Review ArticleDirected glial differentiation and transdifferentiation for neural tissue regeneration
Introduction
Ontogenetic development and the physiological functioning of the central nervous system (CNS), as well as the initiation of the resulting neurorestorative processes entirely rely on multidirectional interactions between neurons and glia. Over the past few decades of a great deal of investigation on glial cells has enhanced the understanding of the multiple roles they play in the nervous tissue. Glia, which functions nowadays are regarded as going far beyond being just a “glue”, comprises the populations of macroglia and microglia. The former corresponds to the cells that originate from the ectoderm and are referred to as astrocytes, oligodendrocytes and ependymal cells, while the latter-the resident microglial cells-are derived from the yolk sac and populate the CNS during its early embryonic development (Hoeffel and Ginhoux, 2018; Lloyd et al., 2017; Rowitch and Kriegstein, 2010). As they play pleiotropic roles in the nervous tissue, glial cells were until some years ago thought to vastly outnumber neurons. However recent studies based on an innovative counting method employing an isotropic fractionator have allowed calculating the glia to neuron ratio being close to 1:1, with a total number of about 100 billion glial cells in the human brain (von Bartheld, 2017; García-Cabezas et al., 2016). In human spinal cords, the other part of the CNS rich in white matter, the same method estimated amount of glia for 1.5-1.7 billion cells and approximately 200 million neurons (which corresponds to 13.4% neurons, 12.2% endothelial cells, 74.8% glial cells, respectively), making the glia-neuron ratio oscillate between 5.6-7.1 (Bahney and von Bartheld, 2018). The proportion of neurons to glia seems to be precisely regulated to ensure efficient support of energetic substrates, as well as delivery of instructive signals and trophic factors, altogether contributing to the effective functioning of the CNS. Injury to the nervous tissue usually triggers a diversified response of glial cells, including their proliferation, migration, change in their secretome profile, and even de- or transdifferentiation aimed at initiating or enhancing endogenous processes associated with tissue repair.
Section snippets
Origin of glia during ontogenesis and in adulthood
Multipotent radial glia, which are perceived as primary neural stem cells (NSCs) and common precursors of both neurons and macroglia, originate from the neuroepithelial cells that line the cerebral ventricles and the spinal canal (Noctor et al., 2002; Rowitch and Kriegstein, 2010). Within the boundaries of the developing nervous system, the composition and concentration gradients of extrinsic instructive signals within the extracellular milieu play a crucial role in adopting cell fate by
Role of glia in development and physiological functioning of the central nervous system
Once derived during ontogenesis, glial cells are actively engaged in forming the nervous system, thus becoming indispensable for establishing the neuronal circuit and signal transduction (Clarke and Barres, 2013). They provide structural support and create local tissue microenvironment by secreting biologically active compounds like trophic factors, cytokines and neuromodulators. Astrocytes express axonal guidance molecules, as well as promote synaptogenesis (by secreting synaptogenic molecules
Response of glial cells to pathophysiological cues
Under pathophysiological conditions or upon injury, resident glial cells are activated and respond to the changed tissue microenvironment in several ways. NG2+ cells which exhibit an inestimable, in the context of tissue regeneration, ability to proliferate throughout the lifespan, serve as a reservoir of glial progenitors for deriving myelinating cells (Simon et al., 2011). They have also been shown to increase their proliferation rate and to initiate migration towards the site of injury (Hesp
Exploring the endogenous reservoir of glial cells
The few last decades of intense research on glia functions have considerably enhanced our appreciation of them as active regulators asserting the physiological function of the CNS and potent defenders in pathological conditions. Alterations in their differentiation process, their malfunctioning or depletion due to neurodegenerative mechanisms usually lead to neurological disorders. To prevent the consequences of tissue homeostasis misbalance evoked by pathological cues, neuroreperative
Targeted reprogramming of glial cells into neurons by transcription factors
As alluded above, NG2+ progenitors giving rise to myelinating oligodendrocytes are abundant in the brain and the spinal cord parenchyma, and known to be activated under pathophysiological conditions or upon injury. Since oligodendrocytes undergo a precisely regulated multi-stage process of maturation (Fig. 1 B, C, D), finalized by gaining by the cells the ability to generate myelin components, they could be extremely prone to reprogramming in their the early stages of differentiation (Huang and
Directed glial differentiation and modulation of their activity
Reprogramming strategies based on viral vector injection are associated however with the necessity of a precise neurosurgery and the introduction of non-human genetic material, which is thought to be controversial in the context of clinical usage (Biasco et al., 2012). Recognizing those limitations, alternative therapies aimed at complex regeneration of the neural tissue are being searched for by testing out various approaches (Table 2). One of the promising strategies is modifying glial cell
Advantages and disadvantages of the transdifferentiation strategies
As previously mentioned, targeting glia for transdifferentiation strategies makes it possible to avoid crossing the neural lineage boundaries, which is the main advantage of this approach. This allows limiting the risk of tumorigenesis and usually shortens procedures, for there is no need to pass through several stages of the differentiation process (including pluripotency state), as glial cells are already neurally committed. The disadvantages of redirecting cell fate into alternative neural
Conclusions
Glial cells, which orchestrate the central nervous system development and ensure its proper physiological functioning, are proven to be highly sensitive to the harmful influence of pathological cues and tissue misbalance, as well as to the modulation of their commitment, differentiation and even the fate-switch by different types of bioactive molecules. The compounds that are potent in guiding in vivo cell fate conversion and driving cell differentiation, include transcription factors,
Acknowledgements
Funding: This study was financially supported by NCN (National Science Centre, Poland) grant no.2014/15/B/NZ4/01875 (to JS) and Wroclaw Research Centre EIT+, grant BioMed/5.4 POIG.01.01.02-02-003/08 (to LB).
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