Enriched Environment and Exercise Enhance Stem Cell Therapy for Stroke, Parkinson’s Disease, and Huntington’s Disease

Abstract

Stem cells, specifically embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (IPSCs), and neural progenitor stem cells (NSCs), are a possible treatment for stroke, Parkinson’s disease (PD), and Huntington’s disease (HD). Current preclinical data suggest stem cell transplantation is a potential treatment for these chronic conditions that lack effective long-term treatment options. Finding treatments with a wider therapeutic window and harnessing a disease-modifying approach will likely improve clinical outcomes. The overarching concept of stem cell therapy entails the use of immature cells, while key in recapitulating brain development and presents the challenge of young grafted cells forming neural circuitry with the mature host brain cells. To this end, exploring strategies designed to nurture graft-host integration will likely enhance the reconstruction of the elusive neural circuitry. Enriched environment (EE) and exercise facilitate stem cell graft-host reconstruction of neural circuitry. It may involve at least a two-pronged mechanism whereby EE and exercise create a conducive microenvironment in the host brain, allowing the newly transplanted cells to survive, proliferate, and differentiate into neural cells; vice versa, EE and exercise may also train the transplanted immature cells to learn the neurochemical, physiological, and anatomical signals in the brain towards better functional graft-host connectivity.

1 Introduction

Neurological diseases such as stroke, Parkinson’s disease (PD), and Huntington’s disease (HD) remain significant contributors to long-term disability and financial burden for patients worldwide. Despite decades of research into their underlying pathology and potential therapeutic targets, limited treatment options exist for these conditions. Regenerative medicine offers a promising intervention for these pathologies, but still faces significant hurdles to overcome. Of these issues, the ability to use stem cell-derived neural progenitors and integrate them fully into existing neural circuits to provide a more functional benefit while also enhancing the general outcome of transplantation has possible solutions; exercise and rehabilitation. This paper aims to discuss some of the current therapeutic uses of regenerative medicine and how rehabilitation strategies may increase the efficacy of stem cell grafts for long-term recovery. Stroke, PD, and HD were explicitly chosen due to the relative abundance of literature about exercise, EE, and stem cells (Table 1).

Regenerative medicine utilizes a multitude of progenitor cell lines that vary based on biological origin, differentiation, advantages, and disadvantages (Table 2). Embryonic Stem Cells (ESCs) are undifferentiated pluripotent cells derived from mammalian blastocysts and can differentiate into any cell of all three germ layers, but pose major ethical concerns and have potential for immune rejection (Niwa et al., 2000; Chew et al., 2005). Induced pluripotent stem cells (IPSCs) are generated from adult somatic cells and bypass the ethical and immunogenicity concerns seen in ESCs, but may be tumorigenic, and it can be challenging to produce specific neurons with high purity (Okita et al., 2007; Qin et al., 2013; Doi et al., 2014; Yu et al., 2014). Nonetheless, IPSCs are a popular cell line for studying neurodegenerative diseases such as PD and HD. IPSCs can be differentiated into disease-specific neurons (ex. dopaminergic neurons in PD) that reflect the donor’s genetic markers and provide insight into changes in neurite morphology during disease progression (Park et al., 2008; de Rus Jacquet, 2019; Simmnacher et al., 2020). Mesenchymal stem cells (MSCs) are multipotent cells that secrete therapeutic substances and may migrate to the site of injury and putatively differentiate into the neural lineage (Pittenger et al., 1999; Ries et al., 2007; Waterman et al., 2010). MSCs’ anti-inflammatory effects make this an effective cell type for transplantation in ischemic stroke; indeed, MSC transplantation improves neurologic function in stroke models (Lee et al., 2016; Stonesifer et al., 2017). However, human MSCs exhibit distinct stemness properties from murine MSCs; thereby, it is important to consider the species source of the cells (Bonab et al., 2006; Miura et al., 2006). MSCs are routinely harvested from the bone marrow, and referred to as bone-marrow-derived derived MSCs (BM-MSCs). Controversy exists on the migration of BM-MSCs across the BBB and thereafter differentiating into neural cells. While a few peripherally transplanted BM-MSCs may reach the brain, most of the grafted cells lodged into inflammation-riches peripheral organs, such as the spleen, thymus, and cervical lymph nodes. Accordingly, whereas a few BM-MSC may differentiate into neural lineage and may accompany functional recovery of transplant recipients, the most likely regenerative mechanism entails the bystander effects via secretion of growth factors and other therapeutic substances. Nonetheless, these multi-pronged regenerative processes, including cell replacement and bystander effects, may aid in the cerebrovascular restoration post-ischemia (Eckert et al., 2013; Chen et al., 2015; Shichinohe et al., 2015; Stonesifer et al., 2017; Li et al., 2021). Finally, neural stem cells (NSCs) are primarily located in the subventricular zone (SVZ) and subgranular zone (SGZ) zones of the brain and can be derived from adults (Eriksson et al., 1998; Doetsch et al., 1999). NSCs are utilized for studying stroke, neurodegenerative disease, and trauma and can be produced in vivo and in vitro. They bypass ethical and immunogenic concerns and secrete growth factors promoting neuronal survival, but may promote tumor growth and can be difficult to isolate (Laywell et al., 2007; Amariglio et al., 2009; Bacigaluppi et al., 2009). Recent advances in regenerative medicine also include organoids and directly induced neurons. Organoids are in vitro 3D models grown from either pluripotent embryonic stem cells or adult stem cells (Grassi et al., 2019). Such a 3D model reflects the complex tissue organization of the host tissue that a single cell layer culture cannot and can generate from all three germ layers if derived from ESCs or IPSCs. More specifically, brain tissue organoids are made from neural progenitor cells (NPCs), which can differentiate into neurons and astrocytes (Rossi et al., 2018; Grassi et al., 2019; Corrò et al., 2020). Directly induced neurons may be used for studying age-related neurodegenerative diseases, where transcription factors and chemical signals are used to convert terminally differentiated cells across stages of aging (Mertens et al., 2018).

Environmental enrichment (EE) is the addition of physical, sensory, or social stimulation into an animal’s environment. In experimental models, EE exerts a positive role in promoting regeneration, neurogenesis, and CNS remodeling. Exposure prevents relapse, enhances attention performance, reduces anxiety levels during development, prevents DNA methylation changes brought by aging, and enhances neurogenesis by increasing NPCs (Korkhin et al., 2020; Zocher et al., 2021; Zorzin et al., 2021; Pintori et al., 2022). Similarly, exercise promotes positive effects on neurogenesis, trophic factor secretion, motor recovery following ischemia, cognitive and motor function, and neuroprotection (Pang et al., 2006; Mang et al., 2013; Tsai et al., 2019). Harnessing these beneficial effects of EE and exercise in combination with stem cell therapy holds significant promise for advancing treatment in stroke, PD, and HD, where therapeutic options remain limited.

1.1 Stroke

Stroke is the second leading cause of death globally, costing patients in the United States nearly $103.5 billion in 2016 (Girotra et al., 2020). Approximately 87% of strokes are ischemic, where thrombotic or embolic events disrupt blood supply and deprive neurons of oxygen, leading to acute neuronal injury and death (Kuriakose and Xiao, 2020). The affected brain tissue with <20% of cerebral blood flow is defined as the ischemic core, where hypoxia results in irreversible damage and apoptosis within minutes to hours following the insult. Surrounding this core is the ischemic penumbra, where the neuronal function may still be recovered by restoring blood flow to the region (Anrather and Iadecola, 2016). Ischemic injury induces neuroinflammation, oxidative stress, and excitotoxicity, which contribute to underlying stroke pathology and impede healing (Kuriakose and Xiao, 2020; Anrather and Iadecola, 2016). Current reperfusion strategies utilize thrombolytic agents such as tissue plasminogen activator (tPA) or surgical intervention via mechanical thrombectomy (Table 1). The recent DAWN trial showed that the therapeutic window for mechanical thrombectomy could be prolonged to 24 h in select ischemic cases (Khaku and Tadi, 2021). Interestingly, after the critical period, reperfusion by mechanical thrombectomy or tPa amplifies existing neuronal injury due to reactive oxygen species (ROS) and subsequent neuroinflammation (Mandalaneni et al., 2021). While these techniques confer therapeutic advantages, they may also lead to hemorrhage following ischemic reperfusion (Nogueira et al., 2018). Additionally, tPA’s narrow therapeutic window, short half-life, and poor penetration of large clots warrant further investigation into effective therapies for stroke (Zamanlu et al., 2018).

1.2 Parkinson’s Disease

PD is the second most common age-related neurodegenerative disease globally, characterized by the death of dopaminergic neurons in the substantia nigra. This complex disease process leads to motor and non-motor symptoms, with neurodegeneration implicating the central, autonomic, and enteric nervous systems (Table 1) (Reeve et al., 2014; Simon et al., 2020; Mak et al., 2017; Stoker and Barker, 2020). Classic motor manifestations include cogwheel rigidity, an asymmetric resting tremor, bradykinesia, and non-motor features such as depression, dementia, and rapid-eye-movement (REM) sleep disorders that precede motor symptoms and contribute to cognitive decline (Pantcheva et al., 2015; Hayes et al., 2019; Simon et al., 2020; Balestrino and Schapira, 2020). Current therapeutic approaches for PD focus on replenishing dopamine stores, as in the case of levodopa, which is considered the gold standard treatment for PD. Levodopa is the biological precursor to dopamine that improves motor function early in the disease process, but may cause dyskinesias and fluctuating periods of enhanced and impaired motor function due to alterations in extra-striatal dopamine (Stoker and Barker, 2020; Hayes et al., 2019). In patients with mid-stage and advanced-stage PD, deep brain stimulation (DBS) confers therapeutic benefit by alleviating dyskinesias and medication-refractory tremors. Surgically implanted electrodes stimulate the subthalamic nucleus and globus pallidus internus, and stimulation parameters are tailored to the patient’s clinical state (Figure 1). While DBS is a well-established treatment option for PD, adverse effects may include dyskinesias, imbalance, and dysarthria, which should be weighed against its therapeutic benefits (Habets et al., 2018; Hayes et al., 2019; Stoker & Barker 2020).

FIGURE 1

1.3 Huntington’s Disease

HD is a neurodegenerative disorder characterized by trinucleotide (CAG) repeat expansions in the huntingtin gene (HTT) on chromosome 4. It is inherited in an autosomal dominant manner, with genetic anticipation creating longer CAG expansions via paternal transmission. This mutation leads to a degeneration of GABAergic medium spiny neurons (MSNs) in the basal ganglia, disrupting neural circuitry and associated symptomology (Figure 2). Individuals with more repeats experience the disease earlier and progress more rapidly than those with fewer repeats (Wyant et al., 2017; Kim et al., 2021). HD’s molecular pathology is complex, involving aggregate formation, transcriptional dysregulation, altered synaptic plasticity, and glial dysfunction (Jimenez-Sanchez et al., 2017). Clinically, patients present with choreiform movements, which may progress to dystonia, rigidity, and ataxia as the disease progresses. Psychiatric conditions such as depression, anxiety, and suicidal ideations are also associated with HD. Currently, treatments for HD are primarily palliative (Table 1). Tetrabenazine (TBZ) is a monoamine transporter inhibitor that effectively reduces dopamine levels but has a black-box warning for increased risk of depression and suicidal ideation from concurrent depletion of serotonin and norepinephrine (Wyant et al., 2017; Kumar et al., 2020).

FIGURE 2

The pathophysiology and genetic mechanisms of stroke, PD, and HD have been well-studied, yet current therapeutic options leave much to be desired. tPA, the FDA-approved fibrinolytic agent, is commonly used to treat acute ischemic stroke, has a narrow therapeutic window and short half-life. A mechanical thrombectomy may be performed when patients do not meet tPA criteria. However, procedural and post-operative complications such as access-site vessel and nerve damage, intracerebral hemorrhage, and pseudoaneurysm may occur (Balami et al., 2018). Current strategies for PD and HD remain palliative and primarily focus on dopamine replacement and monoamine depletion. Finding targeted therapies that harness a disease-modifying approach for these conditions and a wider therapeutic window in the case of stroke will likely improve clinical outcomes for patients.

2 Regenerative Medicine for Treating Central Nervous System Disorders

Regenerative medicine, specifically stem cell-derived neural progenitor therapy, offers promising therapeutic potential for treating these CNS disorders. These three pathologies exhibit cell death and prove to be good candidates for stem cell-derived neural progenitor therapy. This option provides cell regeneration, endogenous neural progenitor recruitment, anti-inflammatory properties, and circuitry reconstruction. While the exact mechanisms of stem cell-derived neural progenitors remain elusive, the therapeutic void for stroke persists and begs for new strategies for recovery.

2.1 Regenerative Medicine for Stroke

In stroke, mass cell death presents unique complications as it is the death of neurons and the neurovascular unit as a whole within the ischemic core. The neurovascular unit comprises neurons, astrocytes, endothelial cells of the blood-brain barrier (BBB), myocytes, pericytes, and extracellular matrix components (Yasuhara et al., 2006; Muoio et al., 2014). The rescue of neurons and the neurovascular unit in the ischemic penumbra is feasible if acted upon promptly and thoughtfully using the suitable stem cells, dosage, and delivery route (Borlongan, 2019). In models of ischemic stroke, transplanted stem cell-derived neural progenitors not only replace infarcted tissue, but are neuroprotective, combat neuroinflammation, promote angiogenesis, reduce glial scar formation, and recruit endogenous neural progenitors to the area of injury (Doeppner and Hermann, 2010; Stonesifer et al., 2017; Borlongan, 2019; Saft et al., 2020). The discovery of endogenous neural stem cells (NSCs) in the human brain led to a new avenue of experiments with stem cell-derived neural progenitors and the eventual discovery of the biobridge (Renolds and Weiss, 1992; Ming and Song, 2011). The biobridge is the concept that transplanted neural progenitors not only replace dying cells and mitigate aberrant inflammation via the bystander effect but guide native neural progenitor cells from the host’s neurogenic niches to the area of infarction as well (Tajiri et al., 2013). The bystander effect is the process where transplanted stem cells secrete therapeutic substances rather than differentiating into neural cells, and may involve rapid attenuation of inflammation by reducing expression of proinflammatory factors, decreasing microglial activation, and promoting BBB repair. This anti-inflammatory effect was displayed when human-induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs) were transplanted into rodents 24 h after the onset of stroke. By the 48-h period, these transplanted cells migrated to the area of infarction and downregulated aggravating molecules such as tumor necrosis factor-α (TNF- α), IL-6, IL-1β, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1a (MIP-1a), intracellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) (Eckert et al., 2015). In addition to the bystander effect, the endogenous NSCs from the neurogenic niche essentially replace transplanted stem cells and recapitulate the secretion of anti-inflammatory cytokines, proteomes, and neurotrophic factors to mitigate the harsh environment and facilitate functional recovery (Crowley and Tajiri, 2017; Liska et al., 2017). Additionally, these progenitor cells can differentiate into tissue-specific neurons, astrocytes, and oligodendrocytes to result in more favorable outcomes (Corey et al., 2019; Zhang et al., 2020). However, successful integration into fully functional neurons persists as a problem for both transplanted and endogenous neural progenitors.

Entry of peripherally administered cells across the BBB remains a controversial topic. Grafted BM-MSCs may use upregulated P- and E-selectins after stroke to adhere to endothelial cells in the cerebral vasculature (Huang et al., 2000; Yilmaz et al., 2011). Additionally, the upregulation of VCAM-1 after stroke aided NSC adhesion in another study, further highlighting the ability of these cells to use selectin mediated rolling and integrin associated adhesion to penetrate the BBB (Guzman et al., 2008). MSC adhesion to the cerebral endothelial cells led to secretion of CXCl-11 which binds CXCR-3 and increases BBB permeability through the ERK1/2 signaling pathway (Feng et al., 2014). Interestingly, MSCs have also shown to reduce BBB disruption by inhibiting matrix metallopeptidase 9 (MMP-9) and decreasing ICAM-1 (Cheng et al., 2018). This discrepancy may be due to the different stem cells used and the different stages of these stem cells, which needs to be further studied (Zhou et al., 2021). There seems to be a two-pronged mechanism where stem cells will use BBB permeability to extravasate and migrate to the injured area and then begin to secrete growth factors and therapeutic substances through the bystander effect (Ao et al., 2018).

2.2 Regenerative Medicine for Parkinson’s Disease

Preclinical studies prove the viability of stem cell-derived neural progenitors in PD treatment. However, clinical trials display findings that show incongruities between preclinical and clinical results (Yasuhara et al., 2006; Kirkeby et al., 2017). Like in stroke, translating results from the preclinical to clinical settings poses barriers, including which type of stem cells to use, the route of administration, the timing, the induction of cell differentiation, and facilitating transplanted cell survival. Regardless, stem cells have proven to be an effective treatment in rodent models due to their ability to differentiate into tissue-specific cells, secrete neuroprotective factors, induce endogenous repair mechanisms, recruit endogenous neural progenitors, modulate immune processes, increase survival of existing cell populations, and lead to a more functional recovery (Yasuhara et al., 2017; Takahashi, 2018; Yasuhara et al., 2006; Tajiri, Yasuhara, Shingo et al., 2010). Current stem cell therapies utilize MSCs, NSCs, ESCs, and IPSCs (Table 2). ESCs are pluripotent, but create ethical concerns, may trigger tumorigenesis, and stand frequent immunological rejection (Bradley et al., 2002; Bieberich et al., 2004). Compared with other artificially-induced neural progenitors, IPSC cell lines can be differentiated into dopaminergic neurons in vitro before transplantation, genetically tailored to match the dysfunctional transcription factor responsible for the patient’s phenotype, and permit patient-specific human leukocyte antigen (HLA) matches to reduce immune incompatibility. The use of IPSC-derived neural progenitor cells additionally circumvents a crucial ethical dilemma in stem cell research, as embryos are not utilized in this technology. (Takahashi and Yamanaka, 2006; Morizane et al., 2017; Playne and Connor, 2017; Stoddard-Bennett and Pera, 2019).

After successful stem cell therapy in PD, an overarching issue still exists, specifically the full integration of the immature cells into the host’s neural circuitry (Weiss et al., 2006). In one preclinical study, human NSCs cloned by v-myc gene transfer (HB1.F3 cells), were transplanted into the 6-hydroxydopamine-lesioned striatum of rats. The treated rats showed significant recovery of parkinsonian symptoms in comparison to controls. The lesioned rats exhibited a nearly complete restoration of spontaneous motor activity after intracranial transplantation and a small fraction of the neurons were positive for tyrosine hydroxylase (TH) along the nigrostriatal pathway, indicating a successful integration into tissue-specific neurons. However, many of the neurons remained nestin-positive or lacked TH in the presence of MAP2, suggesting many of the grafted cells remained immature or mature with a lack of complete differentiation into dopaminergic neurons, respectively (Yasuhara et al., 2006). Despite lack of dopaminergic differentiation, the transplanted NSCs exhibited neuroprotective effects. Studies have also shown improved Parkinson’s symptomatology even with minimal dopaminergic differentiation, suggesting that the bystander effects may play a more substantial role as grafts improve functional recovery after the loss of dopaminergic neurons in the substantia nigra (Jung et al., 2004; Goldman, 2005; Rafuse et al., 2005; Yasuhara et al., 2006). In addition to increased secretion of neurotrophic factors such as human recombinant stem cell factor (SCF) in both the neural progenitor cells of the SVZ and the grafted HB1.F3 cells, the study also observed increases in endogenous neural stem cell production and preservation of existing neuronal circuitry and dopaminergic neurons (Yasuhara et al., 2006). This study suggest the efficacy of the stem cell treatment in early PD can ameliorate the functional loss associated with the disease pathology with minimal or even lack of neural differentiation and maturation. In another study by Kirkeby et al., human ESC derived neural progenitor cells were transplanted into the striatum of 6-hydroxydopamine (6-OHDA) lesioned rats to assess their ability to obtain regional specification and survive. Tumor-free grafts were able to proliferate and reach full maturity, displaying an affinity for axonal outgrowth (Kirkeby et al., 2012). Another issue that regenerative medicine faces is the threat of inflammation after injection of stem cells in PD models. One investigation administered ESC derived neuronal cells into the brains of rats that received surgery to cause brain injury. At the 7-week mark after implantation, histological analysis discovered extensive loss of the grafts at the ipsilateral site of only one animal. Further analysis revealed that macrophages infiltrated the graft site at a high concentration and activated astrogliosis despite the administration of immunosuppressants (Molcanyi et al., 2007).

With a compelling body of evidence, strategies adjunct to stem cell therapy have been designed to enhance neuronal survival, development, and differentiation into fully functional dopaminergic neurons capable of mitigating PD deficits. Two potential strategies to achieve this improved graft function involve exercise and EE, as discussed in section 3.2 below.

2.2.1 Regenerative Medicine for Parkinson’s Disease in Clinical Trials

In a 2001 double-blind open clinical trial, embryonic dopamine neurons were surgically transplanted in 20 out of 39 patients with PD. Imaging and postmortem studies showed a significant increase in dopaminergic neurons and neuronal differentiation in 17 out of 20 patients. Only 15% of the patients reported a recurrence of dystonia and dyskinesias after a one-year follow-up. The results proved human embryonic dopamine neuron transplants survive and lead to functional recovery in younger patients compared to older (over 60). This difference between younger and older patient recovery is likely due to a lack of robust neural plasticity in the older patients (Freed et al., 2001). While the use of embryonic grafts remains controversial, these findings indicate a viable option in the treatment of early PD. However, the lack of neuroplasticity in the aged brain may be overcome by specific interventions such as exercise and enriched environments (EE) to reinforce the circuitry provided by cell transplantation. The TRANSEURO clinical trials are ongoing but have problems collecting the human fetal ventral mesencephalic tissue needed for transplantation and have subsequently stopped. This barrier, alongside ethical dilemmas, has led to researchers searching for an alternative tissue supply (Barker et al., 2017). In response to this need, momentum has continued after the trials by Freed et al. and TRANSEURO despite the ethical concerns concerning embryonic stem cell use with the modern use of pluripotent stem cell (PSC)-derived dopamine neurons in humans (Barker et al., 2017).

2.3 Regenerative Medicine for Huntington’s Disease

HD continues to be an incurable disease, and current therapeutic options primarily focus on symptomatic treatment. Significant barriers to HD therapy include limited knowledge on molecular mechanisms implicated by the Huntington protein (HTT), extra-striatal atrophy throughout disease progression, and its broad impact on multiple systems, thus necessitating a systemic approach to treatment. Fortunately, advances in cell reprogramming and gene therapy offer promising potential to regenerate the damaged circuitry in the striatum and improve motor outcomes (Zheng and Kozloski, 2017; Cho et al., 2019; Monk and Connor, 2020). Cho and colleagues utilized gene therapy and neural progenitor cell transplantation to improve the motor deficits seen in the HD phenotype. The authors genetically corrected a mutant HTT NPC line and produced a viable cell therapy product that, like the WT NPC line, improved motor performance and lifespan when grafted into the striatum of HD mice (Cho et al., 2019). However, it is worth noting that inducing genetic changes before transplantation may introduce genetic instability (i.e., malfunctions in DNA repair, spindle formation, and telomere abnormalities) that can collectively contribute to tumor formation (Ross et al., 2011). Nonetheless, stem cell-derived neural progenitor cell transplantation stands as a promising therapeutic tool for HD.

2.4 The Need for Enhanced Graft-Host Integration and Function

Altogether, the developments in stem cell research for these three pathologies offer an exciting new avenue of possible subacute and chronic treatments. However, one problem remains, specifically, the use of immature cells in a previously integrated neural network. The use of immature cells, while key in recapitulating brain development, presents the challenge of young grafted cells forming neural circuitry with the mature host brain cells. To this end, exploring strategies designed to nurture graft-host integration will likely enhance the reconstruction of the elusive neural circuitry. The subsequent section discusses the use of EE/exercise in stem cell therapy-induced repair of the neural circuitry after stroke, PD, and HD.

3 Enriched Environment/Exercise and Pathology

Environmental enrichment and exercise are validated animal models for rehabilitation that can be measured through behavioral assessments (Huo et al., 2021). Clinical rehabilitation strategies vary based on subjective criteria such as patient characteristics, clinician preferences, and preferred outcomes. This makes it hard to standardize and attribute preferable outcomes to specific strategies (Huo et al., 2021). However, it is well known that rehabilitation and exercise lead to better functional outcomes, but the mechanisms by which they accomplish this and the effective period for intervention can be elusive. Recent findings in understanding motor learning, neuroplasticity, and functional recovery have led researchers to dive deeper into possible mechanisms by which EE and exercise lead to better outcomes and how they may be used in conjunction with other treatments and interventions. Here we will evaluate the preclinical data for stroke, PD, and HD regarding EE and exercise and show possible mechanisms of recovery that are used in combination therapies and can be further used in translational studies.

3.1 Enriched Environment/Exercise and Stroke

EE and exercise have been well studied in the context of stroke. EE strategies lead to increased gross neuroglia, sensorimotor function, spatial learning, and memory. However, outcomes are primarily based on the animal’s activity (Zhan et al., 2020). A three-phase paradigm has been proposed for the evolution of the EE throughout the healing process in an ischemic stroke rat model. Rats were initially exposed to social interaction, voluntary exercise, and small cabins for the first 2–7 days. They were then moved to a two-layer cage with more environmental interaction such as tunnels, swing boards, ladders, and balance beams for days 8–14. The third and final phase consisted of a three-layered cage with increasing slopes of the ladders and balance beams as well as floating cabins for days 15–30. The study showed significant restorative benefits with increased survival of neurons in the striatum and cortex, improved cerebral blood flow, increased angiogenesis, increased endogenous progenitor cell proliferation, increased endogenous neuronal differentiation in the ischemic regions, increased axonal guidance proteins, and reduced ischemic BBB capillary damage compared to standard housing rats (Zhan et al., 2020). Many molecular mechanisms induced by EE supported these incredible findings. Angiogenesis and the rescue of the neurovascular unit were portrayed through signaling pathways such as phosphorylated PI3K, AKT, and GSK-3, but reduced phosphorylated β-catenin. In tandem with modified expressions of vascular endothelial growth factor (VEGF), Angiopoietin-1 (Ang-1), and Angiopoietin-2 (Ang-2), the benefit from a modified EE program highlights the importance of rehabilitation in the recovery from stroke (Zhan et al., 2020). It has been shown that neuronal and endothelial cell proliferation happen together in the context of the neurovascular unit. The effects of EE on adult neurogenesis are replicable and have been displayed in many studies. Spatial learning significantly increased when rats were subjected to EE, and the positive results diminished when adding temozolomide, a drug that decreases neurogenesis (Garthe et al., 2016).

In addition to the combined benefits on neuronal proliferation, endogenous repair mechanisms, and neurogenesis, EE has proven to effectively induce neuroplasticity, cell maturation, genetic changes, and neuronal integration in host tissue (Kempermann, 2020). The theory posits that the actual benefits of EE come from the physical activity, social interaction, and cognitive stimulation elicited by the environment and must be assessed together. When studying hippocampal-dependent memory in rats, spatial enrichment modified the PKA dependence of long-term potentiation (Duffy et al., 2001). The study of genetic modifications in response to EE began in 2000 and has progressed (Rampon, 2000; Zhang et al., 2018). Enrichment modifies DNA methylation, including a regulator of adult neurogenesis, NeuroD1 (Zhang et al., 2018). Along with the genetic effects, neuronal maturation and integration are essential for portraying the benefits of EE. The experience of the animal leads to differing synaptogenesis and dendritic spine formation in the dentate gyrus (DG) during neurogenesis (Zhao et al., 2015). New neurons need stimulation to mature into tissue-specific neurons that are capable of remaining viable. Yu et al. demonstrated the neurovascular and behavioral outcomes after rehabilitation in an ischemic stroke model. EE in the form of climbing platforms, plastic tubes and tunnels, chains, and small boxes elicited neuroprotective effects and accelerated motor coordination recovery, progenitor cell integration, memory performance and more after partial middle cerebral artery occlusion. In addition, higher levels of CD31 were detected in the ischemic penumbra, revealing an increase in vascular differentiation (Yu et al., 2014).

Immunological studies also highlight the ability of EE in the form of nest boxes, fabric tubes, running wheels, and swing to change genetic factors and T Cell phenotype, leading to increases in IL-10 and IL-17 with subsequent decreases in IFN-γ (Rattazzi et al., 2016). This resolution of inflammation points to a broader immunological role of behavior and recovery. A review paper published in 2014 revealed the immunological changes were largely based on the EE in which the animals were placed. Physical exercise (PE), a form of EE, led to downregulation of toll-like receptors on macrophages and monocytes, reduced secretion of adipokines, modulation of hippocampal T cells, upregulation of mitogen-activated protein kinase phosphatase-1, and decreases in IL-1β and TNF-α. These immunomodulatory effects last after the stimulus and point to a long-term positive effect of EE and exercise (Singhal et al., 2014). A novel form of apoptosis, named pyroptosis, is a mechanism of cell death through membrane pore formation in response to infection and danger signals (Kuang et al., 2017). An experiment by Liu et al. displayed that an EE with ladders, platforms, swings, colorful balls, different-shaped wooden blocks, plastic tunnels, and a running wheel led to neuronal anti-pyroptosis through inhibition of Nuclear Factor kappa B (NF-kB) p-65 signaling pathway resulting in decreased levels of the inflammasome NLRP1 and NLRP3 after ischemia. Downstream, this pathway led to decreased levels of IL-1B, IL-18, and pyroptosis in neurons showing EE’s anti-inflammatory effects (Liu et al., 2021).

Exercise after an ischemic event has been combined with stem cells transplants (Table 3). However, it should be noted that timing for exercise, especially intense exercise, after an ischemic event is a determining factor for rehabilitative efficacy. Very early exercise interventions have a negative overall effect on the outcome of recovery after traumatic brain injury and may follow a similar pattern in stroke.

3.2 Enriched Environment/Exercise and Parkinson’s Disease

EE and exercise may offer a solution to the maintenance and protection of dopaminergic neurons, evidenced through rat models. A study was conducted to investigate the neuroprotective functions of exercise in rats that were treated with 6-OHDA to emulate PD. A baseline was taken, with rats having access to an exercise wheel 2 weeks before the 6-OHDA injection. Rats would travel 3,361 ± 932 m/day before treatment, and after the brain lesions were induced they traveled 1,292 ± 770 m/day (Tsai et al., 2019). The study also assessed gait patterns and akinesia and took histological samples before and after the brain lesion. The immunohistochemistry analysis revealed that rats in the exercise condition displayed a significantly higher amount of dopaminergic neurons than the control group. Ultimately, the study’s results support the long-term neuroprotective effects of exercise through immunehistological results and behavioral assessments (Tsai et al., 2019). This research is further supported by Rezaee et al., who also investigated the effects of exercise in rats treated with 6-OHDA. This experiment assessed the expression of various genes that play critical roles during neurodegeneration and regeneration such as Ampk, Sirt1, Pgc1a. The study found that treadmill exercise for rats with the 6-OHDA injection significantly increased TH expression and brain derived neurotrophic factor (BDNF). This also contributed to the amelioration of the behavioral abnormalities of the rats in exercises like the apomorphine-induced rotations (Rezaee et al., 2020). The increased expression of neurotrophic factors and TH levels supports that exercise has neuroprotective properties that can play a critical role in the treatment of PD. EEs are another tool that shows promise in the treatment of PD, but these settings are not standardized, which emphasizes the importance of descriptive details for each study (Table 4). Jadavji et al. found that rats with PD that were placed in an EE with ladders, multileveled cages, and toys saw significant improvements in motor deficits such as skilled reaching, walking, and apomorphine-induced rotation compared to rats with PD in a standard housing environment. Furthermore, a histological assay that measured the amount of TH-positive cells found that rats in the EE group had a significantly higher amount than the standard environment group (Jadavji et al., 2006). However, an important consideration to these results is that the rats were placed in an EE before 6-OHDA treatment as well. This timeline for exposure to EEs, particularly before the onset of PD has been a point of interest because a relationship may exist. Jungling et al. conducted another study where they placed rat pups in an EE with larger cages and were exposed to intensive complex stimuli for 5 weeks after birth and then were placed in a regular environment afterward. They then received 6-OHDA injections at 3 months old. The study results demonstrated that the rats with early exposure to an EE performed significantly better on motor function tests and had less dopaminergic neuron loss after 6-OHDA treatment (Jungling et al., 2017). However, in this study, the maximal lesion of dopaminergic neurons was only 24%. Regardless, this investigation still supported the use of EEs as a preventative tool against PD (Jungling et al., 2017). Other studies have extended these findings to measure the effects of a combined intervention utilizing both EEs and exercise. An investigation by Pradhan incorporated both treatments through exercise video games with human subjects. This study recruited patients with mild PD, and selected games that specifically target PD-induced deficits such as balance, reflex responses, and cognitive engagement (Pradhan, 2019). The specific games were tailored to each subject based on a 1–10 rating of difficulty each participant provided after trialing each game. Participants performed physical assessments before and after the intervention that assessed motor deficits associated with PD such as a functional reach test, single limb stance, and gait speed. These results ultimately displayed behavioral improvements from baseline to post-intervention for the assessments that the games had targeted (Pradhan, 2019). These studies show firm support for practical applications of EEs and exercise as a treatment regimen for alleviating the debilitating symptoms of PD. Increasing expression of neurotrophic factors and protecting dopaminergic neurons from decay allow for improvements in motor skill deficits that originate from PD.

3.3 Enriched Environment/Exercise and Huntington’s Disease

The benefits of EE conditions for HD were first discovered in transgenic HD mice models during a landmark study in 2000. Van Dellen et al. found that HD mice exposed to stimulating environments demonstrate delayed cerebral atrophy and motor coordination compared to non-stimulated HD controls. Mice in the non-stimulated group also developed seizures, whereas the enriched group did not (van Dellen et al., 2000). Cognitive deficits in learning and memory, which typically precede motor manifestations in HD, were improved in the environmentally enriched group, specifically for task-specific flexibility and long-term spatial memory (Nithianantharajah et al., 2008). Furthermore, it is known that HD vastly affects intracellular signaling, transcriptional regulation, and protein expression, including downregulated BDNF expression (Cha, 2000; Spires, et al., 2004; Ferrer, et al., 2000). Environmental enrichment ameliorates the motor manifestations in HD and increases BDNF levels in the striatum and hippocampus, posing positive effects on neurogenesis and cell survival in this neurodegenerative disease (Spires et al., 2004; Lazic, et al., 2006). Like EE, PE demonstrates cognitive and motor benefits in rodent HD models (Pang et al., 2006). When spatial memory was assessed in HD mice by observing running alternations in a T maze, 45% of HD mice housed with running wheels alternated during the task, compared to only 29% of HD mice in standard housing. There was no significant difference in alternation rates between WT and standardized housing HD rodents, supporting that physical exercise can rescue cognitive function in HD. Decreased mRNA BDNF levels were also noted in the striatum, hippocampus, and anterior cortex of HD rodents, supporting dysregulated transcription. However, PE did not affect BDNF protein expression in either WT or HD groups. Running did increase striatal mRNA in this study, which the authors attribute to increased astrocytes secreting BDNF (Pang et al., 2006). Another study tested the long-term effects of PE on improving cognitive reserve in mice models, which interestingly revealed reduced escape latencies and longer survival in mice trained with cognitive stimulation compared with the only motor-trained group (Wood et al., 2011). Taken together, both environmental enrichment and physical exercise prove beneficial for ameliorating cognitive function, protein expression, and motor performance in HD (See Table 5).

3.4 Conclusion

EE and exercise show distinct regenerative effects that may work synergistically with stem cell-derived neural progenitor therapy if used in combination and following certain guidelines with timing, dosage, and intensity. Altogether, the use of these rehabilitation strategies may produce the most impact by potentially training the immature transplanted cells to form functional circuitry with the host’s neural networks leading to improved neuroanatomical graft-host integration and behavioral outcomes.

4 The Role of Enriched Environment and Exercise in Enhancing Neural Circuitry Repair With Stem Cells

Effective stem cell therapy not only hinges on cell replacement but necessitates appropriate functional integration, connectivity, and differentiation into the host environment. Utilizing environmental enrichment and exercise to facilitate this process is an active field of research of great therapeutic value for stroke, PD, and HD. This concept centers around stimulating the graft site through EEs to enhance neuroplasticity and recruit endogenous repair mechanisms that favor survival, growth, and functional integration for transplanted cells (Döbrössy and Dunnett, 2005; Dunnett, 2013; Clinch et al., 2017). However, in the case of PD, restoring dopamine levels alone is able to ameliorate parkinsonian symptoms. The positive benefits from both EE and stem cell transplantation can further be discussed through combination studies rather than the individual applications of both stem cells and EE (Figure 3).

FIGURE 3

4.1 The Role of Enriched Environment and Exercise in Enhancing Neural Circuitry Repair With Stem Cells in Stroke

Studies using a preclinical stroke model with a combination of stem cells and rehabilitation have consistently revealed the importance of using a combination therapy when assessing outcomes. BDNF is a neurotrophic factor correlated with neural plasticity that has been well studied in the context of motor rehabilitation and stem cell transplantation. It has been proposed that rehabilitation strategies that enhance BDNF also enhance motor recovery after ischemia (Mang et al., 2013). Because stem cells and rehabilitation have been shown to increase this neurotrophic factor, it can be theorized that the combination of both therapies will have an additive effect on functional outcome (Ploughman et al., 2009; Mang et al., 2013). In section 2, we assessed the current theories of stem cell mechanisms for brain repair. Indeed, stem cells lead to enhanced recovery through many means, but the biobridge paves a new avenue for understanding the amelioration of deficits after stroke. The increases in endogenous NPCs must be met with increased training to lead to functional integration of the grafts with the host tissue. Rehabilitation offers the means by which grafts mature and integrate effectively. However, the type of rehabilitation method is an important factor. Aerobic exercise has been shown to increase BDNF and endogenous neurogenesis (Mang et al., 2013). Forced low-intensity exercise increases NPC maturation and facilitates a more robust motor recovery (Morishita et al., 2020). Most importantly, both EE and stem cell transplantation increase adult neurogenesis which has been implicated as the main driving force behind recovery (Zhan et al., 2020; Garthe et al., 2016; Tajiri et al., 2103; Singhal et al., 2014; van Praag et al., 1999) The stem cells induce neuroprotection early and influence proliferation when the rodents are still in recovery. Once the rodents begin to display functional recovery, EE should be implemented quickly to increase neurogenesis and neuronal integration into the host tissue. The timing and implementation of exercise and EE remains questionable. Exercise, if implemented too early, results in increased thalamic atrophy and worse functional motor outcomes and should be further evaluated in combination studies (Kozlowski et al., 1996; Risedal et al., 1999). EE, byways of housing enrichment, is safe and effective when implemented early or late in the disease course and may not pose the same problems (Tang et al., 2019; Zhan et al., 2020).

The three-phase paradigm might combat this careful balancing effect between exploiting the positive results and mitigating adverse effects based on timing and the intervention needed (Zhan et al., 2020). Treadmill exercise enhances the therapeutic potency of MSCs by increasing the survival of existing neurons and transplanted neurons (Zhang et al., 2015). In addition, combined therapy led to reduced infarct volume, increased synaptogenesis, and overall improved behavioral outcomes compared to lesioned rats treated with either stem cells or rehabilitation (Akhoundzadeh et al., 2017). The timing for implementation between the stem cells and the rehabilitation strategy needs more data to find a balance accurately, as many studies show differences in timing and results. There is believed to be a defined plastic window in which neural plasticity can be exploited for better outcomes after a pathologic event or process (Hara, 2015; Zhan et al., 2020).

4.2 The Role of Enriched Environment and Exercise in Enhancing Neural Circuitry Repair With Stem Cells in Parkinson’s Disease

Exercise induces morphological changes in toxin-induced PD rat models. When dopaminergic grafts from the rat fetal ventral mesencephalon were transplanted into the striatum of 6-OHDA lesioned rats, rodents exposed to exercise had enhanced dopaminergic graft survival, maturation, and neurite extension into the dorsolateral striatum. These neurite extensions specifically grew in the same pathway taken by A9 dopaminergic neurons, which project into the striatum and are crucial for improved behavior (Figure 4). This is an important finding as A9 dopaminergic neurons preferentially degenerate in PD (Björklund and Dunnett, 2007; Torikoshi et al., 2020). Additionally, hemispheric dominance plays an influential role in dopaminergic neuroplasticity post-transplantation. Rats unilaterally lesioned with 6-OHDA were observed in skilled forelimb experiments pre- and post-DA graft placement. Rats that did not demonstrate a paw preference during the staircase test improved the most post-transplantation. Subjects with skilled movements contralateral to the lesion recovered moderately whereas those with ipsilateral lateralization recovered the least (Nikkah et al., 2001). Clinically, exercise-induced neuroplasticity plays a profound impact on long-term rehabilitation in PD patients. 8 weeks of balance training improved functional mobility and reduced falls in PD patients for up to 12 months following treatment, and Tai Chi training for 12–24 weeks reduced falls for up to 6 months post-training (Li et al., 2012; Gao et al., 2014; Shen and Mak, 2015; Wong-Yu and Mak, 2015; Mak et al., 2017). Furthermore, patients with early PD who practiced intensive treadmill exercise had improved postural control and increased striatal dopaminergic graft binding to the dopaminergic receptor, D2R, as confirmed by PET imaging. These changes were not observed in the non-exercise PD group (Fisher et al., 2013).

FIGURE 4

4.3 The Role of Enriched Environment and Exercise in Enhancing Neural Circuitry Repair With Stem Cells in Huntington’s Disease

A seminal study by Brasted and colleagues revealed the importance of targeted training to recover lost motor function in HD rat models. These animals were specifically trained to perform a lateralized choice reaction task before receiving quinolinic acid injections into the neostriatum and retrained for 30 days to perform the same task with or without a striatal graft. After retraining post-recovery, only rats that received striatal grafts showed marked performance and eventually achieved similar results as non-HD controls. Additionally, motor training ipsilateral to the lesion did not confer additional benefits, whereas training the contralateral side resulted in marked recovery. Since ipsilateral lesions affect the contralateral side, this supports that rehabilitative training specific and targeted to the lesion is vital for functional recovery in HD (Brasted, et al., 1999). Further investigation into post-graft recovery with lateralized training showed that HD rats with striatal lesions trained to perform a food retrieval task with the ipsilateral paw performed similarly as non-HD controls, whereas those trained on the paw contralateral to the lesion showed motor deficits that recovered with graft transplantation (Döbrössy and Dunnett, 2006b). Döbrössy and Dunnett also investigated changes in BDNF levels, dendritic spinal densities, and cell volume in rodent HD models subjected to EE and exercise, post-striatal graft transplantation (Döbrössy and Dunnett, 2006a). The HD group exposed to EEs in the form of several cardboard tunnels, ladders and platforms revealed increased BDNF levels, spinal densities, and cell volume. In contrast, decreased spinal densities and BDNF were found in the exercise group, suggesting that surrounding environmental factors influence neural connectivity and plasticity post-transplantation (Döbrössy and Dunnett, 2006a).

4.4 Conclusion

Stem cell therapy not only relies on cell replacement, but also necessitates successful graft-host functional integration. Enhancing graft integration through rehabilitative strategies advances current treatment options for stroke and HD. This concept may not be as important for PD as replacement of dopaminergic neurons and the presence of dopamine ameliorates the symptoms. EE and exercise facilitate stem cell graft-host reconstruction of neural circuitry that may involve at least a two-pronged mechanism that creates a conducive microenvironment into the host brain, allowing the newly transplanted cells to survive, proliferate, and differentiate into neural cells. Both may additionally train the transplanted immature cells to learn the neurochemical, physiological, and anatomical signals in the brain towards better functional graft-host connectivity.

5 Summary and Future Directions

Limited therapeutic options exist for stroke, PD, and HD, prompting further research into their underlying pathology to improve functional recovery and slow disease progression. Regenerative medicine, specifically stem cell therapy, is a promising avenue that consistently improves outcomes in preclinical studies. This is an active field of research with underlying mechanisms that include cell replacement, endogenous stem cell recruitment, neurotrophic effects, and induction of anti-inflammatory properties. While replacing damaged neurons is the first step to functional recovery, grafts must integrate, differentiate, and enhance synaptic plasticity to maintain and promote healing. EE and exercise combined with stem cell therapy achieve this via enhanced synaptogenesis, neuronal survival, axonal regrowth, dendrite extension, and enhanced receptor binding. There is a continued need for clinical trials that demonstrate the rehabilitative effects of combined EE, exercise, and stem cell therapy. Further research is also required to elucidate appropriate timing between stem cell transplantation and rehabilitation. Ultimately, understanding how these rehabilitative strategies facilitate graft integration and neural repair encourages a team-based and multi-faceted approach to treating these diseases and is core to developing robust therapeutic options for patients across the globe.

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