Are oligodendrocyte precursor cells stem cells?
Are Oligodendrocyte Precursor Cells stem cells?
During development, cells become progressively more restricted in the cell types which they can become. In the central nervous system (CNS), there are multipotent stem cells which can give rise to cells identical to itself, various tissue-specific specialized cells and also precursor cells which intermediate cells. In this essay, I aim to focus on the properties of the oligodendrocyte precursor/progenitor cells (OPCs) and stem cells before carrying out a comparison and concluding whether OPCs are classified as stem cells.
Oligodendrocyte Precursor cells
The primary role of OPCs is to differentiate into myelinating oligodendrocytes, which is involved in myelin sheath production, required for primary myelination and remyelination of neurons in the CNS. The discovery of oligodendrocytes came with the identification of a bipotent progenitor cell in cultures of optic nerve (Raff et al, 1983b) which can differentiate into oligodendrocytes or type-2 astrocytes (Raff et al, 1983a) The uncertainty of these cells' differentiation potential in vivo led to the use of their two names; oligodendrocyte-type2 astrocyte (O-2A) precursor cell and oligodendrocyte precursor cell (OPC). Both names reflect important differential properties of this cell and subsequent studies indicated that perinatal O-2A cells were committed to becoming oligodendrocytes in almost all cases hence the switched terminology to OPC.
The ancestor of the OPCs is the pluripotent neuroepithelial stem cells (NSC), found in the subventricular zone (SVZ) and the dentate gyrus of the hippocampus. The NSCs can give rise to two antigenically distinct lineage-restricted precursor cells, the neuron restricted precursor cells (NRP) and the glial restricted precursor cells (GRP), which are restricted to becoming neurons or glia respectively. Mayer-Proschel et al 1997 showed that NRP cells can give rise to several populations of neurons while Rao et al 1997 showed that GRP cells can give rise to OPCs, type 1 and type 2 astrocytes. The OPCs in turn can give rise to myelinating oligodendrocytes and also type-2 astrocytes.The lineage diagram for an OPC is shown in figure 1.
Perinatal OPCs have also been show to give rise to a second generation of adult-specific OPCs, with different properties to their perinatal counterparts and more appropriate for the physiological needs of the adult CNS. Nevertheless, it is important to note that there are other differences between perinatal OPCs and adult OPCs. For example, experimental evidences have shown that adult OPCs have a more restricted differentiation potential than perinatal OPCs. However, this will not be further discussed here.
As the question being addressed here involves both OPCs and stem cells, it is crucial that we now consider the properties possessed by stem cells. Stem cells are unspecialized cells which are capable of renewing themselves through mitotic divisionsand differentiating into a wide range of specialized cell types. The primary roles of adult stem cells are to maintain the cells' homeostasis and, with limitations, to replace dead or injured cells (Leblond 1964 and Holzer 1978). Their behaviour differs in different tissues, depending on their local environment.
Stem cells are characterized by the following properties. Firstly they are able to undergo mitotic divisions to produce identical replicates of themselves for a long period of time and this ongoing proliferative ability is referred to as long term self-renewal. Secondly, they are able to give rise to mature cell types with characteristic morphologies and specialized functions to the tissue that the cell is in. Often, stem cells divide, giving rise to an intermediate cell type before reaching their fully differentiated state. These intermediate cells are referred to precursor or progenitor cells. Precursor cells are partly differentiated cells which can divide to give rise to fully differentiated cells, which are then regarded as committed to a specific differentiation developmental pathway (Robey 2000). They can also be thought of possessing partial characteristics of a specialized cell, which can undergo division to give two specialized cells.
A stem cell division thereby results in an additional daughter stem cell with the same capabilities of the original parent cell, and a specialized cell or often an intermediate precursor cell.
Again, it is important to note that there are differences between embryonic stem cells and adult stem cells. For example, embryonic stem cells are derived from the inner cell mass of the blastocyst whereas the origin of adult stem cells is still relatively unknown. Definitions of adult stem cells vary in the scientific literature, ranging from a simple description of the cells to a strict set of experimental criteria which must be fulfilled before characterizing a specific cell as an adult stem cell. Thereby, in order to be classified as an adult stem cell, the cell should be able to undergo long term self-renewal. It should also be able to generate fully differentiated cells which are fully integrated into the tissue and are capable of performing specialized functions appropriate for the tissue that the cell is in.
Returning our focus to OPCs, although they are bipotent and capable of self-renewal through mitotic cell divisions, the absence of asymmetric cellular division and their rapid proliferative response to an injury suggests that OPCs might have more in common with precursor cells than stem cells.
It is extremely difficult to distinguish an adult tissue-specific stem cell from a precursor cell. Precursor cells are partly differentiated cells which divide further to give fully differentiated cells. Their primary role is to replace cells when necessary and maintain the integrity of the tissue. Since precursor cells are unable to develop into all the cell types of a tissue, they are not truly stem cells and consequently, as OPCs appear to lack the ability to generate cell types derived by NRP cells, they cannot be classified as stem cells. This perhaps makes OPCs the best-characterized precursors in the CNS. These bipotent OPCs are produced followed by their migration throughout the developing CNS (Hardy et al 1991, Noll et al 1993, Yu et al 1994). They then undergo a limited number of mitotic cell divisions before most of them would terminally differentiate into postmitotic oligodendrocytes (Temple et al 1986, Gard et al 1990) although some persist in the adult CNS (Ffrench-Constand et al 1986, Wolswijk 1989). Even though precursor cells are shown to give rise to cell specific to their own lineage, recent studies have resulted in controversial findings.
Transdifferentiation, reversion & alternative cell fates
Although it was shown that neurons are derived from NRP cells, which are antigenically different to GRP cells, studies by Belachew et al 2003 and Kondo et al 2004 have shown that GRP derived OPCs can also give rise to neurons in the hippocampus. Kondo et al 2004 found that OPCs are not irreversibly committed to becoming oligodendrocytes or type 2 astrocytes (24). Cell differentiation is often thought to be a tightly regulated unidirectional event, however increasing evidence is suggesting that certain cells have the capability of reverting back to more primitive cells like tissue-specific stem cells, or undergo transdifferentiation into cells from other lineages. In Kondo's experiments, sequential exposure to fetal calf serum (FCS) or bone morphogenic proteins (BMPs) along with basic fibroblast growth factor (bGFG) induces OPC reversion to a state which resembles that of a multipotent CNS neural stem cell. These reverted cells are capable of self-renewal and the generation of neurons, type 1 astrocytes
and oligodendrocytes. The
transdifferentiation and reversion of
an OPC in relation to its ancestor and lineages is shown in figure 2.
Lyssiotis et al 2007 confirmed Kondo's finding that OPCs can be converted to multipotent neural stem-like cells, capable of generating both neurons and glia after BMP exposure. They found the inhibition of histone deacetylase (HDAC) activity in the OPCs can act as a priming event in the induction of developmental plasticity, thereby expanding the differentiation potential to include neuronal lineage. This conversion was found to be mediated, in part, through the reactivation of sox2 gene. Further, it was also found that sox2 and 12 other genes were activated by the HDAC inhibitor treatment, these activated genes were identified to play a role in maintaining the neural stem cell state while silencing oligodendrocytes lineage-specific genes. Overall, it showed that developmental plasticity can be induced by histone acetylation induced by HDAC inhibition.
The experiment examples mentioned above are only a few of the recent studies supporting the idea of a wider developmental potential in OPCs. In addition, Alonso 2005 and Talbott 2006 have shown that OPCs can generate glia-scar astrocytes or even Schwann cells respectively. However, these alternative differentiation fates have yet to be confirmed by further lineage-tracing studies. Sufficient experimental evidence has shown that OPCs can acquire multipotency in specific conditions and redifferentiate into neurons as well as astrocytes and oligodendrocytes. Restriction on their cell fate during development is likely to be due to local environmental cues from the tissue which the cell is in.
OPCs are derived from the pluripotent NSCs. OPCs are capable of limited self-renewal by mitotic division before terminally differentiating into type 2 astrocytes or most often, oligodendrocytes. It is important to note that perinatal OPCs have a less restricted differentiation potential than adult OPCs. Stem cells can undergo long term self-renewal while giving rise to a wide range of tissue-specific specialized cell types. Often, an intermediate cell type referred to a precursor cell is generated during a stem cell division. Precursor cells are partly differentiated cells which divide to give fully differentiated cells, which are then committed to a particular differentiation development pathway.
Limited time and divisions allowed for self-renewal before terminal differentiation
Pluripotent, can generate all possible cell types in the specific tissue
Bipotent (generate astrocytes, oligodendrocytes only)
Shows plasticity under experimental conditions.
Returning to the essay title, I do not consider OPCs as stem cells but as precursor cells with a greater developmental potential under specific experimental conditions. Firstly, although OPCs are capable of self-renewal but this is limited before their differentiation into a terminal cell fate whereas stem cells are capable of long term self-renewal. Secondly, although OPCs are bipotent and produce astrocytes and oligodendrocytes, unlike stem cells, they are not multipotent and are unable to give rise to all possible cell types in a tissue. The differences in their properties are summarized in a table in figure 3.
With the growing evidence showing the OPCs' capability to transdifferentiate into cells of a different lineage or revert to more primitive stem-like cells, it is reasonable to say that OPCs can gain differentitation plasticity under the right conditions or when forced to express unique combinations of genes (Watanable et al 2004, Takahashi et al 2006). With a possible increase in differentiation plasticity, OPCs might proved to be useful for cell therapy, as specified precursors are generally more abundant in the CNS and are easier to purify than mutlipotent neural stem cells.