Enhancing endogenous capacity to repair a stroke-damaged brain: An evolving field for stroke research

Abstract

Stroke represents a severe medical condition that causes stroke survivors to suffer from long-term and even lifelong disability. Over the past several decades, a vast majority of stroke research targets neuroprotection in the acute phase, while little work has been done to enhance stroke recovery at the later stage. Through reviewing current understanding of brain plasticity, stroke pathology, and emerging preclinical and clinical restorative approaches, this review aims to provide new insights to advance the research field for stroke recovery. Lifelong brain plasticity offers the long-lasting possibility to repair a stroke-damaged brain. Stroke impairs the structural and functional integrity of entire brain networks; the restorative approaches containing multi-components have great potential to maximize stroke recovery by rebuilding and normalizing the stroke-disrupted entire brain networks and brain functioning. The restorative window for stroke recovery is much longer than previously thought. The optimal time for brain repair appears to be at later stage of stroke rather than the earlier stage. It is expected that these new insights will advance our understanding of stroke recovery and assist in developing the next generation of restorative approaches for enhancing brain repair after stroke.

Keywords: Brain plasticity; Brain repair; Restorative timing; Stroke recovery.

Fig. 1.

Schematic diagram of an enriched environment and its effects on neural plasticity. (A) Standard environment. This environment represents a standard housing condition that 3 rats are housed in a standard laboratory cage. (B) Enriched environment. A large group of rats are housed in a large cage furnished with a variety of play objects. Enriched environment housing after experimental stroke leads to increases in dendritic branching and dendritic spine generation (Johansson and Belichenko, 2002).

Fig. 2.

SCF + G-CSF treatment in the chronic phase of experimental stroke increases dendritic spine size in the cortex adjacent to the infarct cavity. Aged male Thy-1-YFPH mice (16–18 months old) are subjected to cortical infarct in the right hemisphere. In the Thy-1-YFPH mice, yellow fluorescent protein (YFP) is selectively expressed in the somas, axons, dendrites and dendritic spines of the layer V pyramidal neurons. Through a thinned skull window prepared in the right side of the head, the dynamics of dendritic spines in the layer V pyramidal neurons adjacent to the infarct cavity are captured with a 2-photon microscope before treatment as well as 2 and 6 weeks after treatment on live animals. (A) Three imaging sites above the cortex next to the infarct cavity. (B) The thinned skull window prepared for live brain imaging. (C) Live brain imaging by 2-photon microscopy on the right side of the head. (D) Schematic diagram showing the flowchart for the experiment. (E and F) YFP-expressing layer V pyramidal neurons and their apical dendrites in layer I–II where are scanned by a 2-photon microscope. (G) The different types of dendritic spines and the representative images of dendritic spines in the brains of intact, stroke-vehicle control, or stroke-SCF + G-CSF-treated mice. (H) Live brain imaging data. Note that the mushroom spines (M-type) are decreased and the uncertain spines (U-type) are increased in the stroke mice before treatment (week 0). SCF + G-CSF (S + G) treatment results in increases in the mushroom spines and reductions in the uncertain spines during the period of 2 to 6 weeks after treatment. *p < 0.05. (Cui et al., 2013).

Fig. 3.

Schematic diagram of synaptic networks in different conditions. In the condition of acute stroke, the mushroom type spines undergo retraction/degeneration in the surviving neurons outside the infarct core because the neurons that have synaptic connections with the surviving neurons die off in the infarct area. As a result, the number of the mushroom type spines is reduced and the number of the spines that are unable to form synapses (U-type) is increased in the peri-infarct-cavity cortex in the chronic phase of stroke. SCF + G-CSF treatment in the chronic phase of stroke enhances axon sprouting and mushroom spine formation, suggesting that the neural network rewiring in the peri-infarct-cavity cortex is enhanced by the treatment.

Fig. 4.

Biological effects of stem cell therapy. Cell therapies are capable of producing direct and indirect effects to elicit brain repair. This is accomplished through both the secretion of trophic factors and cytokines and release of extracellular vesicles, or exosomes, containing trophic factors, enzymes, micro RNA, etc. These factors can directly act on infarcted brain tissue to support function or can stimulate endogenous neural cells to also produce reparative factors. Some of the known biologic effects of stem cell therapy include increased angiogenesis; increased neurogenesis; decreased apoptosis and cell death; synaptic plasticity of both the axons and dendrites; shifting the peripheral immune and both central and peripheral inflammatory cells from a pro-inflammatory (M1/Th1) to an anti-inflammatory (M2/Th2) phenotype; and altering both the production of free radicals and anti-oxidant enzymes. A, astrocyte; Ap, apoptotic cell; M, microglia; Mac, macrophage; N, neuron; NSC, neural stem cell; O, oligodendrocyte; S, synapse; T, T cell.