Abstract
Stroke is a major cause of death and disability worldwide. Yet therapeutic strategies available to treat stroke are very limited. There is an urgent need to develop novel therapeutics that can effectively facilitate functional recovery. The injury that results from stroke is known to induce neurogenesis in penumbra of the infarct region. There is considerable interest in harnessing this response for therapeutic purposes. This review summarizes what is currently known about stroke-induced neurogenesis and the factors that have been identified to regulate it. Additionally, some key studies in this field have been highlighted and their implications on future of stroke therapy have been discussed. There is a complex interplay between neuroinflammation and neurogenesis that dictates stroke outcome and possibly recovery. This highlights the need for a better understanding of the neuroinflammatory process and how it affects neurogenesis, as well as the need to identify new mechanisms and potential modulators. Neuroinflammatory processes and their impact on post-stroke repair have therefore also been discussed.
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Introduction
Stroke is a debilitating disease condition defined as either an interruption of blood supply to the brain due to a clot or embolism, or the rupture of a blood vessel in the brain, which then leads to neurological impairments [1]. It remains the 3rd leading cause of death worldwide, with nearly 15 million people being affected every year [2], while in the USA, it is the number 5 killer, killing nearly 140,000 people every year (https://www.cdc.gov/stroke/facts.htm). Currently, the treatment for ischemic stroke is to administer a thrombolytic agent such as tissue Plasminogen Activator (tPA) or to perform a surgical thrombectomy procedure to mechanically remove the blood clot (thrombus) [3]. However, the optimal time window for these treatments is very small and survivors often exhibit a high degree of morbidity, as well as limited functional recovery [4]. New modes of therapy are therefore urgently needed, especially ones that can be administered after longer periods following stroke onset, that can lead to better functional recovery and reduced morbidity. To this end, post-stroke brain repair processes are of particular research interest. Here, in this review, we discuss stroke-induced neurogenesis as a potential target for therapeutic intervention, as it represents a major repair mechanism that by itself falls short in achieving full recovery in surviving patients, and presumably could be modulated to achieve better outcomes. A detailed understanding of this phenomenon is needed to guide future research and the development of effective intervention strategies.
Neurogenesis in the Post-stroke Brain
Neurogenesis, or the birth of new neurons, is known to be induced in response to ischemic stroke, in the infarct and surrounding areas. Neural stem cells originating from the sub-ventricular zone (SVZ) and the sub-granular zone of the dentate gyrus are considered to give rise to these new neurons [5,17], while an alternate method could involve treating with a cocktail with components that would compensate for effects on angiogenesis specifically that might occur as a concurrent effect of one or more of the other components. It might have to be a combination of the two methods or others to achieve maximum targeting efficiency.
Drugs Targeting Neuroinflammation to Alter Neurogenesis
Minocycline is a tetracycline derivative that inhibits microglial activation and has been shown to be neuroprotective following focal cerebral ischemia [109, 110]. It has also been shown to be able to upregulate neurogenesis in multiple models [111,112,113]. Therefore, this remains the most promising pharmacological agent in this regard. Srivastava and collaborators [114] reported it as safe and efficacious in their clinical trial, which was further supported by the meta-analysis conducted by Malhotra and colleagues [115], of seven randomized clinical trials. It is safe to be administered for sure, but its efficacy still needs some more validation before it is widely accepted for treatment of stroke.
Another study reported that the drug Sildenafil promoted neurogenesis and was able to enhance functional recovery after perinatal/pediatric ischemia in mice [116]. While this is not exactly the same as the hypoxia occurring during ischemic stroke, it is consistent with previous findings that sildenafil promotes neurogenesis after focal cerebral ischemia [117,118,119]. Engels and collaborators [116] proposed that Sildenafil altered the levels of Wnt signaling pathway members β-catenin and GSK-3, via inhibition of phosphodiesterase type 5, and subsequent increase in cGMP levels. Although they did not find any direct evidence of affected neuroinflammation, GSK-3 and Wnt signaling has been implicated in the regulation of neuroinflammation in several studies [120, 121]. One GSK inhibitor called Tideglusib has been investigated in clinical trials as well, where it was deemed clinically safe but was not effective [122, 123]. Other GSK inhibitors that may be worth exploring include 6-bromoindirubin-30-oxime (BIO) [46, 48] and lithium chloride [47, 124].
Based on several in vitro and in vivo studies investigating the role of IL-1 in stroke, recent studies have considered IL-1 receptor antagonist (IL-1Ra) as an attractive new therapy. Indeed, a small phase 2 clinical trial showed that IL-1Ra is safe in stroke and may be effective [125], and the more recent SCIL-STROKE study confirmed this hypothesis that IL-1Ra may be potent neuroprotective therapy in stroke [126]. IL-1Ra may improve stroke outcome through inhibition of the inflammatory response; however, an interesting recent study found that IL-1Ra administration in rat stroke model potently promotes long-term neurogenesis and functional recovery [127]. This study suggests that, although acute inflammation is an important trigger for post-stroke neurogenesis, a more controlled neuroinflammatory response appears critical for an optimum neurogenic response after stroke. These are only a few of the drugs being tested for efficacy in stroke treatment, via neurogenesis modulation. It is widely recognized that pharmacological modulation of neurogenesis can be a valuable tool to treat stroke and is, therefore, likely to be active area of research focus for the foreseeable future.
Potential of Stem Cell–Based Therapy and Considerations of Challenges
One major observation in ischemia-induced neurogenesis is that only a small quantity of the newborn neurons survive in the peri-infarct area [7, 15]. Therefore, to overcome this, in addition to modulating endogenous neurogenesis, stem cell therapy to treat stroke has also been investigated as a possible alternative or as a potential way to augment the endogenous stroke-induced neurogenesis [128,129,130].These exogenous stem cells can become the source of some much-needed trophic factors and exert paracrine reparative effects. In turn, this could lead to the microenvironment in the peri-infarct area more supportive of new neuron differentiation and integration into the circuitry.
In one study, transplanting human fetal neural stem cells into the hippocampus 24 h after surgically occluding the middle cerebral artery in mice was reported to have improved behavioral recovery and reduced infarct volume, compared with animals without the transplant [131]. They also noted improved BBB repair and lower number of activated microglia in the transplanted brains, as well as higher abundance of Brain derived neurotrophic factor (BDNF). A subsequent study by the same research group reported the transplant procedure as highly beneficial in combination with tissue plasminogen activator (t-PA) treatment, resulting in lower levels of pro-inflammatory cytokines, tumor necrosis factor (TNF-α) and IL-6, as well as MMP-9 [129]. Taken together, these validate the potential of transplanting fetal neural stem cells as a mode of therapy. Of course, the ethical challenges of obtaining and maintaining such stem cells remain a major limitation of such a process.
The alternative approach to using fetal stem cells is to use inducible pluripotent stem cells (iPSCs) or mesenchymal stem cells (MSCs). Oki et al. [132] used human iPSC-derived neuroepithelial-like stem cells that they transplanted into mice 1 week and 48 h after MCAO. They reported improved forelimb motion recovery, increased VEG-F deposition, and successful differentiation of iPSCs into neurons in the striatum.
Use of MSCs is limited by the observation that most of the systemically transplanted MSCs end up in the lungs and do not make it to the infarct area of the brain [133, 134], where they are actually intended to proliferate and repair the damage. Tobin and colleagues [135] have proposed the use of MSCs that have been activated by Interferon gamma (aMSCs). They reported that both activated and naïve MSCs induced complete behavioral recovery, reduced infarct volumes, and reduced microglial activation and levels of IL-1β, TNF-α, and IL-6 in treated animals, compared with vehicle-treated control stroke animals. However, they propose the activated MSCs are a better treatment option than naïve MSCs because of an increased yield of anti-inflammatory factors from microglia. Interestingly, they did not observe any induction of neurogenesis in the SVZ after MSC treatment.
A phase 1 clinical trial (PISCES) involving the administration of CTX0E03 human neural stem cells via stereotactic ipsilateral putamen injection reported that a dose of up to 20,000 cells is safe and well tolerated in patients [136]. The treatment also resulted in functional improvements and upon further investigation, may very well become a mainstream intervention strategy. Since the study was conducted only on 11 men, it needs to be followed up with the inclusion of female patients and a larger patient population [136].
Another phase 2 clinical trial involving the administration of bone marrow stem cells to stroke patients proved safe in patients, but ineffective in terms of treating stroke [137]. Similar results were obtained in another phase 2 clinical trial where patients were treated with bone marrow derived ALD-401 stem cells [138]. Taken together, these studies indicate that the administration of stem cells is safe. As for effectiveness, there is potential for the stem cells to promote functional recovery in more tightly controlled settings, which was a limitation of all three studies, along with the small population of patients that have been tested.
The process of preconditioning the MSCs and using the resulting media may prove even more effective in stroke treatment [128, 139]. A recent systemic review highlighted the therapeutic potential of extracellular vesicles secreted by various cells like MSCs, macrophages, and neural stem cells, identifying these vesicles as an attractive approach. However, being a recent trend, there is a significant amount of heterogeneity among the results of applications, presumably due to isolation and administration techniques, as well as cell-type of origin [140]. Further work on MSCs preconditioning with various inflammatory mediators found that IL-1α can be used as a key priming stimulus to induce MSCs to produce anti-inflammatory and neurotrophic factors [141], and a further in vivo study in mice demonstrated that conditioned medium of IL-1α-primed MSCs administered peripherally after stroke had beneficial effects on stroke outcome and functional recovery [139]. Further work investigating the efficacy of targeted delivery of IL-1α-primed MSCs in stroke is ongoing.
Conclusion and Future Therapeutic Perspective
Stroke affects millions of people every year. With the world populations steadily rising, the global burden of stroke keeps rising proportionally. As a result, there remains a global and critical need to develop better treatment options. Stroke-induced neurogenesis presents a promising therapeutic target, since it can allow the brain to, essentially, rewire and refresh itself, and heal the damage caused by the ischemia or hemorrhage. However, harnessing neurogenesis remains a challenge because of the intricate interplay of the factors involved, especially ones involved in neuroinflammation. It is now well understood that the two processes much more deeply connected than a simple inverse relationship. Moreover, both processes are interconnected with angiogenesis and together work towards post-stroke brain repair. In order to harness them and improve functional recovery, it is imperative, now more than ever, to characterize the roles played by each immune cell, cytokine, and chemokine, as part of the post-injury microenvironment, taking into special consideration their temporal expression patterns, specific effects on angiogenesis, neurogenesis, neuroprotection, and neuron elimination. All of these need to be considered carefully to craft effective therapeutic cocktails that are to achieve maximum treatment efficiency.
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Rahman, A.A., Amruta, N., Pinteaux, E. et al. Neurogenesis After Stroke: A Therapeutic Perspective. Transl. Stroke Res. 12, 1–14 (2021). https://doi.org/10.1007/s12975-020-00841-w
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DOI: https://doi.org/10.1007/s12975-020-00841-w