Growth proteins: They call the shots
Growth proteins help our tissues develop and grow, build and repair.
Conclusion:
The growth proteins discussed in this article are essential for growth and repair of tissues. They are critical in the health of our bodies. This article is a snapshot and a prelude for future articles on how to much growth protein activation of cells can be detrimental over time.
Growth proteins: Replacing 330 billion cells a day
Growth proteins are molecules that we can't live without. These are the proteins that go into action when we cut ourselves or suffer a bruise. But they are also always working behind the scenes telling stem cells to produce daughter cells to replenish lost intestinal or skin cells.
Our small intestinal lining replaces its cells every 3-5 days (1) and the skin cells from our epidermis are replaced every 6-8 weeks (2). This cell turnover means that the body has to replace a whole lot of cells every day, to the tune of 330 billion cells (when you add blood cells that are also replaced) (3)!
To do this, tissues use growth proteins. They are non-stop helpers. Throughout our life, they are critical in the repair, rebuilding, and replacing injured and dying cells. In this article, I will introduce some of the positive effects of growth proteins.
Growth proteins in development
Let's take an example of two of the most commonly studied growth proteins, the Insulin-like growth Factor-1 (IGF-1) and the Transforming Growth Factor-beta. While many of us think of growth factors as building proteins, they are also critical in the organ development in the fetal stages of life.
Insulin-like Growth Factor-1
During fetal development, the IGF-1 protein promotes the proliferation of cartilage-forming cells (chondrocytes). The new cartilage transforms into bone to generate our skeletal structure.
The IGF-1 protein is also involved in muscle development. Cells differentiate into muscle cells (myocytes) and then fuse to organize into muscle. Thus, the IGF-1 protein is critical in the musculoskeletal development of the growing fetus.
In humans, low levels of IGF-1 during pregnancy have been linked to Intrauterine Growth Restriction (IUGR). The fetus does not grow at a normal rate and has a low birth weight. Unfortunately, having IUGR puts the infant at higher risk for multiple diseases later in life (diabetes, cardiovascular disease) (4).
Transforming Growth Factor-beta
During fetal development, the TGF-β protein promotes the formation of the cardiovascular system. This protein tells the cells which line blood vessels (endothelial cells) to proliferate and create new ones. This angiogenesis process ensures that there are new blood vessels that oxygenate the tissues of the growing fetus.
The TGF-β is also involved in the heart organ's development. It supports the specialization of cells into cardiac cells as a prelude to the formation of the heart chambers and valves.
Abnormalities in the TGF-β protein systems are associated with abnormalities in the skull/face during fetal development (for example, cleft palate) as well as vascular abnormalities. For example, the Loeys-Dietz syndrome is caused when there are abnormalities in the TGF-β protein/receptor system: This condition is characterized by skeletal defects in the spine and skull, vascular abnormalities involving the aorta, as well as skin pathology (5).
TGF-beta is critical in early amphibian development
To emphasize the importance of growth factors like TGF-beta, one has to look at development in lower life forms. For example, the metamorphosis of tadpoles to frogs relies critically on this growth factor. Tadpoles cannot develop into healthy frogs (tail remains and limbs do not form normally) when there is defective signaling in the TGF-β family of proteins.
Both IGF-1 and TGF-β are essential to normal fetal development and their disruption results in significant pathology. Let's explore other growth proteins and their role in tissue repair.
Growth proteins in tissue repair
Many factors are responsible for tissue repair. The two I have already touched on - Insulin-like Growth Factor-1 and the Transforming Growth Factor-beta are known to have strong roles in controlling cell growth as well as producing the cementing matrix that cocoons the cells within tissues. Both IGF-1 and TGF-beta are important in tissue healing (6, 7).
Here are four other growth proteins that are critical in tissue repair:
- Epidermal growth factor (EGF)
- Fibroblast Growth Factor (FGF)
- Platelet-derived Growth Factor (PDGF)
- Vascular Endothelial Growth Factor (VEGF)
Interestingly, each has a role in activating different cells within tissues. Can you visualize what the skin has to do when there is a cut?
Very quickly, inflammatory proteins are released into the area and platelets are recruited to the injured area. They aggregate and create a clot to stop further bleeding.
Further steps in wound healing
As importantly, platelets release many of the growth factors listed. Here is their role in wound healing (8, 9):
- PDGF attracts neutrophils come to the area to attack any bacteria.
- TGF-β helps monocytes transform into scavenger cells (macrophages). This results in even more growth factor release into the injured tissue. (FGF, EGF, TGF-β, and PDGF)
- VEGF and FGF released from platelets help endothelial cells proliferate and form new blood vesses.
- This sets the stage for many of the growth proteins to allow fibroblasts to infiltrate into the injured tissue. These specialize into myofibroblasts to create boundaries for the newly formed tissues;
- Epidermal growth factor (EGF) helps skin cells migrate towards areas of injury. The cells help lay a matrix of collagen fibers that lays the foundation for cells to build granulation tissue .
- FGFs also encourages fibroblast proliferation; these cells are critical for collagen deposition which leads to healthy granulation tissue.
Within hours, there is a barrier formed by a collagen-studded matrix, and a thin layer of immature skin cells form on the surface. This is followed by adding layers of skin cells such that the barrier becomes fully epithelialized.
Clinical benefits from Growth proteins
Chronic wounds cause major morbidity and disability. Patients with diabetes and neuropathy in their legs are prone to developing foot ulcers. I remember clearly using one of the growth factors mentioned above (PDGF). We used a topical gel called becaplermin (Regranex), which is FDA-approved for the treatment of diabetic foot ulcers.
As noted, this growth protein recruits fibroblasts to the area, as well as stimulates new blood vessel formation by increasing levels VEGF in the injured area (9).
Thus, growth proteins are vital in the repair and rebuilding of injured cells. They help cells divide, migrate to the area of injury, and help cells change into the necessary type of cells for the tissue. As importantly, the lay down the protein cement that serves as scaffolding for the newly available cells.
References
- Kai Y. Intestinal villus structure contributes to even shedding of epithelial cells. Biophys J. 2021 Feb 16;120(4):699-710. doi: 10.1016/j.bpj.2021.01.003. Epub 2021 Jan 14. PMID: 33453270; PMCID: PMC7896031.
- Koster MI. Making an epidermis. Ann N Y Acad Sci. 2009 Jul;1170:7-10. doi: 10.1111/j.1749-6632.2009.04363.x. PMID: 19686098; PMCID: PMC2861991.
- Sender, R., Milo, R. (2021). The distribution of cellular turnover in the human body. Nature Medicine, 27, 45-48.
- Martín-Estal I, de la Garza RG, Castilla-Cortázar I. Intrauterine Growth Retardation (IUGR) as a Novel Condition of Insulin-Like Growth Factor-1 (IGF-1) Deficiency. Rev Physiol Biochem Pharmacol. 2016;170:1-35. doi: 10.1007/112_2015_5001. Erratum in: Rev Physiol Biochem Pharmacol. 2016;170:129. doi: 10.1007/112_2016_1. PMID: 26634242.
- Loeys BL, Dietz HC. Loeys-Dietz Syndrome. 2008 Feb 28 [Updated 2018 Mar 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.
- Yakar, S., & Adamo, M. L. (2012). Insulin-like growth factor 1 physiology: lessons from mouse models. Endocrinology and Metabolism Clinics of North America, 41(2), 231-247.
- Massagué, J. (2012). TGFβ signalling in context. Nature Reviews Molecular Cell Biology, 13(10), 616-630.
- Singh B, Carpenter G, Coffey RJ. EGF receptor ligands: recent advances. F1000Res. 2016 Sep 8;5:F1000 Faculty Rev-2270. doi: 10.12688/f1000research.9025.1. PMID: 27635238; PMCID: PMC5017282.
- Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008 Sep-Oct;16(5):585-601. doi: 10.1111/j.1524-475X.2008.00410.x. PMID: 19128254.