Research Article: Roles of FGF signaling in stem cell self-renewal, senescence and aging

Date Published: October 9, 2011

Publisher: Impact Journals LLC

Author(s): Daniel L. Coutu, Jacques Galipeau.

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Abstract

The aging process decreases tissue function and regenerative capacity, which has been associated with cellular senescence and a decline in adult or somatic stem cell numbers and self-renewal within multiple tissues. The potential therapeutic application of stem cells to reduce the burden of aging and stimulate tissue regeneration after trauma is very promising. Much research is currently ongoing to identify the factors and molecular mediators of stem cell self-renewal to reach these goals. Over the last two decades, fibroblast growth factors (FGFs) and their receptors (FGFRs) have stood up as major players in both embryonic development and tissue repair. Moreover, many studies point to somatic stem cells as major targets of FGF signaling in both tissue homeostasis and repair. FGFs appear to promote self-renewing proliferation and inhibit cellular senescence in nearly all tissues tested to date. Here we review the role of FGFs and FGFRs in stem cell self-renewal, cellular senescence, and aging.

Partial Text

In the 1960’s, Hayflick observed that human cells displayed a finite lifespan when cultured in vitro [1]. He later determined that most cells had a maximal capacity to proliferate in vitro of about 50 population doublings (the Hayflick limit) after which they entered what he termed cellular senescence, a process characterized by irreversible growth arrest [2]. These observations led him to propose a cellular theory of aging whereby cellular senescence accounts for the aging process and on the contrary, escape from senescence leads to cellular transformation and cancer. This theory is still widely accepted today although direct proof of it is lacking. It is also still debated whether cellular senescence causes aging or conversely if aging causes cellular senescence [3, 4]. Nevertheless, there is an increasing amount of experimental data demonstrating an accumulation of senescent cells in aged tissues [3, 5].

In early murine embryonic development FGF-4 is the first member to be expressed, from the 4 cell stage onto the blastocyst, egg cylinder and primitive streak [11]. Its deletion causes peri-implantation embryonic lethality (E4-5); early development appears normal up to the blastocyst stage but embryos die within hours after implantation owing to deficient inner cell mass formation and maintenance [12]. FGF-4 signaling appears to be important as early as the fifth cell division to promote cell proliferation onto the blastocyst stage [13]. FGF-4 probably signals through FGFR2 as this receptor is the first detected in development, although early expression of FGFR1, 3 and 4 have also been inconsistently reported (probably owing to the few reliable antibodies available)[14, 15]. Moreover, FGFR2 deletion recapitulates FGF-4 deletion, causing early embryonic lethality (E6-8) due to defects in inner cell mass. FGFR1 deletion is also lethal (E7.5-9.5) and appears to cause defects in gastrulation, mainly by affecting axial patterning and migration/proliferation of cells through the primitive streak, thus inhibiting mesoderm and endoderm specification [16, 17]. FGFR3 deletion on the other hand is not embryonic lethal but mice display skeletal malformations that may lead to premature death (see section on skeletal/mesenchymal stem cells below), whereas FGFR4 null mice show no obvious phenotype. The functions of this latter receptor in development and postnatal life remain unclear as well as that of FGFR5.

“Fibroblast growth factor” was first isolated in 1974 from bovine pituitary gland and shown to have a mitogenic effect on many cells types [30]. The prototypical FGF ligands, acidic FGF (aFGF or FGF-1) and basic FGF (bFGF or FGF-2), were then purified by heparin affinity chromatography in the early 1980’s as the first potent endothelial cells mitogens [31-33]. Latter observations showed that FGF signaling inhibition impairs mesodermal patterning and bone formation, and that mutations in FGFRs cause skeletal abnormalities in mice and humans. It is thus not surprising that the FGFs/FGFRs systems have been mostly studied in mesodermal and mesenchymal tissues to date. This section will review the roles of FGF signaling in three mesoderm-derived tissues and their associated stem cells: skeletal tissue, vascular tissue and hematopoietic tissue.

The importance of FGF signaling in central and peripheral nervous system both during development and postnatal life has been long recognized. In addition to the difficulties in studying FGF signaling mentioned above for other tissues, our knowledge of brain development and neural stem cells has greatly evolved in the last two decades rendering previous conclusions obsolete or in any case requiring re-evaluation. The skin is another ectoderm-derived tissue containing various stem cell populations where FGFs and their receptors are widely distributed, yet very little is known about the precise role of FGF signaling in skin homeostasis or repair and it will not be discussed here. This section will review what is known about FGF signaling in neural tissue.

Throughout this review, we have seen that FGFs and their receptors play important roles in the embryonic development, homeostasis and repair of most organs. The effects of FGF signaling can be in part attributed to the stimulation of self-renewal in endogenous somatic stem cells within these organs, but there is also much evidence that FGF signaling also plays a role in the concomitant inhibition of cellular senescence in stem cells. The evidence presented here also suggests a role of FGF signaling in the more committed cells downstream of stem cells, a role that appears to stimulate differentiation. Moreover, in most cell types studied, FGF seems to play a permissive role rather than a direct inductive or instructional role, usually by modifying the responsiveness of the cells to other factors or by potentiating and synergizing with other signals. That seems to hold true in both stem cell self-renewal and differentiation of more committed cells. Although not discussed here FGF signaling also plays a major role in endodermal tissues, in lung patterning, liver and pancreas specification, and in self-renewal of stem cells in the intestinal crypts for instance. However, these tissues have not received as much attention in publications and little is yet known about the roles of FGF signaling in their maintenance into adulthood. Nevertheless, the roles we have described for FGF signaling in regulation of stem cells self-renewal and aging, the fact that our definitions and understanding of these same stem cells is better refined every day, and the development of more advanced reagents and techniques to study stem cells should stimulate more research into this field.

 

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