Growth Factors in Stem Cell Biology

Growth factors are naturally occurring regulatory molecules, which bind to receptors on the cell surface. They stimulate cell and tissue function through influencing cell differentiation by changing their biochemical activity and cellular growth, and regulating their rate of proliferation. Though structurally they are peptide-like hormones, growth factors are not limited to defined tissues1. They act on target tissues in both diffusible (endocrine, autocrine and paracrine) and nondiffusible (juxtacrine or metacrine) manners and regulate a variety of cellular events including cell migration, survival, adhesion, proliferation and differentiation2.

Medical researchers recognize the important role growth factors play in stem cell biology and its various biomedical applications.

Regenerative medicine: Regenerative medicine shows promise for repair of damaged tissues and organs, deliver safer and more efficient drugs, better disease models, and cures for numerous devastating diseases. Growth factors provide biochemical cues for stem cell differentiation and are used to develop novel strategies to treat human diseases by investigating cellular processes controlling development, aging, and tissue regeneration. Modulation of growth factors at the injury site is one of the strategies to stimulate tissue regeneration. Some of the clinically-approved growth factors include3:

  • Platelet-derived growth factor-BB (PDGF-BB) – for diabetic neuropathic ulcers and periodontal defects
  • Bone morphogenetic factor-2 (BMP2) – tissue regeneration at sites of tibia fracture and nonunion
  • Bone morphogenetic factor-7 (BMP7) – tissue regeneration for tibia nonunion

Cell therapy / Organ transplantation: Stem cell treatment could put an end to inefficient disease treatments and lack of donors for organ transplants. Embryonic pluripotent stem cells have the ability to differentiate into three germ layers (endoderm, mesoderm, and ectoderm) and unlimited capacity for self-renewal5. The ethical issues around the use of embryonic stem cells led to the introduction of induced pluripotent stem cells or iPSCs. iPSCs are adult cells reprogrammed with the transfection of specific set of transcription factors - Oct3/4, Sox2, Klf4 and c-Myc6. In the presence of growth factors, iPSCs differentiate into majority of the progenitor cells required for development (Table 1). Therefore, the role of growth factors in differentiation of iPSCs provides an avenue for creating an unlimited supply of embryonic-like stem cells, bypassing the current ethical issues (Figure 1). Also, iPS cells allow for personalized medicine as both the nuclear and the mitochondrial DNA matches the donor. Using iPS cells would also not require any immune suppression during transplant, making them a superior choice over donor embryonic stem cells for therapeutic uses.

iPSCs differentiate into majority of the progenitor cells required for development in the presence of Growth Factors

Figure 1. iPSCs differentiate into majority of the progenitor cells required for development in the presence of Growth Factors

This image shows cells derived from the culture of neural stem cells grown in the presence of EGF (Cat. No. E9644) and LIF (Cat. No. L5283). The cells were expanded in neural stem cell expansion medium (Cat. No. S3194) and then moved to conditions to allow them to differentiate.

This photo shows differentiated cells fixed and stained with an antibody for GFAP (an astrocyte marker in green, Cat. No. G9269). Actin is labeled with TRITC phalloidin (Cat. No. P1951) and the nuclei are labeled with DAPI (Cat. No. D8417).

 

Growth factor Sub-types Functions
Activins/Inhibin Activin A, Activin B, Activin C, Activin AB, Activin AC, Inhibin and Inhibin A –  Mesodermal induction –  Neural cell differentiation
BMPs Homodimers: BMP-1, BMP-2, BMP-2aBMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-8a, BMP-8b, BMP-9, BMP-10, BMP-15 Heterodimers: BMP-2/BMP-4, BMP-2/BMP-7, BMP-4/BMP-7 –  Bone formation –  Induction of ventral mesoderm
FGF FGF acidic, FGF basic, FGF-3, FGF-4, FGF-5, FGF-6, FGF-7, FGF-8, FGF-9, FGF-10, FGF-11, FGF-12, FGF-13, FGF-15, FGF-16, FGF-17, FGF-18, FGF-19, FGF-20, FGF-21, FGF-22 and FGF-23 –  Cell proliferation, differentiation and migration –  Embryonic development and angiogenesis
IGF IGF-I, IGF-II and IGFL-3 –  Maintenance of pluripotentency, differentiation and proliferation of myeloid cells –  Promotion of neural stem cell self-renewal, neurogenesis and cognition  
TGF-beta TGF-β1, TGF-β2, TGF-β3, TGF-β5 –  Maintenance and differentiation of embryonic stem cells and somatic stem cells
Wnt Wnt-1, Wnt-2, Wnt-2b, Wnt-3a, Wnt-4, Wnt-5b, Wnt-6, Wnt-7a, Wnt-7a/b, Wnt-7b, Wnt-8a, Wnt-9a, Wnt-9b, Wnt-10a, Wnt-10b, Wnt-11 and Wnt-16b –  Cell survival,  proliferation and  polarity –  Tissue homeostasis, tissue patterning and cell fate  
Table 1. Roles of Growth Factors in Differentiation of Stem Cells

 

Researchers are enhancing their already significant understanding of how growth factors affect stem cell expansion and differentiation. Once they can completely control the fate of pluripotent stem cells, which is influenced by both physical (attachment factors) and biochemical cues (growth factors), they will be able to direct these cells to become the specialized cells that make up all the tissue in the body. This enables subsequent use of stem cells in cell-based therapies, drug development, and disease modeling7.

Materials

     

Adapted from Growth Factors in Stem Cell Biology by Jennifer Fries, BioFiles 2009, 4.5, 11.

 

References

  1. Tada, S., Kitajima, T., and Ito, Y. (2012) Design and synthesis of binding growth factors. Int. J. Mol. Sci. 13, 6053–6072.
  2. Hajimiri, M., Shahverdi, S., Kamalinia, G., and Dinarvand, R. (2015) Growth factor conjugation: strategies and applications. J. Biomed. Mater. Res. A 103, 819–838.
  3. Mao, A. S., and Mooney, D. J. (2015) Regenerative medicine: Current therapies and future directions. Proc. Natl. Acad. Sci. U. S. A. 112, 14452–14459.
  4. Clevers, H. (2016) Modeling Development and Disease with Organoids. Cell 165, 1586–1597.
  5. Yu, J., and Thomson, J. A. (2008) Pluripotent stem cell lines. Genes Dev. 22, 1987–1997.
  6. (6) Takahashi, K., and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676.
  7. Yin, P. T., Han, E., and Lee, K.-B. (2016) Engineering Stem Cells for Biomedical Applications. Adv. Healthc. Mater. 5, 10–55.