The Szele Laboratory has been focused on defining the biological functions and role of the subventricular zone (SVZ). Every day the SVZ generates tens of thousands of new neurons, rendering it a likely source of cells for repair. These cells normally migrate long distances to the olfactory bulbs where they serve to modulate odorant discrimination. The major questions we address are whether SVZ cells are true stem cells, whether neurogenesis increases after injury or disease, and how SVZ cells migrate towards injury. Since the postnatal SVZ is readily accessible, and can be cultured in a variety of ways, it is also an excellent system for studying fundamental questions about stem cells, neurogenesis, and migration. Our program has five overlapping projects that address these issues utilizing methodologies of developmental biology, neuroanatomy, and molecular neurobiology.

Current Research Programme

Are there stem cells in the adult brain?

Although it is assumed that SVZ cells exhibit the two defining properties of stem cells, self-renewal and multipotentiality, this has only been shown in vitro. We asked whether the same stem cells in vivo give rise to both neurons and glia. Using a degenerate oligonucleotide library-containing retroviral lineage tracer, we found no evidence of multipotentiality in normal adult, or after traumatic brain injury (TBI); SVZ cells remained unipotential. We also showed that after brain injury there were no changes in self-renewal or multipoteniality using the cell culture neurosphere assay. These studies beg the question of when multipotentiality is lost during development.

Molecular regulation of SVZ migration

We are actively pursuing the environmental as well as cell-intrinsic molecular control of migration. Amongst a host of candidate genes tested, epidermal growth factor (EGF) and interleukin-6 (IL6) increased after TBI. We are conducting mechanistic experiments examining the role of molecular signaling in SVZ migration. We also knocked down Dcx, with RNA interference, and showed that it is needed for SVZ migration in vitro. Recently, we cast a wide net with DNA microarray analyses and found changed expression of several hundred genes which may regulate migration and other biological functions of the SVZ after TBI.

SVZ cells migrate toward injury

After TBI, both glia and neurons derived from the SVZ migrated towards the injury, survived for several weeks, and began differentiation. Since migration is a dynamic process, it is best viewed in real-time. Two-photon (2-P) time-lapse allows imaging of fluorescently labeled SVZ cells at great depths and for long periods. We have developed long-term postnatal slice cultures, visualized migration, and quantitatively analyzed in 4-dimensions (collaboration with P. Hockberger, NU). We are now showing that brain injury decreases speed and increases exploratory migration. Thus our work demonstrates that cells emigrate from the SVZ in an attempt at repair. 

SVZ cells emigrate constitutively

We have serendipitously uncovered several important features of the normal adult SVZ. The SVZ generates cells that emigrate dorsally into the corpus callosum and others that emigrate ventrally into the nucleus accumbens, an area highly implicated in addiction. Interestingly, ventral emigration was amongst radial glia-like cells that persisted into adulthood. We are testing the hypothesis that, as during embryogenesis, these radial glia are both neurogenic and substrates for migration.

Roles of hematopoietic cells in the SVZ

Hematopoietic cells maintain constitutive dentate gyrus neurogenesis and dampen it during inflammation, but very little is known about their functions in the SVZ. We showed that microglia were not activated in the SVZ after cortical lesions, whereas they were in adjacent non-neurogenic regions. We next plan to examine their infiltration with 2-photon microscopy and test the hypothesis that activated macrophages modulate SVZ derived oligodendrocyte genesis.

Francis Szele