Ageing stem and progenitor cells: implications for rejuvenation of the central nervous system

As part of our attempts to understand principles that underly organism development, we have been studying the development of the rat optic nerve. This simple tissue is composed of three glial cell types derived from two distinct cellular lineages. Type-1 astrocytes appear to be derived from a monopotential neuroepithelial precursor, whereas type-2 astrocytes and oligodendrocytes are derived from a common oligodendrocyte-type-2 astrocyte (O-2A) progenitor cell. Type-1 astrocytes modulate division and differentiation of O-2A progenitor cells through secretion of platelet-derived growth factor, and can themselves be stimulated to divide by peptide mitogens and through stimulation of neurotransmitter receptors. In vitro analysis indicates that many dividing O-2A progenitors derived from optic nerves of perinatal rats differentiate symmetrically and clonally to give rise to oligodendrocytes, or can be induced to differentiate into type-2 astrocytes. O-2A perinatal progenitors can also differentiate to form a further O-2A lineage cell, the O-2A adult progenitor, which has properties specialized for the physiological requirements of the adult nervous system. In particular, O-2A adult progenitors have many of the features of stem cells, in that they divide slowly and asymmetrically and appear to have the capacity for extended self-renewal. The apparent derivation of a slowly and asymmetrically dividing cell, with properties appropriate for homeostatic maintenance of existing populations in the mature animal, from a rapidly dividing cell with properties suitable for the rapid population and myelination of central nervous system (CNS) axon tracts during early development, offers novel and unexpected insights into the possible origin of self-renewing stem cells and also into the role that generation of stem cells may play in helping to terminate the explosive growth of embryogenesis. Moreover, the properties of O-2A adult progenitor cells are consistent with, and may explain, the failure of successful myelin repair in conditions such as multiple sclerosis, and thus seem to provide a cellular biological basis for understanding one of the key features of an important human disease.

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Monofocal origin of telencephalic oligodendrocytes in the anterior entopeduncular area of the chick embryo

Development ◽

10.1242/dev.128.10.1757 ◽

2001 ◽

Vol 128 (10) ◽

pp. 1757-1769 ◽

Cited By ~ 3

Author(s):

C. Olivier ◽

I. Cobos ◽

E.M. Perez Villegas ◽

N. Spassky ◽

B. Zalc ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Chick Embryo ◽

Embryonic Development ◽

Progenitor Cells ◽

Oligodendrocyte Progenitor Cells ◽

Chick Brain ◽

The Central Nervous System ◽

The Brain

Oligodendrocytes are the myelin-forming cells in the central nervous system. In the brain, oligodendrocyte precursors arise in multiple restricted foci, distributed along the caudorostral axis of the ventricular neuroepithelium. In chick embryonic hind-, mid- and caudal forebrain, oligodendrocytes have a basoventral origin, while in the rostral fore-brain oligodendrocytes emerge from alar territories (Perez Villegas, E. M., Olivier, C., Spassky, N., Poncet, C., Cochard, P., Zalc, B., Thomas, J. L. and Martinez, S. (1999) Dev. Biol. 216, 98–113). To investigate the respective territories colonized by oligodendrocyte progenitor cells that originate from either the basoventral or alar foci, we have created a series of quail-chick chimeras. Homotopic chimeras demonstrate clearly that, during embryonic development, oligodendrocyte progenitors that emerge from the alar anterior entopeduncular area migrate tangentially to invade the entire telencephalon, whereas those from the basal rhombomeric foci show a restricted rostrocaudal distribution and colonize only their rhombomere of origin. Heterotopic chimeras indicate that differences in the migratory properties of oligodendroglial cells do not depend on their basoventral or alar ventricular origin. Irrespective of their origin (basal or alar), oligodendrocytes migrate only short distances in the hindbrain and long distances in the prosencephalon. Furthermore, we provide evidence that, in the developing chick brain, all telencephalic oligodendrocytes originate from the anterior entopeduncular area and that the prominent role of anterior entopeduncular area in telencephalic oligodendrogenesis is conserved between birds and mammals.

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Recruitment of Endogenous Neural Progenitor Cells by Malignant Neoplasms of the Central Nervous System

Current Stem Cell Research & Therapy ◽

10.2174/157488807780599257 ◽

2007 ◽

Vol 2 (2) ◽

pp. 113-119 ◽

Cited By ~ 3

Author(s):

Henry Klassen

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Progenitor Cells ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

Malignant Neoplasms ◽

The Central Nervous System

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P48. Formation of blood vessels is controlled by neural progenitor cells in the central nervous system

Differentiation ◽

10.1016/j.diff.2010.09.054 ◽

2010 ◽

Vol 80 ◽

pp. S33

Author(s):

Teruaki Takahashi ◽

Yuta Takase ◽

Ryosuke Tadokoro ◽

Yoshiko Takahashi

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Blood Vessels ◽

Progenitor Cells ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

The Central Nervous System

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mTORC2 loss in oligodendrocyte progenitor cells results in regional hypomyelination in the central nervous system

10.1101/2022.01.04.474811 ◽

2022 ◽

Author(s):

Kristin D Dahl ◽

Hannah A Hathaway ◽

Adam R Almeida ◽

Jennifer Bourne ◽

Tanya L Brown ◽

...

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Corpus Callosum ◽

Signaling Pathways ◽

Progenitor Cells ◽

Myelin Proteins ◽

Oligodendrocyte Progenitor Cells ◽

Oligodendrocyte Progenitor ◽

The Central Nervous System

In the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) differentiate into mature oligodendrocytes to generate myelin, which is essential for normal nervous system function. OPC differentiation is driven by signaling pathways such as mTOR (Mechanistic Target of Rapamycin), which functions in two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), containing Raptor or Rictor respectively. In the current studies, mTORC2 signaling was selectively deleted from OPCs in PDGFRα-Cre X Rictorfl/fl mice. This study examined developmental myelination in male and female mice, comparing the impact of mTORC2 deletion in the corpus callosum and spinal cord. In both corpus callosum and spinal cord, Rictor loss in OPCs resulted in early reduction in myelin RNAs and some myelin proteins. However, these deficits rapidly recovered in spinal cord, where normal myelin abundance and thickness was noted at post-natal day 21 and 1.5 months. By contrast, the losses in corpus callosum resulted in severe hypomyelination, and increased unmyelinated axons. The current studies focus on uniquely altered signaling pathways following mTORC2 loss in developing oligodendrocytes. A major mTORC2 substrate is phospho-Akt-S473, which was significantly reduced throughout development in both corpus callosum and spinal cord at all ages measured, yet this had little impact in spinal cord. Loss of mTORC2 signaling resulted in decreased expression of actin regulators such as gelsolin in corpus callosum, but only minimal loss in spinal cord. The current study establishes a regionally-specific role for mTORC2 signaling in OPCs, particularly in the corpus callosum.

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