Fibroblast growth factors as tissue repair and regeneration therapeutics

Abstract

Cell communication is central to the integration of cell function required for the development and homeostasis of multicellular animals. Proteins are an important currency of cell communication, acting locally (auto-, juxta-, or paracrine) or systemically (endocrine). The fibroblast growth factor (FGF) family contributes to the regulation of virtually all aspects of development and organogenesis, and after birth to tissue maintenance, as well as particular aspects of organism physiology. In the West, oncology has been the focus of translation of FGF research, whereas in China and to an extent Japan a major focus has been to use FGFs in repair and regeneration settings. These differences have their roots in research history and aims. The Chinese drive into biotechnology and the delivery of engineered clinical grade FGFs by a major Chinese research group were important enablers in this respect. The Chinese language clinical literature is not widely accessible. To put this into context, we provide the essential molecular and functional background to the FGF communication system covering FGF ligands, the heparan sulfate and Klotho co-receptors and FGF receptor (FGFR) tyrosine kinases. We then summarise a selection of clinical reports that demonstrate the efficacy of engineered recombinant FGF ligands in treating a wide range of conditions that require tissue repair/regeneration. Alongside, the functional reasons why application of exogenous FGF ligands does not lead to cancers are described. Together, this highlights that the FGF ligands represent a major opportunity for clinical translation that has been largely overlooked in the West.

FGF2-mediated attenuation of myofibroblast activation is modulated by distinct MAPK signaling pathways in human dermal fibroblasts

“…FGF2 activates its target receptor tyrosine kinases, the FGFRs, on the cell surface in order to activate numerous downstream pathways, including several mitogen activated protein kinase (MAPK) pathways [10]. Importantly, it has been determined that application of exogenous FGF2 has both accelerative and anti-fibrotic effects in various types of skin wounds, reviewed extensively in [11]. This has been demonstrated in humans for acute incisional wounds, avulsions, and burn wounds [12–14], as well as in several animal models [15, 16].…”

Characterization of clostridium botulinum neurotoxin serotype A (BoNT/A) and fibroblast growth factor receptor interactions using a novel receptor dimerization assay

“…Whether binding of BoNT/A to FGFRs results in pharmacological effects in vivo and in patients is unclear, and it should be kept in mind that clinical toxin doses are in the pM range. Interestingly, unlike most FGFs which are specific to either the b or c isoform of the different receptor subtypes, rH C /A dimerized both b and c isoforms, suggesting that H C /A has the potential to effect a large number of cell types that express FGFRs [38, 39, 41, 69, 70]. rH C /A did not dimerize EGFR at the highest concentration tested here (150 nM) (EC 50 >150 nM), which indicates rH C /A‘s specificity for FGFR over other tyrosine kinase growth factor receptors (summary of the results shown in Table 1 ).…”

Materials Science and Design Principles of Growth Factor Delivery Systems in Tissue Engineering and Regenerative Medicine

“…They are produced by macrophages, chondrocytes, osteoblasts, and mesenchymal cells and promote cell growth. FGFs are reviewed in detail by Nunes et al, Yun et al, and Ornitz et al[23a-c] Hepatocyte growth factors (HGFs) are produced by stromal cells. They stimulate epithelial cell proliferation, motility, morphogenesis, and angiogenesis .…”