Understanding Growth Factors

By Dr Anna Hemming / 15 Oct 2019

In the first of a two-part article, Dr Anna Hemming discusses the science behind growth factors

The science and research behind medical aesthetic treatments continues to develop with new products, therapies and procedures emerging and the boundaries are being pushed continuously. In the late 1990s, during the research dissertation for my anatomy degree, I studied the effect of growth factors, specifically insulin-like growth factors (IGFs) and tumour necrosis factor (TNF), and their potential to kill breast cancer cells. Little did I realise that my laboratory research would feature in my aesthetic medicine career. Several years ago, I attended a session at the CCR conference where Singapore surgeon Mr Ivor Lim reignited my interest in the world of growth factors and the body’s ability to regenerate and heal from within.

By understanding and using our natural ability to mend, we can learn and reproduce some key elements to help speed up healing and increase stimulation to benefit our aesthetic procedures and use them as stand-alone treatments. In this article, I want to immerse you in the world of molecular biology. You will gain a greater understanding of what growth factors are, the different types and gain an understanding of where they come from.

The science

A growth factor is a signalling molecule; a natural substance with the capability to control cell activities in an autocrine, paracrine and endocrine manner.1 Growth factors can be a protein or hormone and are important for regulating a variety of cellular processes by acting as signalling molecules inside and between cells. They exert their biological functions by binding to specific receptors and activating signalling pathways which, in turn, regulate gene transcription in the nucleus and ultimately stimulate a biological response, shown in Figure 1.2 

The term ‘growth factor’ can be interchangeable with ‘cytokine’.3 It was initially thought that the two molecules had different affects; growth factors focused on cell growth and proliferation while cytokines linked to immunological or hematopoietic response. However, it has been found that they both have similar functions and therefore the terms are now used interchangeably. Similar to hormones, they bind to specific receptors on the surface of their target cell.3 A growth factor can have various functions on different cell types and affect a wide variety of physiological processes to stimulate cell growth, cell proliferation, wound healing, cellular differentiation, apoptosis, immunological or haematopoietic responses, angiogenesis or metabolism.1 

The activity can be productive as well as destructive and the abnormal production or regulation of growth factors can cause a variety of diseases including cancer,4 liver fibrosis5 and bronchopulmonary dysplasia.6 These properties were the instigation of my initial research in the potential use of growth factors to target and kill breast cancer cells in 1998.3

Figure 1: The communication between neighbour cells using signalling molecules2

Growth factors signal by different mechanisms:3

  1. Paracrine signalling between neighbouring cells to elicit a quick response for a brief duration due to degradation of the paracrine ligands
  2. Autocrine signalling within the cell through synthesis leading to a biological response within the same cell. Typically, within the cell cytoplasm or by secreting a growth factor which interacts with receptors on the surface of the same cell
  3. Endocrine signalling through the secretion of growth factors into the blood which are transported to the target cells where the response is triggered

There are family (simple groups) and super family (a group with lots of members, like IGF) classifications of growth factors based on structural and functional characteristics.7 The family groups often regulate specific responses and can help target their use within aesthetic medicine.

The history

In 1867, stem cells became of interest to scientists when research evidenced their ability to migrate to a site of injury8 and participate in tissue regeneration.9

The first growth factor, the nerve growth factor, was discovered by neurobiologist Rita Levi-Montalcini and sociologist Stanley Cohen in 1952.10 They succeeded in isolating the nerve growth factor, after transferring pieces of cancer tumours from mice into chicken embryos and observing the rapid growth of nerves around the tumour, proving the tumour was secreting a substance causing nerve growth. They won the Nobel prize in 1986 for the discovery of growth factors, before Cohen then went on to discover epidermal growth factor (EGF), discussed more below.10

There was a breakthrough in 1962 whereby biologist John Gurdon discovered that the specialisation of cells is reversible and researcher Shinya Yamanaka reprogrammed a mature cell in mice to become immature in 2006.11-13 Gurdon and Yamanaka14 won the Nobel Prize for this in 2012. Considering that stem cells were only isolated from embryonic mice in 1981, the research has shown huge potential for future therapeutic treatments.

There is now an extensive list of growth factors isolated with the ability to stimulate different signals on cells and control many cellular activities. Many will be familiar with some of the larger families of growth factors, which include transforming growth factor (TGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), and insulin-like growth factor (IGF).7 Different growth factors promote different activities. For example, EGF enhances osteogenic differentiation,15 while fibroblast growth factors and vascular endothelial growth factors stimulate blood vessel differentiation (angiogenesis).

Understanding cells

Growth factors are created by and act on stem cells as well as other cells in the body. In order to understand growth factors, we need to understand how cells are regenerated, their origin and how they can be stimulated for their specific use within aesthetic medicine.16

Stem cells are the cell factories of the body, providing the new cells the body needs after they die or are damaged. Stem cells have a remarkable potential to develop into many different cell types and are fundamental in the body’s regeneration and repair process.16

There are two broad types of stem cell; the embryonic stem cell (present in the early blastocyst in the developing foetus – these are ethically and physically difficult to isolate and seldom used) and the specialised cells in the foetus (ectoderm, endoderm and mesoderm).17,18 All stem cells after this phase of foetal development are adult stem cells, including those found in the umbilical cord lining cells. The adult stem cell is an undifferentiated cell, found in most differentiated tissues and organs. The three most accessible sources of autologous adult stem cells in humans are bone marrow, adipose tissue and blood. Adult stem cells can also be taken from the umbilical cord immediately after birth and stored for future use.18

Acting as a repair system for the body, the adult stem cell divides and differentiates without limit to replenish other cells as long as the person or animal is alive, maintaining the normal turn-over of regenerative organs such as blood, skin and intestinal tissue.

The number of stems cells we have in our body decreases with time, slowing our ability to heal and maintain our body’s demands for repair, contributing to ageing. By the time we are 50 years old we have 1/400000 of the stem cells present at birth (Figure 2).21

Figure 2: The number of stem cells during an adult life21

The direct use of human growth factors in medical treatments is forbidden under EU law,20 however growth factors can now be engineered by inserting the human genetic code into a non-human host cell (single cell bacteria).19 The host cell produces the particular growth factor which can be harvested. Creating recombinant growth factors of a human nature, but not from a human origin, allows treatment products to be created with known concentrations of selected growth factors (and their use is allowed under EU law).20

Conclusion

The depth of history and award-winning research behind the humble growth factor indicates how important these small molecules are. Aesthetic medicine is becoming more focused on regenerative medicine where the use of stem cell science aids the repair process of our skin and decreases the down time following aggressive treatments. By understanding how growth factors work enables us to use specific targeted actions of individual selected growth factors within medical treatments.

This article is the first of two on growth factors by Dr Anna Hemming. Her next article will detail the use of growth factors within regenerative and aesthetic medicine.

References
  1. Alberts B, Johnson A, Lewis J et al., Molecular Biology of the Cell, Garland Science, 2002 <https://www.ncbi.nlm.nih.gov/books/NBK26813/>
  2. Nicola N, Guidebook to cytokines and their receptors, Oxford ; New York: Oxford University Press; 1994.
  3. Yorio T, Clark AF, Wax MB, Ocular Therapeutics: Eye on New Discoveries, Academic Press,(15 October 2007).
  4. Sporn MB, Roberts AB, Peptide growth factors and inflammation, tissue repair, and cancer, The Journal of clinical investigation 1986
  5. Milani S, Herbst H, Schuppan D, Stein H, Surrenti C, Transforming growth factors beta 1 and beta 2 are differentially expressed in fibrotic liver disease, The American journal of pathology, 1991
  6. Thebaud B, Abman SH, Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease, American journal of respiratory and critical care medicine 2007
  7. Bafinco A, Aaronson S, Classification of growth factors and their receptors, Cancer Medicine, 1993 <https://www.ncbi.nlm.nih.gov/books/NBK12423/>
  8. Cohnheim J, Cohnheim’s Vorlesungen über allgemeine Pathologie, vol. 2, Lectures on general pathology, 1880
  9. Afanasyev BV, Elstner E, Zander AR, Friedenstein AJ, Founder of the mesenchymal stem cell concept, Cell Therapy Transplantation, June 2009
  10. NobelPrize.org, Stanley Cohen – Facts, Nobel Media AB 2019, Aug 2019 <https://www.nobelprize.org/prizes/medicine/1986/cohen/facts/>
  11. Goujon E, Recherches expérimentales sur les propriétés physiologiques de la moelle des os, J Anat Physiol, 1869
  12. Gurdon J.B, The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles, Journal of Embryology and Experimental Morphology, 1962
  13. Gurdon JB, The egg and the nucleus: a battle for supremacy. Development, 2013
  14. Takahashi, K., Yamanaka, S, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors, Cell, 2006
  15. Del Angel-Mosqueda C, Gutiérrez-Puente Y, López-Lozano AP, Romero-Zavaleta RE, Mendiola-Jiménez A, Medina-De la Garza CE, Márquez-M M, De la Garza-Ramos MA, “Epidermal growth factor enhances osteogenic differentiation of dental pulp stem cells in vitro”, Head & Face Medicine, September 2015
  16. Mao A S, and Mooney, D. J, Regenerative medicine: Current therapies and future directions. Proc. Natl. Acad. Sci. U. S. A, 2015
  17. National Institute of Health, Stem Cell Basis, 2016, <https://web.archive.org/web/20160831113614/http:/stemcells.nih.gov/info/basics/pages/basics3.aspx>
  18. Mahla RS, “Stem cells application in regenerative medicine and disease threpeutics”, International Journal of Cell Biology. 2016
  19. Schuldiner M, Yanuka O, Itskovitz-Eldor J et al., Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells, PNAS, October 10, 2000
  20. Hilling C, Human growth factors as natural healers: current literature application, April 2013 <https://www.cosmeticsandtoiletries.com/formulating/function/active/premium-Human-Growth-Factors-as-Natural-Healers-Current-Literature-and-Application-204553091.html#targetText=The%20FDA%20allows%20the%20use,cosmetics%20in%20the%20European%20Union.>
  21. Brusahan SK, McGuire TR et al., Human blood and marrow side population stem cell and Stro-1 positive bone marrow stromal cell numbers decline with age, with an increase in quality of surviving stem cells: correlation with cytokines, November 2010 <https://www.ncbi.nlm.nih.gov/pubmed/21035480>

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