Adult brain stem cells: from mechanisms to disease
The Szele group studies the developmental process of neurogenesis in the subventricular zone (SVZ) – the largest neurogenic niche in the adult brain. The SVZ contains stem cells, transit amplifying progenitors and neuroblasts that migrate to the olfactory bulbs. We are particularly interested in molecular mechanisms that regulate stem and progenitor cell proliferation and neuroblast migration. The SVZ is a convenient biological system to study fundamental developmental questions since it does not rely on embryonic surgeries and since one can easily modulate gene expression with DNA plasmid electroporation. SVZ stem cells represent one of the most promising endogenous progenitor pools for neural repair and have been shown to be neuroprotective and beneficial. We are actively investigating the role of the SVZ in models of traumatic brain injury, stroke, and multiple sclerosis. Adult neurogenesis has become increasingly implicated in neuropsychiatric disorders thus we are also examining the SVZ in animal models of schizophrenia. Finally the human SVZ responds to injury and illness by increasing proliferation. Thus, we study the human SVZ in post-mortem sections from humans with neuropsychiatric disorders and in normal controls.
We recently discovered that the protein Galectin-3 (Gal-3) which is normally expressed in activated microglia after injury is uniquely expressed in the SVZ in healthy rodents (Comte et al., 2011). Gal-3 binds to multiple proteins and has myriad effects in inflammation and cancer, however in the SVZ it had a very specific effect. Loss of Gal-3 decreased rostral migration of SVZ neuroblasts. We also showed that Gal-3 nulls had higher levels of phosphorylated epidermal growth factor receptor (EGFr). This was interesting because he had shown that a subset of neuroblasts express EGFr and that activating it decreases migration (Kim et al., 2009). Tracy Lane (postdoc) is now using 2-P time-lapse microscopy and probing the molecular interactions through which Gal-3 acts on SVZ migration. Osama Al-Dalahmah (grad student) is discovering binding partners of Gal-3 in the SVZ and testing the hypothesis that loss of Gal-3 is necessary for lineage progression.
In addition to studying its role in the healthy SVZ, we are probing the role of Gal-3 in the SVZ’s response to stroke and multiple sclerosis. We have shown that Gal-3 is necessary for angiogenesis in stroke, via a VEGF dependant manner. This effect was very specific; loss of Gal-3 did not affect rates of SVZ neurogenesis, migration to injury, or stroke size, suggesting angiogenesis is dispensable for recovery from stroke. Gal-3 is upregulated in multiple sclerosis (MS) and James Hillis (grad Student) is studying the idea that depending on the stage of cuprizone-induced demyelination, Gal-3 is deleterious and beneficial to SVZ mediated repair. In collaboration with Prof. Stephen Miller, we have shown that another model of MS, the Theiler's murine encephalomyelitis virus (TMEV), targets the SVZ and induces massive periventricular inflammation (Goings et al., 2008). Loss of Gal-3 decreased the immune cell infiltration into the SVZ but increased the number of SVZ progenitors emigrating into the overlaying white matter.
The role of inflammation in the SVZ is another strand of work in the lab. We discovered that SVZ microglia are constitutively activated but resistant to further activation in a model of traumatic brain injury (Goings et al., 2006). Abeer Al-Shammari (grad student) is now testing the hypothesis that postnatal inflammation combined with specific gene mutations implicated in schizophrenia leads to long-lasting decreases in neurogenesis. We are concurrently comparing the human SVZ in patients with schizophrenia, bipolar disorder and depression. Schizophrenia and autism share several features and in collaboration with Prof. Margaret Esiri and Dr. Stephen Chance, we have shown that the septal SVZ seems to be particularly affected (Kotagiri et al., 2013).
A large number of studies have shown that the endogenous stem and progenitor cells of the SVZ attempt to repair the injured brain, but only do so inefficiently. Thus many of our studies are leading to the goal of augmenting SVZ multipotency and enhancing emigration towards brain injury. Using floxed Ezh2 mice, Bin Sun (grad student) is probing the role of polycomb repressive complex 2 in SVZ neurogenesis and repair. Rod Walker (postdoc) in collaboration with Dr. Angela Russell and Prof. Steve Davies is screening a library of small molecules for their potential to increase adult neurogenesis. These studies are designed to lead to informed and coordinated approaches to augmenting endogenous stem and progenitor cell mediated treatment of brain diseases.
We use a wide range of in vivo and in vitro techniques including neurosphere stem cell cultures, explant migration assays, in vivo plasmid electroporation of fluorescent markers, over expression and knockdown constructs, Cre-lox conditional knockouts, immunohistochemistry, confocal microscopy, stereological cell counting, histological techniques, immunohistochemistry. We are using 2-photon time-lapse microscopy in slices to record and quantitatively analyse cell behaviours in the SVZ (Nam et al., 2007; James et al., 2011). We have weekly lab meetings Tuesdays from 9-10.30 AM, weekly one-on-one meetings with lab members, regular social outings and yearly lab retreats, usually in Wales. The lab is organized into subclusters of researchers interested in overlapping biological questions or technical approaches. We are located in the Le Gros Clark Building on the first floor and welcome enquiries for collaboration, postdoctoral fellowships or studentships.
List of funding bodies
BBSRC, MRC, Dana Foundation, Simons Foundation, Qatar Foundation, Shionigi Drug Company
- Prof. Michael Brand, Visiting Professor from Dresden Germany, April - September, 2013.
- Anna Gerhartl, Masters Student from Austria, August, 2013 - January, 2014