Table of Contents
Abstract 0
Introduction 1
Background 2
Natural repair mechanism following a stroke 2
Current treatments for stroke 4
Neurogenesis-promoting treatments 5
Monoclonal antibodies 6
Small molecule drugs 7
Growth factors 8
Stem cell therapy 9
Neural stem cells 10
Mesenchymal stem cells 10
Embryonic stem cells 10
Induced pluripotent stem cells 11
Bioscaffold 12
Drawbacks to stem cell therapy 12
Conclusions 13
Bibliography 14

Abstract

Current treatment for stroke is limited in that, while some brain function can be regained, the lost brain tissue cannot be regenerated. Recently, research into stroke treatment has focused on repair treatments that promote neurogenesis, in the hope that this will partially restore brain function following stroke.
Chemical agents including growth factors, small molecule drugs and monoclonal antibodies have all been shown to have positive effects in some trials. Nonetheless, some trials have displayed negative results, so more extensive trials are needed to confirm the validity of these treatment options.
Stem cell therapy is also being trialled as a stroke treatment. With more testing and research, it is hoped that the problems associated with stem cell therapy can be mitigated.
Stem cell therapies using induced pluripotent stem cells and mesenchymal stem cells were found to be the most promising so should receive the largest amount of funding. Monoclonal antibodies, growth factors and small molecule drugs also seem effective in treating stroke and merit funding for research.

These funds should be used to increase our knowledge of the mechanisms behind these treatments, to find out the optimal time-period and dosage for these treatments and to test their safety.

Introduction

Stroke is one of the major causes of death across the world, especially in developed countries. Every year, more than 100,000 people in the UK experience a stroke, costing the NHS and social care system around £1.7 billion (Stroke association, 2017). Not only does stroke kill many people, but those who survive suffer a drastically reduced quality of life. Additional economic effects also include the cost of treatment and the impact of missed days of work. For these social and economic reasons, a cure for stroke or even a treatment that reduces its impact would be greatly beneficial for society.
There are two main types of stroke: ischaemic stroke and haemorrhagic stroke. Stroke occurs due to a blockage of the blood vessel (ischaemic stroke) or the rupturing of the blood vessel (haemorrhagic stroke) supplying part of the brain. Due to the key mechanistic differences between these two types of stroke, the successful treatment for ischaemic stroke may not always translate to the successful treatment of haemorrhagic stroke. This paper will focus purely on ischaemic stroke because it is more common, with roughly 85% of strokes being ischaemic in nature (Rammal and Almekhlafi, 2016).

Figure 1: An image showing the two main types of stroke in the brain: ischaemic stroke (L) and haemorrhagic stroke (R) (Scientific Animations, 2018)

This paper aims to summarise the latest developments in treatments which promote neurogenesis after stroke, to evaluate the different types of treatment and to draw conclusions about which treatments should receive funding for future research.

Background

Following a stroke, many biological changes take place inside the brain. An ischaemic stroke occurs in the brain when an artery is blocked by a build-up of either fatty deposits within its lumens or blood clots that usually form in the heart, neck or base of the skull and then travel through the bloodstream into the brain arteries. These blockages cause a reduction in blood flow to parts of the brain (Healthline, n.d.).
Brain tissue supplied mainly by the blocked arteries is irreversibly damaged due to the lack of blood supply. The tissue surrounding this core region, called the penumbral zone, also suffers but can receive some oxygen and glucose from collateral arteries. Stroke also causes the swelling of the brain, which can cut off blood supply from the collateral arteries, thus killing the penumbral tissue (Lindvall and Kokaia, 2015) (The Internet Stroke Center, n.d.).
The key to saving this penumbral tissue, before the damage becomes irreversible, is to begin treatment as quickly as possible to re-establish blood supply and prevent further swelling. Even partly restoring blood flow to this penumbral area can help reduce cell death in the area.

Natural repair mechanism following a stroke

To some extent, the brain can repair damage caused by a traumatic brain injury, however, the capacity to do so is greater in the young and decreases steadily with age. It is widely acknowledged that neuroplasticity of the brain is the major way in which the body copes with losing brain tissue after a stroke (Dąbrowski, et al. , 2019). This is where the brain spontaneously rewires itself by forming new connections between synapses. By reorganising the function of the brain into undamaged parts, the body can cope with the reduced volume of brain tissue.
To date, there has been much controversy about whether adult humans can grow new neurons following brain injury, with many believing that the adult brain is hard-wired and unable to repair brain damage by growing new neurons (Cell Press. \”Older Adults Grow Just As Many New Brain Cells As Young People.\” Science Daily, 2018).
Research carried out by researchers at Columbia University seems to counter this belief as it has shown that older people may have the ability to generate new neurons from progenitor cells (a type of differentiated stem cell). Nevertheless, it is unclear whether these neurons can form connections with the existing brain tissue (Boldrini et al. 2018).
The dead brain tissue must be removed before any regrowth can occur. Central to this regeneration is the role of a type of peripheral cell called macrophages. These cells migrate from the bone marrow before diffusing through the blood-brain barrier and into the infarct area. There, the macrophages eliminate debris and other neurotoxic molecules, thus allowing neuronal growth in the region (Larochelle, et al., 2016). As such, the migration of these macrophages is critical for any restorative treatment.

Figure 2: An image of a macrophage stretching to engulf two smaller particles (Obil, 2006)

Natural repair in the brain following a stroke is not a constant process. Instead, various biological mechanisms occur during different time periods called epochs. Due to the unique characteristics of the brain at different stages in these epochs, any neurogenesis-promoting treatment has a specific time-window that it is effective in (Coleman, et al., 2017) (Ren, et al., 2000).
This paper uses Crammer’s definition of these time periods, in which three epochs of recovery occur (Cramer, 2019).
During the first epoch, which occurs in the first hours after a stroke, the penumbral region is still recoverable, so the priority of treatment is to reduce the extent of irreversible injury. Generally, treatment in this stage can be performed using neuroprotective techniques or treatments that promote the reperfusion of the infarct region (Cramer, 2019).
Meanwhile, the brain’s natural repair occurs during the second epoch, which occurs in the days and weeks after the stroke. As a result of this natural repair, treatment is very effective in this stage.
In the third epoch, which occurs months after the stroke, the brain is reasonably stable. Nevertheless, treatments which change the function and structure of the brain are still possible. In this stage, spontaneous recovery has ended, so treatment is concentrated on increasing the neuroplasticity of the brain (Cramer, 2019).

Current treatments for stroke

As stated in NICE guidelines, the current treatment for ischaemic stroke revolves around removing blood clots from cerebral arteries and preventing clots from reforming (NICE, Initial assessment and treatment: stroke, 2020). Common treatments to do this include the administration of aspirin or other antiplatelet medication, the use of anticoagulant medication and, in severe cases, a thrombectomy, where a doctor inserts a device down the artery to remove or break up the clot (NICE, Acute stroke: management in a specialist stroke unit, 2020).

Figure 3: An image showing how a thrombectomy can remove clots in cerebral arteries (Neilbarman, 2008)

It is important to note that while these treatment options do not promote neurogenesis in the brain, they still must be performed in conjunction with neurogenesis-promoting treatments as they prevent further damage to the brain tissue.
Any treatment of stroke must also be followed by rehabilitation, where stroke survivors receive therapy and support to partially regain motor function and eventually return to work and improve quality of life (NICE, Stroke rehabilitation 2020).

Neurogenesis-promoting treatments

I propose that providing more funding for research into treatments that promote neurogenesis are essential. Current treatments for stroke are limited in that they don’t allow the damaged area of the brain to regenerate. Instead, treatment focuses on preventing the penumbral zone from dying and rewiring the remaining brain to cope with the loss of brain tissue.
According to the American Stroke Association, 25% of people who have a stroke suffer minor impairments and a further 40% recover with moderate to severe impairments that are severe enough to require special care (Association, 2019).
Neurogenesis is the process of generating functional neurons from stem cells precursors. Treatments that promote neurogenesis and repair damaged brain tissue would decrease the number of people who have impairments, increasing the quality of life for stroke survivors.
Promoting neurogenesis in the brain following stroke is difficult due to the inhibitory nature of the brain for neuronal growth. Following a stroke, a scarring process is initiated in the brain, resulting in the formation of a glial scar (Wang, et al., 2018). Glial cells are a type of supportive cell found in the CNS, whose primary function is to surround neurons and hold them in place (Jäkel and Dimou, 2017).

Figure 4: A micrograph showing reactive astrocytes (a component of the glial scar) in the cerebral cortex (Nephron, 2010)

Even a small disruption of the glial cell composition can cause changes in the molecular environment of the brain. This change in environment inhibits axon growth in the area (Bähr, 2006) and causes problems for stroke treatment. Bähr notes that in trial transplantation of neurons, while axon growth through spinal cord white matter was observed, when the axons neared the glial scar tissue, axonal growth no longer occurred. Consequently, one of the major challenges of neurogenesis-promoting treatment is to overcome the issues this hostile environment creates. This can be achieved by allowing macrophages, or other molecules which perform the function of macrophages, to migrate to the damaged area, clear away dead cells and prepare the area for successful neurogenesis-promoting treatment.
The following treatment options for stroke will be explored:

1. Monoclonal antibodies
2. Small molecule drugs
3. Growth factors
4. Stem cell therapy

Monoclonal antibodies

Ordinarily, the molecular environment in the brain inhibits axonal regeneration and thus neurogenesis. This problem can be overcome by the use of humanised monoclonal antibodies (Li and Carmichael, 2006).
These monoclonal antibodies bind to antigens on the molecules that inhibit growth in the CNS, thus neutralising them (Lin, Finklestein and Cramer, 2018). This increases the permissiveness of the CNS growth environment, allowing neurons to grow in the region. Nevertheless, while the use of monoclonal antibodies in stroke treatment sounds promising, this treatment is in a very early stage and still requires more research and clinical study before it can become mainstream.
Furthermore, monoclonal antibodies are very expensive to produce, limiting their widespread use. This is because monoclonal antibodies are large, complicated proteins so need complex eukaryotic cells to produce them (Chames, et al., 2009). Moreover, monoclonal antibodies also need to be administered in large quantities to be effective. As such, monoclonal antibodies are still very far away from becoming a mainstream treatment for stroke.

Figure 5: A diagram showing the general representation of the production of monoclonal antibodies (Adenosine, 2010)

Small molecule drugs

A range of drugs have been investigated in human clinical trials and show promise in promoting tissue repair following a stroke. There are two main classes of drugs that have used in these trials: serotonergic drugs and dopaminergic drugs (Lin, Finklestein and Cramer, 2018). Serotonergic drugs were found to be effective in increasing mobility and decreasing depression and neurological impairment (Mead, et al., 2013). Meanwhile, the use of dopaminergic drugs in clinical trials has had mixed results. In addition, other drugs such as noradrenergic drugs (Wang, et al., 2010) and cholinergic drugs (Barrett, et al., 2011) have also been trialled, with mixed results.

Figure 6: A diagram illustrating the location of serotonergic neurons (Jähnichen, 2010)

The key to making this type of therapy successful is ensuring that it is administered during the correct time-window. Therefore, we must fund more research to work out the exact time-window that each drug should be administered in. Furthermore, currently, we do not fully understand why these drugs work. By funding additional research, we could increase our knowledge in this area. This could not only help us work out the correct time-window for treatment, but it could also explain why the drugs work on some patients but not others. Thus, we can alter to whom we prescribe these medications accordingly.

Growth factors

Growth factors can also be introduced into the brain to promote neural repair. Several clinical trials have shown that many growth factors encourage neurogenesis in the brain following stroke. They do this by increasing neural sprouting, the formation of new synapses and the proliferation of stem cells to the infarct area. They also modulate the immune system and encourage the growth of new blood vessels (Lin, Finklestein and Cramer, 2018) (Lanfranconi, et al., 2009). Indeed, preclinical studies have also shown that the administration of growth factors 24 hours after stroke onset significantly improved patient outcome (Lin, Finklestein and Cramer, 2018).
The main problem with the use of growth factors is that these proteins are too large to cross the blood-brain barrier, limiting their ingress into the brain. This problem is mitigated by joining the growth factor molecules to a molecular trojan horse, which can cross the blood-brain barrier (Cramer, 2019). For example, it has been shown that growth factor molecules can be attached to peptidomimetic monoclonal antibodies, thus allowing them to pass through the blood-brain barrier (Zhang and Pardridge, 2001).
The use of growth factors in stroke treatment should receive funding as it seems to be a viable treatment option for stroke. These funds should be used for further research to study the mechanism behind which they work, the correct time-window for the application of the growth factors and the dosage required for optimal effects.

Stem cell therapy

It is broadly acknowledged that stem cells do exist inside the brain, however, there is much debate about whether these endogenous stem cells are enough on their own to repair brain tissue and restore function (Hao, et al., 2014). Indeed, the evidence seems to suggest that the production of new neurons is limited to the subventricular zone, so is unable to provide much regrowth in other areas (Gonzalez-Perez, 2012). Stem cell therapy provides the answer to this, as it allows us to supplement endogenous stem cells with stem cells harvested from other parts of the body. These stem cells can then differentiate and form neurons and other brain cells which can replace the damaged tissue.

Figure 7: A diagram depicting the location and anatomy of the subventricular zone (Arias-Carrión, 2009)

Moreover, stem cells also provide additional support for neurogenesis through the secretion of neural trophic factors which further enhance recovery. Trophic factors, which are molecules that support the survival of cells, include growth factors, cytokines (which affect the immune response), and chemokines (which are involved in attracting cells) (Lavoie and Rosu-Myles, 2013). The extra support that these factors provide exacerbate the beneficial properties of stem cells and increase the likelihood that stem cell therapy can be successful.
There are numerous ways to administer stem cells to repair damage to the brain. Perhaps the most obvious way is to do so is injecting stem cells straight into the brain. Studies in rats have shown that this is effective in restoring function (Darsalia, Kallur and Kokaia, 2007). This method is not ideal, however, as in order to transplant these cells, a cranial window has to be opened and the brain parenchyma has to be damaged (Fernández-Susavila, et al., 2019).
Many types of stem cell can be used in stem cell therapy. This paper will focus on the following four groups of stem cells that have been researched for stem cell therapy:

1. Neural stem cells
2. Mesenchymal stem cells
3. Embryonic stem cells
4. Induced pluripotent stem cells

Neural stem cells

One of the most researched types of stem cells are neural stem cells (NSCs), due to their neurorecovery capabilities (Laso-Garcia, et al., n.d.). These are self-renewing stem cells, which are harvested from the striatum in the brain of donors or from foetal tissue, can differentiate to form many types of brain cell, including neurons (Zhou, et al., 2019). While the theory behind the use of NSCs sounds promising, trials using NSCs have not shown a noticeable impact on stroke recovery (Matthew B, et al., 2013). Research into NSC use is also difficult as human NSCs are rejected from mouse models. Furthermore, it is hard to produce NSCs on a large scale for use in clinical trials, so more funding for NSCs is unlikely to yield results.

Mesenchymal stem cells

Aside from NSCs, the most researched stem cells for use in stroke treatment are mesenchymal stem cells (MSCs) (Fernández-Susavila, et al., 2019). Overall, the use of MSCs seems promising, especially as they are heterogeneous. This means that they can be sourced from multiple locations inside the human body, including from bone marrow and perivascular tissue (Zhou, et al., 2019). Moreover, MSCs also have great trophic capabilities, which further underline their effectiveness in stroke treatment. On this basis, a journal article published in 2019 described MSC treatment as ‘one of the most promising treatments to restore function after stroke’ (Fernández-Susavila, et al., 2019). While MSC research is still in its infancy, extra funding would help enormously, as one of the main setbacks for research in this area is that MSC procurement is prohibitively expensive (Ullah, Subbarao and Rho, 2015). Increased funding would allow scientists to overcome this obstacle.

Embryonic stem cells

Embryonic stem cells (ESCs), which are originally derived from human blastocysts (Thomson, 1998), are pluripotent. This means that they have the capacity to self-renew forever and can differentiate to form any cell in the human body. These abilities make them uniquely suited for use in stem cell therapy as they produce a virtually limitless supply of brain cells to replace those which have been lost (Hao, et al., 2014). Indeed, studies using mouse models have confirmed that motor dysfunction following an ischaemic stroke can be improved using ESC transplantation (Tae-Hoon and Yoon-Seok, 2012).
Unfortunately, ESC transplantation has a high risk of malignant transformation. This is where the division of ESC becomes out of control, leading to tumour growth (Afify and Seno, 2019). Nevertheless, this risk can be reduced by developing the required neural cells (using ESCs) in vitro and then transplanting them into the brain. Trials for these ESC-derived neural cells have shown that these cells do not form tumours in the brain as long as the cells are differentiated in vitro for a sufficient amount of time before transplantation. A trial in 2006 showed that if the cells had been pre-differentiated in vitro for 16 days severe tumours formed, however, if they were pre-differentiated for over 20 days, then the cells remained healthy for the whole of the experiment (Brederlau, et al., 2006).
Despite this, studies into the application of ESC transplantation to alleviate brain damage have been limited, due to severe ethical concerns. Since ESCs are harvested from human embryos that have been fertilised in vitro, there issues about consent, as the embryo is not able to give consent for the procedure. There is also pro-life opposition to the destruction of the unused embryos. Consequently, I would contend that the future of ESC therapy to treat stroke is slim.

Induced pluripotent stem cells

The ethical concerns of the use of ESCs can be avoided by using induced pluripotent stem cells (IPSCs). IPSCs have similar properties to ESCs in that they are also pluripotent (Afify and Seno, 2019), with the advantage that their use in therapy is safer. They also avoid ethical concerns due to the mechanism of their production. IPSCs are formed from genetically reprogramming adult somatic cells, such as skin fibroblasts (Merek KgaA, n.d.). Since this procedure is done as an adult, the person can give consent for the procedure.
Over the last decade, a huge amount of research has been conducted into the use of the IPSCs in repairing stroke damage. While one study suggested that no tumours formed for at least 4 months after treatment (Oki, et al., 2012), the overall consensus is that the direct transplantation of IPSCs has a high risk of forming tumours (Hao, et al., 2014). Nevertheless, studies have also shown that the direct injection of IPSCs into the damaged area of the brain of rats decreased the volume of infarcted tissue and increased motor function (Chen, et al., 2010). One trial also showed that transplanted iPSCs in rats were able to migrate to the damaged areas of the brain and differentiate to form neural cells. It also notes that 4-16 days after treatment, the function of rats significantly improved (Jiang, et al., 2011). In addition, Chen, et al. also noted that combining the IPSCs with fibrin glue is much more effective and safer and that tumours don’t form when it is used. Further, IPSC implantation saw a reduction in the quantity of pro-inflammatory cytokines and an increase in the number of anti-inflammatory cytokines (Chen, et al., 2010).
Nevertheless, the use of IPSCs is not without risks. In mouse studies, the viruses used to create ISPCs have been shown to result in the formation of cancers (\”Pros And Cons | Stem Cells | University Of Nebraska Medical Center\”, 2020). Additionally, according to stem cell biologist Robert Lanza, when IPSCs and ESs were compared, IPSCs differentiated at a much slower rate and cell death was much more likely (Hendricks, 2010). Furthermore, there are also some ethical concerns regarding their use as, in certain conditions, IPSCs can form embryos (\”Pros And Cons | Stem Cells | University Of Nebraska Medical Center\” 2020).
As such, in conclusion, IPSC transplantations seems like a somewhat promising treatment option for repairing stroke damage. Unfortunately, we are still many years away from this treatment being available on the NHS. Even if more research is done to figure out how to reduce the risk of tumorigenicity, the use of IPSCs in stroke treatment is still not possible until we figure out the optimal cell dose as well as the optimal time window for treatment (Fernández-Susavila, et al., 2019).

Bioscaffold

Stem cell therapy can be used in conjunction with a bioscaffold (an artificial structure which the new brain tissue can grow upon). According to research carried out by the University of Pittsburgh, the failure of the regeneration of brain function is mainly due to a lack of a structure for the cells to build in the cavity (Modo, 2019). If the implantation of stem cells is combined with a bioscaffold, however, then functional brain tissue can be grown. This is because the bioscaffold provides physical support for growth in the damaged region of the brain. The structure also controls the differentiation of stem cells in the region and ensures that they grow to form a viable tissue structure (Wang, et al., 2019). Additionally, treatments with bioscaffolds could be combined with growth factors, as this has been shown to increase axonal growth in the repair of spinal cord injuries (Grulova et al., 2015) .

Drawbacks to stem cell therapy

Despite some promising studies, stem cell therapy for ischaemic stroke is still in its infancy. Additionally, stem cell therapy has many drawbacks which must be considered. Firstly, stem cell therapy has a high risk of forming tumours. Before stem cell therapy can become a mainstream treatment option for stroke, this risk must be drastically reduced, otherwise treatment could be causing more harm than good (Krause, et al., 2019). There is also a risk of immune rejection if the new cells are recognised as foreign. Moreover, stem cell production generally produces a low yield of cells, which increases the cost of production. There are also many difficulties in scaling up treatment to the large-scale production of these stem cells.
Further, it should be stressed that stem cell therapy has only been proven to have a positive impact in some trials – others have shown the opposite result. In addition, it is not yet known how exactly the therapy increases function. If more research is completed in this area of treatment, we may gain more knowledge about how it works, which could potentially enhance stem cell therapy.
The timing of stem cell implantation is also critical as it affects the mechanism of therapy. As discussed earlier in this paper, following stroke onset, there are three epochs of spontaneous recovery in the brain. Therefore, stem cell therapy must be tailored to the exact stage of recovery the brain is in, otherwise the effectiveness of therapy is reduced. According to the University of Miami, stem cells should be introduced 36 to 72 hours after stroke (University of Miami Health System, n.d.). Another trial states that delivery of stem cells should occur 24 hours to one month after stroke (Meamar, et al., 2013). While this research agrees that stem cell therapy should occur during the first epoch, we still need more research to find the exact time-window for each type of stem cell.

Conclusions

To conclude, it would be a stretch to suggest that we are close to developing a cure for stroke. The brain, as the most complex organ in the body, remains shrouded in mystery. Treatment to date is effective at minimising further damage to the brain, reducing the risk of stroke recurrence and, through rehabilitation, providing some regain of function.
Neurogenesis-promoting treatments should receive heavy investment over the next few decades. According to the World Health Organisation, in recent years, the incidence of stroke has increased by over 100% in developing countries, such as India and Indonesia (Johnson, et al., 2016). These developing countries are expected to increase in population size significantly, so it seems reasonable to suggest that the number of strokes in these countries will also increase. Additionally, stroke prevalence in the UK is projected to increase by 120% between 2015 and 2035 (King, et al., 2020). In the same time period, the cost associated with caring for sufferers is predicted to triple (today it already costs about £26 billion) (King, et al., 2020). While research into neurogenesis-promoting therapy would be expensive, these costs could be recovered in the future, as they would allow some brain function to return to stroke survivors. This would reduce their care needs in the future, thus reducing the cost of stroke care in the future.
Funding for research into treatments that promote neurogenesis in the brain following stroke should be prioritised according to the effectiveness of the treatment. The most funding should go towards research into stem cell therapy, especially where it is used in conjunction with a bioscaffold. While stem cell therapy has the most significant cost in terms of developing a treatment option for stroke, it also has the most potential for repairing the brain. Specifically, MSCs and IPSCs should receive the most investment due to the promise they have shown in increasing function after stroke and the limited ethical concerns regarding their use.
Further, growth factor treatment, medication and monoclonal antibodies should all receive funds as they are all promising treatment strategies which have the potential to become mainstream treatment options for stroke.
Due to the ethical concerns with their use, funding for ESCs should be limited as even if a treatment could be successfully created, ethical concerns would restrict their use. Further, NSC funding should also be scaled down to echo the lack of success that trials of NSC treatment have had to date.

These funds should be used to increase our knowledge in the mechanisms behind how they work to alleviate stroke damage as this may provide clues about new treatment options that should be researched further down the line. Funds should also be used to research the optimal timing and dosage for treatment as well as to assess the effectiveness and safety of these chemicals.

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About the Author

Neil Sardesai is a Year 12 student in Cambridge, UK. He is currently studying maths and science for A-levels and aims to study medicine at university. He is very interested in biomedical research; he writes a weekly blog on various medical topics (bit.ly/HippocratesWeekly). In his free time, Neil enjoys playing music and volunteering at local charities.