Adult neuronal and oligodendrocyte stem cell identified

This is huge. Jackson et al. have identified that the adult stem cell in the human brain for both neurons and oligodendrocytes are the PDGFR-alpha expressing cells and that PDGF-AA causes proliferation of these cells and a shift towards the oligodendrocyte lineage.

A little background. There is this place in the brain called the subventricular zone (SVZ) which is shockingly enough just below the lateral ventricles. This area contains rapidly dividing cells that during development grow outward to populate the cortices. These cells first form radial glia, then most of the glutamatergic neurons (the GABAergic ones migrate laterally in), then astrocytes, then one of the lineages of oligodendrocytes (there are actually three, but that doesn't matter).

A good piece of introduction from the paper:

The subventricular zone (SVZ) in the walls of the lateral ventricles is the largest germinal center and source of stem cells in the adult brain. The stem cells in the SVZ of the adult rodent brain continue to generate neurons destined for the olfactory bulb (reviewed in Lim and Alvarez-Buylla [2001]). A population of GFAP-expressing cells in the SVZ (B cells) are the primary precursor cells. They first produce a transit-amplifying cell population (C cells) that then give rise to the neuroblasts (A cells) that migrate to the olfactory bulb where they mature into neurons (Doetsch et al., 1999a, Garcia et al., 2004 and Parras et al., 2004). Although the SVZ stem cells have characteristics of astrocytes and express GFAP, additional markers that enable further characterization of the stem cells are lacking. New oligodendrocytes are also generated in the SVZ of adult mice (Nait-Oumesmar et al., 1999), and B cells located in this region also serve as their primary progenitors (Menn et al., 2006). Again, additional markers and factors regulating SVZ oligodendrogenesis have not been well characterized.

During mouse development, the platelet-derived growth factor receptor-α (PDGFRα) is expressed by neuroepithelial cells as early as E8.5 (Andrae et al., 2001). However, the role of PDGF in neuroepithelial stem cells is not understood. Instead, PDGF is considered to function later in development as a potent mitogen of oligodendrocyte precursor cells (OPCs). OPCs were first identified and characterized in cultures from rat perinatal optic nerve (Raff et al., 1983), where they give rise to either oligodendrocytes or type-2 astrocytes. In the rat optic nerve and spinal cord, OPCs express PDGFRα (Hall et al., 1996), and PDGF is important for regulating OPC number and oligodendrocyte production in vivo (Calver et al., 1998 and Fruttiger et al., 1999). While most OPCs differentiate into mature oligodendrocytes early in postnatal life, it is believed that a slowly dividing population of OPCs remains widely distributed within the adult brain (Ffrench-Constant et al., 1986 and Wolswijk and Noble, 1989). The adult CNS retains the capacity to generate new oligodendrocytes (McCarthy and Leblond, 1988), and here PDGF is also thought to regulate OPC number (Woodruff et al., 2004).

Specifically related to the oligodendrocytes we knew that the early oligodendrocyte precursor cells (OPCs) derived from the SVZ express PDGFR-alpha and respond by proliferating to PDGF-AA. In fact, I exploit this in lab all the time because I harvest rat OPCs from neonatal rat cortices and proliferate them in culture using media that contains PDGF-AA. What we had thought was that these PDGFR-alpha expressing cells -- these OPCs -- were relatively restricted to the glial lineage, particularly after development.

This study shows that this lineage not only persists into adulthood in both the human and the mouse, but also that it is capable of creating both oligodendrocytes and neurons. Furthermore, we now know that PDGF is a regulator that determine which fate they choose to adopt.

They actually show that PDGFR-alpha expressing cells become neurons using a rather clever trick. The adenovirus AAV5 uses the PDGFR-alpha receptor as its receptor for entry. So if you modify that virus to contain a GFP (a protein that is naturally fluorescent) you can specifically label all the cells that possess that receptor. The toast all the rapidly proliferating cells -- the A and C cells -- and then label all the B cells using this virus. Then they trace to find out where those cells went and find them as neurons and oligodendrocytes.

Here is the money quote:

Our analysis of PDGF receptor expression in the adult SVZ revealed for the first time the presence of a PDGFRα-expressing GFAP+ B cell population present in both the murine and human brain. Furthermore, we demonstrate that these PDGFRα+ B cells are not only precursors of oligodendrocytes, but also of neurons. Depleting SVZ C and A cells and labeling the remaining PDGFRα+ B cells with AAV5-GFP resulted in many labeled granule and periglomerular neurons. In addition, by coinfecting the SVZ with RCAS-AP virus and AAV5-GFP, we showed that PDGFRα+ B cells in the SVZ also generate oligodendrocytes. The PDGFRα is commonly used as a marker of OPCs or glial-restricted progenitors (GRPs) in the CNS (Grinspan and Franceschini, 1995 and Redwine et al., 1997). Our work demonstrates that these PDGFRα+ B cells are not GRPs but instead function as the primary progenitors of both oligodendrocytes and new neurons produced throughout adult life. A common progenitor population of neurons and oligodendrocytes also exists during development. Oligodendrocytes and neurons are derived from the same population of progenitors in the ventral region of the embryonic spinal cord (Lu et al., 2002, Takebayashi et al., 2002 and Zhou and Anderson, 2002) and in the developing cerebral cortex (He et al., 2001). Furthermore, it has recently been shown that PDGF-responsive progenitors capable of generating multipotent neurospheres can be isolated from the embryonic medial ganglionic eminence (Chojnacki and Weiss, 2004).

Our data suggest that PDGF signaling may be involved in the normal regulation of oligodendrogenesis and neurogenesis in the SVZ. We confirmed the presence of PDGF-A and to a lesser extent PDGF-B ligand in the SVZ by Western blot, and cells actively signaling from the PDGFRα were revealed by immunostaining for phospho-PDGFRα. Analysis of PDGFRαFl/Fl; Z/EG animals demonstrated that the PDGFRα is required for SVZ-derived oligodendrogenesis, and prelabeling B cells with RCAS-GFP demonstrated that PDGF infusion increased oligodendrocyte production from the SVZ. In contrast, loss of the PDGFRα did not interfere with the production of neurons, and PDGF infusion blocked neuroblast production during infusion and resulted in decreased numbers of GFP+ neurons present in the OB 21 days after treatment. Together, these data are consistent with a role for PDGF signaling in balancing neuron and oligodendrocyte production from PDGFRα+ SVZ B cells. The robust expression of the bHLH transcription factor Olig2 by the cells responding to PDGF stimulation suggests a mechanism for this regulation. The Olig family of transcription factors is required for oligodendrocyte development (Lu et al., 2002 and Zhou and Anderson, 2002). Olig2 repressor function is sufficient to repress neuronal differentiation in the postnatal (Marshall et al., 2005) and adult SVZ (Hack et al., 2005). Thus, PDGF may function upstream of Olig2 in regulating fate choice in the SVZ. It will be important to determine the source of PDGF in vivo.

Here is a sample figure from the paper. The figure below shows cells from the SVZ that are GFP positive (green) and colabelled with PDGFR-alpha (red) to show their virus works. Then they show cells in the olfactory bulb that are GFP and doublecortin positive (red, a neuronal marker). They also show a GFP stained cell from the corpus callosum (in this case brown) with oligodendrocyte morphology.

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This paper is important because identifying the markers for this stem cell -- and figuring out its proliferative signals -- is going to be critical to isolating it and putting it to medical use.

Hat-tip: Faculty of 1000.

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