Glial cells were long considered end products of neural differentiation, specialized supportive cells with an origin very different from that of neurons. New studies have shown that some glial cells—radial glia (RG) in development and specific subpopulations of astrocytes in adult mammals—function as primary progenitors or neural stem cells (NSCs). This is a fundamental departure from classical views separating neuronal and glial lineages early in development. Direct visualization of the behavior of NSCs and lineage-tracing studies reveal how neuronal lineages emerge. In development and in the adult brain, many neurons and glial cells are not the direct progeny of NSCs, but instead originate from transit amplifying, or intermediate, progenitor cells (IPCs). Within NSCs and IPCs, genetic programs unfold for generating the extraordinary diversity of cell types in the central nervous system. The timing in development and location of NSCs, a property tightly linked to their neuroepithelial origin, appear to be the key determinants of the types of neurons generated. Identification of NSCs and IPCs is critical to understand brain development and adult neurogenesis and to develop new strategies for brain repair.

The glial nature of embryonic and adult neural stem cells

Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow

Fibroblasts constitute the major mesenchymal cell type in the connective tissue and their functions are remarkably diverse: here, by characterising lineages of mouse skin fibroblasts, it is shown that distinct subpopulations contribute to skin development and repair during injury. Fibroblasts are unremarkable looking cells found in most tissues in the body, where they are mainly concerned with making the collagen that supports other cell types. The cells all look much the same yet are functionally diverse, prompting the question, is there just one cell type responding differently to different stimuli, or do individual cells specialize? A transplantation and lineage tracing study in mice now shows that skin connective tissue arises from two distinct fibroblast lineages that also contribute differentially to skin development and repair after injury. One cell type forms the lower dermis and the other the upper dermis. The latter lineage is required for hair follicle production. In wounded adult skin, the initial wave of dermal repair is mediated by the 'lower' lineage, which may explain the absence of hair follicles in newly closed wounds. The authors develop a comprehensive lineage tree for all fibroblast-derived cell types in mouse dermis, including smooth muscle cells and adipocytes. Fibroblasts are the major mesenchymal cell type in connective tissue and deposit the collagen and elastic fibres of the extracellular matrix (ECM)1. Even within a single tissue, fibroblasts exhibit considerable functional diversity, but it is not known whether this reflects the existence of a differentiation hierarchy or is a response to different environmental factors. Here we show, using transplantation assays and lineage tracing in mice, that the fibroblasts of skin connective tissue arise from two distinct lineages. One forms the upper dermis, including the dermal papilla that regulates hair growth and the arrector pili muscle, which controls piloerection. The other forms the lower dermis, including the reticular fibroblasts that synthesize the bulk of the fibrillar ECM, and the preadipocytes and adipocytes of the hypodermis. The upper lineage is required for hair follicle formation. In wounded adult skin, the initial wave of dermal repair is mediated by the lower lineage and upper dermal fibroblasts are recruited only during re-epithelialization. Epidermal β-catenin activation stimulates the expansion of the upper dermal lineage, rendering wounds permissive for hair follicle formation. Our findings explain why wounding is linked to formation of ECM-rich scar tissue that lacks hair follicles2,3,4. They also form a platform for discovering fibroblast lineages in other tissues and for examining fibroblast changes in ageing and disease.

Distinct fibroblast lineages determine dermal architecture in skin development and repair

Myelin-forming oligodendrocytes (OLs) are formed continuously in the healthy adult brain. In this work, we study the function of these late-forming cells and the myelin they produce. Learning a new motor skill (such as juggling) alters the structure of the brain’s white matter, which contains many OLs, suggesting that late-born OLs might contribute to motor learning. Consistent with this idea, we show that production of newly formed OLs is briefly accelerated in mice that learn a new skill (running on a “complex wheel” with irregularly spaced rungs). By genetically manipulating the transcription factor myelin regulatory factor in OL precursors, we blocked production of new OLs during adulthood without affecting preexisting OLs or myelin. This prevented the mice from mastering the complex wheel. Thus, generation of new OLs and myelin is important for learning motor skills.

/pdf/motor-skill-learning-requires-active-central-myelination-3xmxrnapsk.pdf

Motor skill learning requires active central myelination

NG2 cells (also known as polydendrocytes) are a population of CNS cells that are distinct from neurons, mature oligodendrocytes, astrocytes and microglia. They can be identified by the expression of the proteoglycan NG2, have a highly branched morphology and are distributed throughout the grey and white matter. They differentiate into oligodendrocytes in vitro and have often been equated with oligodendrocyte precursor cells. However, whether polydendrocytes are multipotential cells that can give rise to neurons and astrocytes as well as oligodendrocytes is now highly debated. Furthermore, electrophysiological studies indicate that polydendrocytes receive synaptic input from neurons, suggesting that they are integrated in the neural network. This Review highlights recent findings and unresolved questions related to the lineage and function of polydendrocytes in the CNS.

Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity

About 4% of the cells in the adult rodent brain are PDGFRA+ NG2+ glia, derived from the oligodendrocyte lineage. Rivers and colleagues constructed a transgenic mouse to fate map the PDGFRA+ glia. In the adult corpus callosum, these cells generated substantial numbers of late-myelinating oligodendrocytes. In the cortex, little late myelination was observed; instead, PDGFRA+ precursors seemed to continuously generate small numbers of projection neurons mainly in piriform cortex.

/pdf/pdgfra-ng2-glia-generate-myelinating-oligodendrocytes-and-28t962j42m.pdf

PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice

https://www.ucl.ac.uk/%7Eucbzwdr/publications/Zawadzka%20et%20al%20%28Cell%20Stem%20Cell%202010%29.pdf

CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination.

The adult mammalian brain and spinal cord contain glial precursors that express platelet-derived growth factor receptor α subunit (PDGFRA) and the NG2 proteoglycan. These "NG2 cells" descend from oligodendrocyte precursors in the perinatal CNS and continue to generate myelinating oligodendrocytes in the gray and white matter of the postnatal brain. It has been proposed that NG2 cells can also generate reactive astrocytes at sites of CNS injury or demyelination. To test this we examined the fates of PDGFRA/NG2 cells in the mouse spinal cord during experimental autoimmune encephalomyelitis (EAE)--a demyelinating condition that models some aspects of multiple sclerosis in humans. We administered tamoxifen to Pdgfra-CreER(T2):Rosa26R-YFP mice to induce yellow fluorescent protein (YFP) expression in PDGFRA/NG2 cells and their differentiated progeny. We subsequently induced EAE and observed a large (>4-fold) increase in the local density of YFP(+) cells, >90% of which were oligodendrocyte lineage cells. Many of these became CC1-positive, NG2-negative differentiated oligodendrocytes that expressed myelin markers CNP and Tmem10/Opalin. PDGFRA/NG2 cells generated very few GFAP(+)-reactive astrocytes (1-2% of all YFP(+) cells) or NeuN(+) neurons (<0.02%). Thus, PDGFRA/NG2 cells act predominantly as a reservoir of new oligodendrocytes in the demyelinated spinal cord.

https://www.jneurosci.org/content/jneuro/30/48/16383.full.pdf

Leanne E. Rivers

Papers

PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice

CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination.

NG2 glia generate new oligodendrocytes but few astrocytes in a murine experimental autoimmune encephalomyelitis model of demyelinating disease.