Stimulation of Neonatal and Adult Brain Neurogenesis by Subcutaneous Injection of Basic Fibroblast Growth Factor

Abstract

Mounting evidence indicates that extracellular factors exert proliferative effects on neurogenetic precursors in vivo. Recently we found that systemic levels of basic fibroblast growth factor (bFGF) regulate neurogenesis in the brain of newborn rats, with factors apparently crossing the blood-brain barrier (BBB) to stimulate mitosis. To determine whether peripheral bFGF affects proliferation during adulthood, we focused on regions in which neurogenesis persists into maturity, the hippocampus and the forebrain subventricular zone (SVZ). In postnatal day 1 (P1) rats, 8 hr after subcutaneous injection (5 ng/gm body weight), bFGF increased [(3)H]thymidine incorporation 70% in hippocampal and SVZ homogenates and elicited twofold increases in mitotic nuclei in the dentate gyrus and the dorsolateral SVZ, detected by bromodeoxyuridine immunohistochemistry. Because approximately 25% of proliferating hippocampal cells stimulated in vivo expressed neuronal traits in culture, bFGF-induced mitosis may reflect increased neurogenesis. bFGF effects were not restricted to the perinatal period; hippocampal DNA synthesis was stimulated by peripheral factor in older animals (P7-P21), indicating the persistence of bFGF-responsive cells and activity of peripheral bFGF into late development. To begin defining underlying mechanisms, pharmacokinetic studies were performed in P28 rats; bFGF transferred from plasma to CSF rapidly, levels rising in both compartments in parallel, indicating that peripheral factor crosses the BBB during maturity. Consequently, we tested bFGF in adults; peripheral bFGF increased the number of mitotic nuclei threefold in the SVZ and olfactory tract, regions exhibiting persistent neurogenesis. Our observations suggest that bFGF regulates ongoing neurogenesis via a unique, endocrine-like pathway, potentially coordinating neuron number and body growth, and potentially providing new approaches for treating damaged brain during development and adulthood.

Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS‐5 and delays cartilage degradation in murine osteoarthritis

“…In order to address this, we treated Fgf2 -/-mice with subcutaneous recombinant human FGF-2. Others have achieved therapeutic dosing of FGF-2 by subcutaneous injection (13) following detailed kinetic studies in the mouse (14). Although no data are available on the extent to which FGF-2 is able to penetrate cartilage via subcutaneous administration, the presence of detectable FGF-2 in the plasma suggests that access to the joint is feasible.…”

The Endogenous Regenerative Capacity of the Damaged Newborn Brain: Boosting Neurogenesis with Mesenchymal Stem Cell Treatment

“…105 Another protein that appears to play a role in neurogenic processes after HI is the fibroblast growth factor receptor 1 (Fgfr1), which promotes progenitor proliferation 106 and neuronal fate commitment in proliferating cells. 107,108 A recent study showed that ablation of the Fgfr1 gene from GFAP-expressing cells in mice leads to attenuated cell proliferation in the SVZ and decreased cortical pyramidal neuron production after HI. 109 Interestingly, Fgfr1 knockout does not increase apoptosis when compared with wild-type hypoxic mice, suggesting that Fgfr1 may be involved in mediating neurogenesis rather than neuroprotection after hypoxic injury.…”

The microenvironment of the embryonic neural stem cell: Lessons from adult niches?

“…FGFs are expressed on the stromal cells that provide trophic support for the hematopoitic stem cell as well as by the stem and progenitors cells in the hematopoetic system, and can be used to expand haematopoetic cells in culture suggesting a role in maintenance of the stem cell population (Kashiwakura and Takahashi, 2005). VEGF stimulates cell proliferation of adult rodent cortical cells in vitro and intraventricular administration of VEGF resulted in increased proliferation of SEZ cells (Jin et al, 2002), as it also does with FGF, EGF, or TGF␣ (Craig et al, 1996;Kuhn et al, 1997;Wagner et al, 1999). However these early studies did not distinguish between the stem and progenitor cell populations (including both transit amplifying cells and neuroblasts), and subsequent studies of the EGF-induced proliferation in the SEZ suggest that it is the transit amplifying cells that are responsive to the EGF (Doetsch et al, 2002).…”