FGF‐2‐induced cell proliferation stimulates anatomical, neurophysiological and functional recovery from neonatal motor cortex injury

Monfils, Marie‐H.; Driscoll, Ira; Kamitakahara, Holly; Wilson, Brett; Flynn, Corey; Teskey, G. Campbell; Kleim, Jeffrey A.; Kolb, Bryan

doi:10.1111/j.1460-9568.2006.04939.x

Cited by 49 publications

(33 citation statements)

References 21 publications

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“…37 We asked whether FGF signaling is involved in BM stress response. As a cytotoxic agent, 5FU initiated BM stress response by killing actively cycling cells, including cycling HSPCs, 9,10 causing the number of LSK cells in BM to decline within the first week after 5FU treatment ( Figure 1A).…”

Section: Fgfr1-mediated Signaling Is Dispensable For Homeostatic Hemamentioning

confidence: 99%

FGF signaling facilitates postinjury recovery of mouse hematopoietic system

Zhao

Ross

Itkin

et al. 2012

Blood

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Previous studies have shown that fibroblast growth factor (FGF) signaling promotes hematopoietic stem and progenitor cell (HSPC) expansion in vitro. However, it is unknown whether FGF promotes HSPC expansion in vivo. Here we examined FGF receptor 1 (FGFR1) expression and investigated its in vivo function in HSPCs. Conditional knockout (CKO) of Fgfr1 did not affect phenotypical number of HSPCs and homeostatic hematopoiesis, but led to a reduced engraftment only in the secondary transplantation. When treated with 5-fluorouracil (5FU), the Fgfr1 CKO mice showed defects in both proliferation and subsequent mobilization of HSPCs. We identified megakaryocytes (Mks) as a major resource for FGF production, and further discovered a novel mechanism by which Mks underwent FGF-FGFR signaling dependent expansion to accelerate rapid FGF production under stress. Within HSPCs, we observed an up-regulation of nuclear factor B and CXCR4, a receptor for the chemoattractant SDF-1, in response to bone marrow damage only in control but not in Fgfr1 CKO model, accounting for the corresponding defects in proliferation and migration of HSPCs. This study provides the first in vivo evidence that FGF signaling facilitates postinjury recovery of the mouse hematopoietic system by promoting proliferation and facilitating mobilization of HSPCs. (Blood. 2012; 120(9):1831-1842) IntroductionFibroblast growth factors (FGFs) are a large group of secreted molecules that regulate cell migration, proliferation, and differentiation in both embryonic and adult development. 1,2 FGFs mediate their cellular responses by binding to and activating a family of 4 receptor tyrosine kinases designated as the FGF-receptors FGFR1 through FGFR4, which display different ligand-binding characteristics and biologic functions. 3 FGF signaling is important for hematopoietic developmental regulation, 4,5 and FGFR1 was shown to be preferentially expressed in adult hematopoietic stem and progenitor cells (HSPCs). 6 Although FGF ligands support HSPC expansion in vitro, 7,8 the role of FGF signaling via FGFR1 in vivo has not been elucidated.Treatment with chemotherapeutic drugs, such as cyclophosphamide and 5-fluorouracil (5FU), 9,10 induces a multistep bone marrow (BM) stress response: (1) actively cycling cells are eliminated, including cycling HSPCs 9,10 ; (2) surviving quiescent longterm hematopoietic stem cells (LT-HSCs) are subsequently activated to expand; (3) some expanded HSCs give rise to short-term HSCs (ST-HSCs) for further proliferation; and (4) some HSPCs egress from BM to the blood circulation and extramedullary sites, such as spleen (ie, mobilization), to further proliferate and differentiate. [11][12][13] In homeostatic hematopoiesis, HSPCs are primarily localized within BM where they associate with niches that regulate their activity. [14][15][16][17][18] Although a small percentage of HSPCs routinely circulate from BM to peripheral blood (PB) and home back to BM,19,20 the number of HSPCs that migrate from BM can be markedly increased by certain stimuli dur...

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Section: Fgfr1-mediated Signaling Is Dispensable For Homeostatic Hemamentioning

confidence: 99%

FGF signaling facilitates postinjury recovery of mouse hematopoietic system

Zhao

Ross

Itkin

et al. 2012

Blood

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“…Definition Effect Reference hEGF Human epidermal growth factor Regulation of cell growth, proliferation and differentiation [15] hbFGF Human basic fibroblast growth factor Potent inducer of DNA synthesis in mesoderm and neuroectoderm lineages [19] hLIF Human leukemia inhibitory factor…”

Section: Factorsmentioning

confidence: 99%

Trophic factor induction of human umbilical cord blood cellsin vitroandin vivo

et al. 2007

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The mononuclear fraction of human umbilical cord blood (HUCBmnf) is a mixed cell population that multiple research groups have shown contains cells that can express neural proteins. In these studies, we have examined the ability of the HUCBmnf to express neural antigens after in vitro exposure to defined media supplemented with a cocktail of growth and neurotrophic factors. It is our hypothesis that by treating the HUCBmnf with these developmentally-relevant factors, we can expand the population, enhance the expression of neural antigens and increase cell survival upon transplantation. Prior to growth factor treatment in culture, expression of stem cell antigens is greater in the non-adherent HUCBmnf cells compared to the adherent cells (p < 0.05). Furthermore, treatment of the non-adherent cells with growth factors, increases BrdU incorporation, especially after 14 days in vitro (DIV). In HUCBmnf-embryonic mouse striata co-culture, a small number of growth factor treated HUCBmnf cells were able to integrate into the growing neural network and express immature (nestin and TuJ1) and mature (GFAP and MAP2) neural markers. Treated HUCBmnf cells implanted in the subventricular zone predominantly expressed GFAP although some grafted HUCBmnf cells were MAP2 positive. While short-term treatment of HUCBmnf cells with growth and neurotrophic factors enhanced proliferative capacity in vitro and survival of the cells in vivo, the treatment regimen employed was not enough to ensure long-term survival of HUCBmnf-derived neurons necessary for cell replacement therapies for neurodegenerative diseases.

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“…Administration of TGFα, a mitogenic growth factor, either via intracatheter infusion [175] or via overexpression through adeno-associated virus injection [176] following TBI in rats [177,178]. FGF-2 treatment improved functional recovery following earlyadolescent and neonatal injury to the rat motor cortex [179,180] as well as conferring neuroprotective roles against hypoxic-ischemic insult to the perinatal rat brain [181]. Although these studies demonstrate promising results for growth factor therapy following brain injury, [182,183].…”

Section: Suppression Of Epha4 Activationmentioning

confidence: 99%

Models of CNS injury in the nonhuman primate: A new era for treatment strategies

Teo

Rosenfeld²,

Bourne

2012

Translational Neuroscience

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Central nervous system (CNS) injuries affect all levels of society indiscriminately, resulting in functional and behavioral deficits with devastating impacts on life expectancies, physical and emotional wellbeing. Considerable literature exists describing the pathophysiology of CNS injuries as well as the cellular and molecular factors that inhibit regrowth and regeneration of damaged connections. Based on these data, numerous therapeutic strategies targeting the various factors of repair inhibition have been proposed and on-going assessment has demonstrated some promising results in the laboratory environ. However, several of these treatment strategies have subsequently been taken into clinical trials but demonstrated little to no improvement in patient outcomes. As a result, options for clinical interventions following CNS injuries remain limited and effective restorative treatment strategies do not as yet exist. This review discusses some of the current animal models, with focus on nonhuman primates, which are currently being modeled in the laboratory for the study of CNS injuries. Last, we review the current understanding of the mechanisms underlying repair/regrowth inhibition and the current trends in experimental treatment strategies that are being assessed for potential translation to clinical applications.

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FGF‐2‐induced cell proliferation stimulates anatomical, neurophysiological and functional recovery from neonatal motor cortex injury

Cited by 49 publications

References 21 publications

FGF signaling facilitates postinjury recovery of mouse hematopoietic system

FGF signaling facilitates postinjury recovery of mouse hematopoietic system

Trophic factor induction of human umbilical cord blood cellsin vitroandin vivo

Models of CNS injury in the nonhuman primate: A new era for treatment strategies

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