The foundation of precursor cell biology is cell identification. Without the ability to study well defined cells, it is not possible to develop transplantation therapies or cell recruitment strategies, to identify contributions of precursor cell dysfunction to disease pathogenesis, or to study a wide variety of problems central to developing the field of stem cell medicine. For these reasons, cell discovery has been central to our efforts since entering the field of stem cell biology.
Our criteria for cell identification are particularly stringent. All the cells with which we work have been isolated directly from the animal, studied at the clonal level to confirm that isolation conditions are yielding homogeneous populations, and transplanted back into the animal to determine whether the pattern of differentiation observed in vivo is as predicted from our in vitro experimentation. Moreover, in our studies on oligodendrocyte development, the first decade of our work was focused on development of tissue culture systems in which the pattern and timing of development in vitro successfully mimicked that occurring in vivo. The value of establishing such culture conditions is evidenced by the ability of our in vitro analyses to accurately predict in vivo outcomes in multiple circumstances, as will be discussed in appropriate sections of this overview. Moreover, the ability to study homogeneous populations of well-defined cell types has been central to our analysis of multiple problems in cellular biology and also to our analysis of an increasing variety of clinical problems, as described throughout this overview.
Some of the key milestones in the cell discovery efforts involving members of our research team include:
- 1983 – The first progenitor cell identified in the CNS was the oligodendrocyte-type-2 astrocyte (O-2A) progenitor (referred to by many laboratories as an oligodendrocyte precursor cell) (Raff et al., 1983).
- 1989 – We next isolated O-2A progenitor cells from the adult CNS, and found that these cells differ in multiple respects from the O-2A progenitor cells found in the developing CNS (Wolswijk and Noble, 1989; Wolswijk and Noble, 1992; Wolswijk et al., 1990; Wolswijk et al., 1991).
- 1994 – Olfactory ensheathing cells (OECs) were the next cell type isolated by our research team, in studies that also were the first to demonstrate these cells represented a unique cell population distinct from both O-2A progenitor cells and from Schwann cells of the peripheral nervous system (Barnett et al., 1993).
- 1997/8 – The next lineage-restricted progenitor cells isolated from the developing CNS (by Margot Mayer-Proschel and Mahendra Rao) were the neuron-restricted precursor (NRP) cell and the glial-restricted precursor (GRP) cell, which initially were generated from neuroepithelial stem cells (Mayer-Pröschel et al., 1997; Rao and Mayer-Pröschel, 1997). Both NRP and GRP cells then were isolated from the embryonic rat spinal cord (Rao et al., 1998).
- 2002 – GRP cells were found to be able to give rise directly to O-2A progenitor cells, further strengthening the data that these two cell types have fundamentally different properties but demonstrating for the first time a lineage relationship between these two progenitor cell populations (Gregori et al., 2002).
- 2002 – O-2A progenitor cells isolated from different regions of the developing CNS were found to have strikingly different properties in respect to self-renewal, response to inducers of differentiation, and to essentially represent distinct progenitor cell populations (Power et al., 2002).
- 2002 – Human glial-restricted glial precursor cells were isolated from the embryonic human CNS (Dietrich et al., 2002).
- 2007 – Telencephalic GRP (tGRP) cells were isolated from the embryonic rat telencephalon and found to have different properties from GRP cells that had been previously isolated from the embryonic rat spinal cord (Strathmann et al., 2007).
Cell discovery continues to play an important role in our research program, as it is the ability to work with these different populations that provides an essential part of the tool kit for our other efforts.
Schematic representation of the lineage relationships in the developing CNS: Pluripotent neuroepithelial stem cells (NSC) give rise to glial restricted precursor cells (GRP) and to neuron restricted precursor cells (NRP). NRP cells can give rise to multiple populations of neurons, while GRP cells can generate two different kinds of astrocytes (type-1 and type-2) and O-2A progenitor cells. The O-2A progenitors in turn give rise to oligodendrocytes and also can generate type-2 astrocytes. O-2A progenitor cells of the perinatal CNS also give rise to a second generation of adult-specific O-2A progenitor cells, with properties different from their perinatal counterparts and more appropriate for the physiological needs of the adult CNS. For discussion of these various cell types, and other theories about the origins of oligodendrocytes, please see (Noble et al., 2004)
Noble, M., Pröschel, C., and Mayer-Proschel, M. (2004). Getting a GR(i)P on oligodendrocyte development. Dev. Biol. 265, 33-52. view article in PubMed
Barnett, S. C., Hutchins, A. M., and Noble, M. (1993). Purification of olfactory nerve ensheathing cells from the olfactory bulb. Dev. Biol. 155, 337-50. link
Dietrich, J., Noble, M., and Mayer-Proschel, M. (2002). Characterization of A2B5+ glial precursor cells from cryopreserved human fetal brain progenitor cells. Glia 40, 65-77. link
Gregori, N., Proschel, C., Noble, M., and Mayer-Pröschel, M. (2002). The tripotential glial-restricted precursor (GRP) cell and glial development in the spinal cord: Generation of bipotential oligodendrocyte-type-2 astrocyte progenitor cells and dorsal-ventral differences in GRP cell function. J. Neurosci. 22, 248-256. link
Mayer-Pröschel, M., Kalyani, A., Mujtaba, T., and Rao, M. S. (1997). Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells. Neuron 19, 773-85. link
Power, J., Mayer-Proschel, M., Smith, J., and Noble, M. (2002). Oligodendrocyte precursor cells from different brain regions express divergent properties consistent with the differing time courses of myelination in these regions. Dev. Biol. 245, 362-375. link
Raff, M. C., Miller, R. H., and Noble, M. (1983). A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on the culture medium. Nature 303, 390-396. link
Rao, M., and Mayer-Pröschel, M. (1997). Glial restricted precursors are derived from multipotent neuroepithelial stem cells. Dev. Biology 188, 48-63. link
Rao, M., Noble, M., and Mayer-Pröschel, M. (1998). A tripotential glial precursor cell is present in the developing spinal cord. Proc. Natl. Acad. Sci. U. S. A. 95, 3996-4001. link
Strathmann, F. G., Wang, X., and Mayer-Proschel, M. (2007). Identification of two novel glial-restricted cell populations in the embryonic telencephalon arising from unique origins. BMC Dev. Biol. 7:33. link
Wolswijk, G., and Noble, M. (1989). Identification of an adult-specific glial progenitor cell. Development 105, 387-400. link
Wolswijk, G., and Noble, M. (1992). Cooperation between PDGF and FGF converts slowly dividing O-2Aadult progenitor cells to rapidly dividing cells with characteristics of O-2Aperinatal progenitor cells. J-Cell-Biol 118, 889-900. link
Wolswijk, G., Riddle, P. N., and Noble, M. (1990). Coexistence of perinatal and adult forms of a glial progenitor cell during development of the rat optic nerve. Development 109, 691-8 issn: 0950-1991. link
Wolswijk, G., Riddle, P. N., and Noble, M. (1991). Platelet-derived growth factor is mitogenic for O-2Aadult progenitor cells. Glia 4, 495-503. link
Mark D. Noble
University of Rochester
601 Elmwood Ave.
Rochester, NY 14642
Office: MRB 2-9625