Induction of neuronal type-specific neurogenesis in the cerebral cortex of adult mice: manipulation of neural precursors in situ

Abstract

Over the past 3 decades, research exploring potential neuronal replacement therapies have focused on replacing lost neurons by transplanting cells or grafting tissue into diseased regions of the brain [Nat. Neurosci. 3 (2000) 67–78]. Over most of the past century of modern neuroscience, it was thought that the adult brain was completely incapable of generating new neurons. However, in the last decade, the development of new techniques has resulted in an explosion of new research showing that neurogenesis, the birth of new neurons, normally occurs in two limited and specific regions of the adult mammalian brain, and that there are significant numbers of multipotent neural precursors in many parts of the adult mammalian brain [Mol. Cell. Neurosci. 19 (1999) 474–486]. Recent findings from our laboratory demonstrate that it is possible to induce neurogenesis de novo in the adult mammalian brain, particularly in the neocortex where it does not normally occur, and that it may become possible to manipulate endogenous multipotent precursors in situ to replace lost or damaged neurons [Nature 405 (2000) 951–955; Neuron 25 (2000) 481–492]. Recruitment of new neurons can be induced in a region-specific, layer-specific, and neuronal type-specific manner, and newly recruited neurons can form long-distance connections to appropriate targets. Elucidation of the relevant molecular controls may both allow control over transplanted precursor cells and potentially allow the development of neuronal replacement therapies for neurodegenerative disease and other central nervous system injuries that do not require transplantation of exogenous cells.

Introduction

Neural cell replacement therapies are based on the idea that neurological function lost to injury or neurodegenerative disease can be improved by introducing new cells that can replace the function of lost neurons. Theoretically, the new cells can do this in one of two general ways [11]. New neurons can anatomically integrate into the host brain, becoming localized to the diseased portion of the brain, receiving afferents, expressing neurotransmitters, and forming axonal projections to relevant portions of the brain. Such neurons would function by integrating into the microcircuitry of the nervous system and replacing lost neuronal circuitry. Alternatively, newly introduced cells could more simply constitutively secrete neurotransmitters into local central nervous system (CNS) tissue or they could be engineered to produce growth factors to support the survival or regeneration of existing neurons. Growing knowledge about the normal role of endogenous neural precursors, their potential differentiation fates, and their responsiveness to a variety of cellular and molecular controls suggest that neuronal replacement therapies based on manipulation of endogenous precursors either in situ or ex vivo may be possible.

Neuronal replacement therapies based on the manipulation of endogenous precursors in situ may have advantages over transplantation-based approaches, but they may have several limitations as well. The most obvious advantage of manipulating endogenous precursors in situ is that there is no need for external sources of cells. Cells for transplantation are generally derived from embryonic tissue, non-human species (xenotransplantation), or cells grown in culture. Use of embryonic-derived tissue aimed toward human diseases is complicated by limitations in availability and by both political and ethical issues; e.g., current transplantation therapies for Parkinson’s disease require tissue from several embryos. Xenotransplantation of animal cells carries potential risks of introducing novel diseases into humans, and questions about how well xenogenic cells will integrate into the human brain. In many cases, cultured cells need to be immortalized by oncogenesis, increasing the risk that the cells may become tumorigenic. In addition, transplantation of cells from many of these sources risk immune rejection and may require immunospression, if they are not derived from the recipient.

However, there are also potential limitations to the potential of manipulating endogenous precursor cells as a neuronal replacement therapy. First, such an approach may be practically limited to particular regions of the brain, since multipotent neural precursors are densely distributed only in particular subregions of the adult brain (e.g., the subventricular zone, SVZ, and hippocampal subgranular zone). In some cases, it is possible that there simply may not be sufficient precursor cells to effect functional recovery. In addition, the potential differentiation fates of endogenous precursors may be too limited to allow their integration into varied portions of the brain. Another potential difficulty is that it may be difficult to provide the precise combination and sequence of molecular signals necessary to induce endogenous precursors to efficiently and precisely proliferate and differentiate into appropriate types of neurons deep in the brain.

The substantial amount of prior research regarding constitutively occurring neurogenesis provides insight into the potential and limitations of for endogenous precursor based neuronal replacement therapies. Recent work has partially elucidated the normal behavior of endogenous adult precursors, including their ability to migrate to select brain regions, differentiate into neurons, integrate into normal neural circuitry, and, finally, functionally integrate into the adult brain. Research is also beginning to elucidate biochemical and behavioral controls over constitutively occurring neurogenesis. The location, identity, and differentiation potential of endogenous adult precursors are beginning to be understood. In this review, we will first review research from a variety of labs regarding normally occurring neurogenesis, then review some of our experiments demonstrating that endogenous neural precursors can be induced to differentiate into neurons in regions of the adult brain that do not normally undergo neurogenesis.