Expression of Basic Fibroblast Growth Factor mRNA and Protein in the Human Brain following Ischaemic Stroke

Abstract

Our previous work has demonstrated that angiogenesis occurs in the damaged brain tissue of patients surviving acute ischaemic stroke and increased microvessel density in the penumbra is associated with longer patient survival. The brain is one of the richest sources of FGF-2 and several studies have noted its angiogenic and neuroprotective effects in the nervous system. These findings led us to investigate the expression and localisation of both FGF-2 mRNA and protein in brain tissue collected within 12 h of death from 10 patients who survived for between 24 h and 43 days after acute stroke caused by thrombosis or embolus. Western blot analysis demonstrated increased FGF-2 protein expression in both grey and white matter in the infarcted core and the penumbra region compared to the normal contralateral hemisphere of all 10 patients studied. Using indirect immunoperoxidase staining of paraffin embedded sections, we observed the presence of FGF-2 in neurones, astrocytes, macrophages and endothelial cells. In situ hybridisation was used to localise and quantify mRNA expression in ischaemic brain tissue of the same 10 patients. The expression of FGF-2 in the penumbra of all patients was significantly raised compared with infarcted tissue and normal-looking contralateral hemisphere. In addition, serum FGF-2 was significantly increased between 1 and 14 days (P<0.001) in many patients with both ischaemic stroke (n=28) and intra-cerebral haemorrhage (n=16) compared with age-matched control subjects undergoing routine medical examinations (n=20). We suggest that up-regulation of FGF-2 is one of the mechanisms that leads to angiogenesis and neuro-protection in the penumbra region after acute stroke in man.

The Postischemic Environment Differentially Impacts Teratoma or Tumor Formation After Transplantation of Human Embryonic Stem Cell-Derived Neural Progenitors

“…17 As indicated by the quantitative polymerase chain reaction analysis, early NPG grafts still contained high levels of markers of pluripotency and proliferation. Rather than a dedifferentiating effect of the lesion, 8 this suggests a contamination of the grafts by cells with limited commitment that responded to environmental cues present in the postischemic brain as they did in vitro before transplantation.…”

Targeting the Ischemic Penumbra

“…20 Growth factors such as transforming growth factor-␤ or fibroblast growth factor-2 and the chemokine stromal cellderived factor-1 are overexpressed in the penumbra, being involved in the recruitment of bone marrow-derived cells and neural stem cells to sites of ischemic injury. 21 Stromal cell-derived factor-1 is expressed up to 30 days after stroke in the penumbra, and even later in the ischemic core, when new blood vessels appear. Indeed, stromal cell-derived factor-1 expression in the penumbra was associated with reactive perivascular astrocytes, suggesting that stromal cell-derived factor-1 may play a role in enhancing plasticity after ischemia.…”

Brain Plasticity Following Ischemia: Effect of Estrogen and Other Cerebroprotective Drugs

“…Angiogenesis has a major role in brain regeneration after ischemia as increased blood supply directly enhances cell survival and regenerative processes (Font et al, 2010). Blood vessels not only provide metabolic support but also participate in neurogenesis by leading progenitor cells to the site of injury (Jin et al, 2002;Kojima et al, 2010 as cited in Font et al, 2010;Sun et al, 2010;Udo et al, 2008;Xiong et al, 2010;.There is extensive evidence that neovascularization (both angiogenesis and arteriogenesis) is induced following acute (del Zoppo and Mabuchi, 2003;Issa et al, 2005) and chronic (Busch et al, 2003;Wappler et al, 2011a) brain ischemia.…”

“…In addition, several other factors, such as fibroblast growth factor (FGF) (Issa et al, 2005), angiopoetins (Lin et al, 2000), transforming growth factor (TGF ) (Haggani et al, 2005;Krupinski et al, 1996), platelet derived growth factor (PDGF) (Issa et al, 2005;Krupinski et al, 1997), tissue-type plasminogen activator (Carmeliet and Collen, 1997), etc. are just as critical in new vessel formation after brain injury.…”

“…In addition, nitric oxide derived from endothelial nitric oxide synthetase (eNOS) also induces endothelial cell proliferation and migration, smooth muscle cell differentiation, and other angiogenic processes, where ischemia and shear stress are triggering mechanisms (Amano et al, 2003;Cui et al, 2009;Murohara et al, 1998;Papapetropoulos et al, 1997;Prior et al, 2003;Rudic et al, 1998). Angiogenesis inhibitors, such as endostatin, angiostatin, thrombospondin-1 and thrombospondin-2 have also been detected following brain ischemia (Issa et al, 2005), which provide another avenue for therapeutic interventions.…”