of the Max - MDC

Neuronal Stem Cells
Gerd Kempermann
D
espite ever increasing research interest over the last decade, the function and relevance of stem
cells in the adult brain has so far remained largely unknown. Nevertheless, neural stem cells
apparently contribute to the malleable link between the brain’s structure and its function: the so-called
brain “plasticity”. Epidemiological data and results from lifespan psychology indicate that leading
an active life has positive effects on “successful aging” and, for example, on the risk of developing
Alzheimer’s disease. There is also a beneficial effect of “training” on recovery from brain injury. The
cellular and molecular basis of such activity-dependent plasticity, however, are still hardly understood.
Despite the many intriguing examples of plasticity, many neurological and psychiatric disorders
remain chronic and irreversible and the brain does not heal after injury. Stem cell-based
Regenerative Medicine attempts to change that.
“Adult neurogenesis”, the generation of new neurons in the
adult brain, is a very special case of stem cell-based brain
plasticity. Although neuronal stem cells can be found
throughout the brain, adult neurogenesis is limited to two
privileged regions in the olfactory system and the hippocampus.
The hippocampus is a brain region involved in
learning and memory, and as such plays a fundamental role
in higher cognitive functions. Consequently, hippocampal
impairment plays a major role in the context of age-related
cognitive decline and dementia. We are interested in how
neuronal stem cells and adult-generated neurons contribute
to hippocampal function across the lifespan and if and how
a failure of adult neurogenesis might be involved in the
pathogenesis of complex disorders like age-related memory
loss and cognitive impairment, major depression, and
Alzheimer’s disease. We increasingly use systems genetics
approaches to address the molecular complexities that
underlie such processes. We try to understand how activitydependent
control works on the level of gene-gene interactions
and the genetic networks in the cells.
Neuronal development in the adult hippocampus
The traditional core of our work is phenomenological and
based on histology and immunohistochemistry. The idea is
that without a clear anatomical picture attempts to understand
cellular functions will remain fuzzy. We have thus continued
to describe the details of neuronal development in
the adult hippocampus. Recently, we have placed most
emphasis on the so-called type-2a progenitor cells, which
appear to be radial glia-like cells but without a radial morphology
and with high proliferative activity. We found that
in these “glial” precursor cells the transition to the neuronal
lineage takes place. Type-2b cells with their particular
marker profile represent this transition. These classifications
help to identify the regulatory steps in the course of
adult neurogenesis and to design specific experiments on
the regulation of individual aspects of “neurogenesis”.
On a related note we have extended our previous work on
the activity-dependent regulation of adult hippocampal
neurogenesis by showing that the positive effects of physical
exercise are to some degree transmissible from the exercising
(mouse) mother to their offspring.
Neural stem cells in vitro
Despite the broad interest in adult hippocampal neurogenesis
and stem cell biology of the brain, the available methodology
for studying neuronal stem and progenitor cells has
been rather limited. Most studies relied on the so-called
“neurosphere” model, a simple and quite useful but due to
its heterogeneity problematic culture system. For hippocampal
neurosphere cultures it was neither clear if they contained
stem cells in the stricter sense of the definition nor if
they could in fact generate neurons that corresponded to
their in vivo counter parts, the granule cells of the hippocampal
dentate gyrus. We were successful in establishing
a protocol for enriched monolayer cultures of hippocampal
precursor cells to address these two issues. We found that
the adult murine hippocampus in fact contains stem cells
and that the neurons that can be derived from these precursor
cells behave like granule cells. This strategy is now
applied to study how “activity” controls stem cell activity on
the intra-cellular and molecular level.
Function and Dysfunction of the Nervous System 177