Brain regeneration in physiology and pathology: the immune signature driving therapeutic plasticity of neural stem cells

Abstract

Regenerative processes occurring under physiological (maintenance) and pathological (reparative) conditions are a fundamental part of life and vary greatly among different species, individuals, and tissues. Physiological regeneration occurs naturally as a consequence of normal cell erosion, or as an inevitable outcome of any biological process aiming at the restoration of homeostasis. Reparative regeneration occurs as a consequence of tissue damage. Although the central nervous system (CNS) has been considered for years as a "perennial" tissue, it has recently become clear that both physiological and reparative regeneration occur also within the CNS to sustain tissue homeostasis and repair. Proliferation and differentiation of neural stem/progenitor cells (NPCs) residing within the healthy CNS, or surviving injury, are considered crucial in sustaining these processes. Thus a large number of experimental stem cell-based transplantation systems for CNS repair have recently been established. The results suggest that transplanted NPCs promote tissue repair not only via cell replacement but also through their local contribution to changes in the diseased tissue milieu. This review focuses on the remarkable plasticity of endogenous and exogenous (transplanted) NPCs in promoting repair. Special attention will be given to the cross-talk existing between NPCs and CNS-resident microglia as well as CNS-infiltrating immune cells from the circulation, as a crucial event sustaining NPC-mediated neuroprotection. Finally, we will propose the concept of the context-dependent potency of transplanted NPCs (therapeutic plasticity) to exert multiple therapeutic actions, such as cell replacement, neurotrophic support, and immunomodulation, in CNS repair.

FIGURE 1

Schematic representation of constitutive (physiological) adult neuro(glio)genesis and reactive neuro(glio)genesis occurring as a consequence of a CNS-restricted inflammatory/degenerative lesion. A: constitutive neurogenesis, granting continuous renewal of specific neuronal populations, is restricted to germinal layer-derived neurogenic sites (subventricular zone, SVZ; subgranular zone, SGZ). Although retaining some multipotency, local progenitors, widespread within the parenchyma, mainly contribute to the slow renewal of glial cells. B: as a result of a CNS-restricted lesion (e.g., inflammatory, degenerative), both NPCs within neurogenic niches and parenchymal progenitors are activated and might migrate toward damaged tissue. The final fate of both NPCs and parenchymal progenitors is very much depending of the type of CNS insults they are reactive to and the microenvironment they have to confront with. In particular, the cellular components of such pathological microenvironment - blood-borne mononuclear cells, CNS-resident activated microglia, degenerating neurons and glial cells - play a major role (see also FIG. 2). Reactive neuro(glio)genesis can be abortive (not ensuring a proper tissue healing), detrimental (promoting reactive astrogliosis), but also regenerating. If the latter is the case, newly generated undifferentiated NPCs and parenchymal progenitors (e.g., OPCs, NG2⁺ cells, S100β⁺/GLT1⁺ astrocytes, pericytes) can provide tissue protection by cell replacement or by releasing trophic factor or anti-inflammatory molecules (bystander effect). Replacement of neurons mainly occurs when the damage occurs closely to neurogenic areas (e.g., middle cerebral artery occlusion stroke) while replacement of glial cells might occur in parenchymal areas close or not to neurogenic niches (e.g., OPCs in demyelinating disorders).

FIGURE 2

In vitro and in vivo mechanistic evidence supporting the existence of an intrinsic (innate) self-maintenance program sustaining either CNS homeostasis during adaptive (physiological) conditions, or CNS repair during maladaptive (pathological) conditions. Several molecular and cellular events sustaining this phenomenon have been described so far. They can be divided into three distinct, although strictly interrelated, categories: immune-mediated processes (sustained by blood-borne T cells and monocyte-derived macrophages as well as CNS-resident microglia), axonal and synaptic plasticity, and neuro(glio)genesis. Depending on the context (microenvironment), humoral and cellular components supporting immune-mediated processes may shift sense (function) over time from a tissue-damaging mode to a mode-promoting tissue homeostasis (e.g., neurotrophic support from inflammatory cells). Axonal branching and synaptogenesis are plastic mechanisms maintaining tissue integrity as well as driving the recruitment of alternative “nondamaged” functioning neuronal pathways (cortical maps) as a consequence of brain damage. Whether or not (and to what extent) the recapitulation of precise developmental pathways underlies the whole phenomenon of brain plasticity is still a matter of investigation. Finally, endogenous neural stem/precursor cells (NPCs), the self-renewing and multipotent cells of the CNS capable of driving neurogenesis and gliogenesis in adult life, may promote physiological replacement of neural cells as well as adapt targeted migration into damaged areas to promote repair via several mechanisms of action encompassing neuro(glio)genesis, immunomodulation, and neuroprotection. In this complex interplay, the interaction between cells (e.g., microglia, NPCs) resident within the CNS and those (T cells, monocyte-derived macrophages) derived from the bloodstream, but infiltrating the CNS, is crucial to sustain the adaptive (homeostatic) control of the brain during physiological condition as well as to instructing brain repair during maladaptive (pathological) conditions.

FIGURE 3

The results so far obtained using NPCs as a therapeutic weapon for neurological disorders consistently challenge the sole and limited view that those cells therapeutically work exclusively throughout cell replacement. As a matter of fact, transplantation of NPCs may also promote CNS repair via intrinsic neuroprotective “bystander” capacities, mainly exerted by undifferentiated NPCs releasing, at the site of tissue damage, a milieu of neurotrophic (e.g., growth factors, stem cell regulators) and immunomodulatory (e.g., cytokines, chemokines, complement components) molecules whose release is temporally and spatially orchestrated by environmental needs, and the net final effect is neuroprotection. Thus the concept of stem cell therapeutic plasticity is emerging and can be viewed as the capacity of these somatic cells to adapt their fate and function(s) to specific environmental needs occurring as a result of different pathological conditions. This is just a recapitulation of the homeostatic control exerted by NPCs in normal conditions (FIG. 2). As such, the molecules sustaining the therapeutic plasticity mechanism are pleiotropic and redundant in nature and are “constitutively” secreted by stem cells; they are the very same molecules capable to perform the homeostatic control of CNS integrity by sustaining an interplay between blood-borne immune cells (T cells, monocyte-derived macrophages) surveying the brain and CNS resident neural and nonneural cells (e.g., microglia).