut).

The Tail bud or caudal cell mass is the embryonic structure that is later responsible for the generation of the lower end of the spinal cord [3].

2. How does GDF11 Function?

As a member of the superfamily of the Transforming Growth Factor beta (TGF-β) and the subfamily of the BMP, GDF11 induces cellular signaling through the canonical (classical) signal transduction pathways involving R-SMADS and SMAD4.

However, GDF11 also induces cellular signaling through non-canonical pathways such as the MAPK (Mitogen-Activated Protein Kinase) pathway. Both signalings require the binding of GDF11 to the activin receptors type II A or B [4].

The activation of the canonical and non-canonical pathways results in the transcriptional induction of the expression of genes that control cell proliferation and differentiation, wound healing, and the immune system [5].

3. How Is GDF11 Activated?

Although little is known about the mechanisms that induce the expression of GDF11, a study showed that histone deacetylase 3 (HDAC3), might be involved. The inhibition of HDAC3 using the drug trichostatin A (TSA) promoted the expression of GDF11 [6].

4. What Is the Role of GDF11 in Regeneration?

Although performed in mice, several studies reported that GDF11 can reverse age-related cardiac hypertrophy, and dysfunction of skeletal muscles, accelerate skin wound healing, improve the neuronal activity in the hippocampus, and enhance angiogenesis by promoting the therapeutic functions of mesenchymal stem cells.

A. Does GDF11 Improve Age-Related Vascular and Neuronal Activity in the Hippocampus?

A study reported that bloodstream delivery of GDF11 to older mice improves vasculature and promotes neurogenesis in the hippocampus. The authors suggest that GDF11 could be used to improve the central nervous system function [7].  

B. Does GDF11 Reverse Age-Related Dysfunction of the Skeletal Muscle?

A study reported that the systemic delivery of GDF11 in older mice reverses functional deficiencies and restores the genomic integrity of muscle stem cells. The authors suggest that systemic delivery of GDF11 could be therapeutically used to reverse age-related skeletal muscle and stem cell dysfunction [8].

C. Does GDF11 Reverse Age-Related Cardiac Hypertrophy?

In aged individuals, heart hypertrophy is frequently associated with heart failure. Using a technique called parabiosis which consists of sharing circulation between younger and older mice with cardiac hypertrophy, a study reported that the hypertrophy was completely reversed in the older mice.

The authors identified GDF11 as the factor responsible and suggested that it could be used in therapy to reverse age-related cardiac hypertrophy [9].

D. Does GDF11 Accelerate Skin Wound Healing?

A study investigated the effects of topically applying truncated GDF11 on wound healing of diabetes mellitus (DM) mice models and reported that truncated GDF11 promotes skin wound healing by stimulating dermal fibrosis. They suggest truncated GDF11 could be used as a potential agent for treating skin wounds in the diabetic population [10].

E. Does GDF11 enhance Angiogenesis?

A study investigated the potential use of GDF11 capacity in inducing proangiogenic activities of mesenchymal stem cells (MSCs) for angiogenic therapy. They found that GDF11 promotes the therapeutic functions of MSCs that could be used for ischemic diseases [11].

II. Frequently Asked Questions about Is GDF11 a Rejuvenating Factor?

What is GDF11?

GDF11, or Growth Differentiation Factor 11, is a protein that belongs to the TGF-β superfamily and plays a role in various cellular processes, including cell growth, differentiation, and regeneration.

How does GDF11 relate to rejuvenation?

Studies have suggested that GDF11 levels decrease with age, and replenishing GDF11 levels in older animals has shown promising results in reversing age-related declines in various tissues and organs, suggesting a potential role in rejuvenation.

What evidence supports the rejuvenating effects of GDF11?

Research conducted on animal models, particularly mice, has demonstrated that restoring GDF11 levels can improve cardiac function, enhance muscle regeneration, and even reverse age-related cognitive decline.

Can GDF11 supplementation reverse aging in humans?

While animal studies have shown promising results, the effectiveness and safety of GDF11 supplementation in humans are still being investigated. Clinical trials are needed to determine its potential as a rejuvenating therapy in humans.

Are there any risks associated with GDF11 supplementation?

The long-term effects and potential risks of GDF11 supplementation in humans are not yet fully understood. Some studies have raised concerns about potential adverse effects, such as promoting tumor growth or exacerbating certain age-related conditions.

How is GDF11 administered for rejuvenation purposes?

In animal studies, GDF11 has been administered via injections or infusion directly into the bloodstream. However, the optimal dosage, frequency, and mode of administration for humans have yet to be determined.

What other factors contribute to aging besides GDF11 levels?

Aging is a complex process influenced by various genetic, environmental, and lifestyle factors. While GDF11 may play a role in certain aspects of aging, addressing other factors such as diet, exercise, and stress management is also important for overall health and longevity.

Is there ongoing research on GDF11 and rejuvenation?

Yes, research on GDF11 and its potential as a rejuvenating factor is ongoing. Scientists continue to investigate its mechanisms of action, potential benefits, and safety profile in both animal models and human clinical trials.

Conclusion

A rejuvenating function of GDF11 has been reported by several studies that involved different organs and tissues. However, all these investigations were performed in mice which may not result in similar outcomes in humans. Therefore, clinical trials using GDF11 would certainly determine if this factor is the “Mythical Fountain of Youth”.

References

[1] Morikawa, M., Derynck, R. and Miyazono, K., 2016. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harbor Perspectives in Biology, 8(5), p.a021873.

[2] https://www.proteinatlas.org/ENSG00000135414-GDF11/tissue

[3] Suh, J., Eom, J.H., Kim, N.K., Woo, K.M., Baek, J.H., Ryoo, H.M., Lee, S.J. and Lee, Y.S., 2019. Growth differentiation factor 11 locally controls anterior–posterior patterning of the axial skeleton. Journal of cellular physiology, 234(12), pp.23360-23368.

[4] Simoni-Nieves, A., Gerardo-Ramírez, M., Pedraza-Vázquez, G., Chávez-Rodríguez, L., Bucio, L., Souza, V., Miranda-Labra, R.U., Gomez-Quiroz, L.E. and Gutiérrez-Ruiz, M.C., 2019. GDF11 implications in cancer biology and metabolism. Facts and controversies. Frontiers in oncology, 9, p.1039.

[5] Morikawa, M., Derynck, R. and Miyazono, K., 2016. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harbor Perspectives in Biology, 8(5), p.a021873.

[6] Zhang, X., Wharton, W., Yuan, Z., Tsai, S.C., Olashaw, N. and Seto, E., 2004. Activation of the growth-differentiation factor 11 gene by the histone deacetylase (HDAC) inhibitor trichostatin A and repression by HDAC3. Molecular and cellular biology, 24(12), pp.5106-5118.

[7] Ozek, C., Krolewski, R.C., Buchanan, S.M. and Rubin, L.L., 2018. Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice. Scientific reports, 8(1), pp.1-13.

[8] Sinha, M., Jang, Y.C., Oh, J., Khong, D., Wu, E.Y., Manohar, R., Miller, C., Regalado, S.G., Loffredo, F.S., Pancoast, J.R. and Hirshman, M.F., 2014. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science, 344(6184), pp.649-652.

[9] Loffredo, F.S., Steinhauser, M.L., Jay, S.M., Gannon, J., Pancoast, J.R., Yalamanchi, P., Sinha, M., Dall’Osso, C., Khong, D., Shadrach, J.L. and Miller, C.M., 2013. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell, 153(4), pp.828-839.

[10] Li, Q., Jiao, L., Shao, Y., Li, M., Gong, M., Zhang, Y., Tan, Z., Wang, Y., Yang, X., Wang, Z. and Zhang, Y., 2020. Topical GDF11 accelerates skin wound healing in both type 1 and 2 diabetic mouse models. Biochemical and biophysical research communications, 529(1), pp.7-14.

[11] Zhang, C., Lin, Y., Zhang, K., Meng, L., Hu, X., Chen, J., Zhu, W. and Yu, H., 2021. GDF11 enhances therapeutic functions of mesenchymal stem cells for angiogenesis. Stem Cell Research & Therapy, 12(1), pp.1-17.

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