If your doctor doesn't know about this or can't explain it, you don't have a functioning stroke doctor, they've had 6 years to become well versed in this.
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Mesenchymal stem cell-based treatments for stroke, neural trauma, and heat stroke
Abstract
Background
Mesenchymal stem cell (MSC) transplantation has been reported to improve neurological function following neural injury. Many physiological and molecular mechanisms involving MSC therapy-related neuroprotection have been identified.
Methods
A review is presented of articles that pertain to MSC therapy and diverse brain injuries including stroke, neural trauma, and heat stroke, which were identified using an electronic search (e.g., PubMed), emphasize mechanisms of MSC therapy-related neuroprotection. We aim to discuss neuroprotective mechanisms that underlie the beneficial effects of MSCs in treating stroke, neural trauma, and heatstroke.
Results
MSC therapy is promising as a means of augmenting brain repair. Cell incorporation into the injured tissue is not a prerequisite for the beneficial effects exerted by MSCs. Paracrine signaling is believed to be the most important mediator of MSC therapy in brain injury. The multiple mechanisms of action of MSCs include enhanced angiogenesis and neurogenesis, immunomodulation, and anti-inflammatory effects. Microglia are the first source of the inflammatory cascade during brain injury. Cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, are significantly produced by microglia in the brain after experimental brain injury. The proinflammatory M1 phenotype of microglia is associated with tissue destruction, whereas the anti-inflammatory M2 phenotype of microglia facilitates repair and regeneration. MSC therapy may improve outcomes of ischemic stroke, neural trauma, and heatstroke by inhibiting the activity of M1 phenotype of microglia but augmenting the activity of M2 phenotype of microglia.
Conclusion
This review offers a testable platform for targeting microglial-mediated cytokines in clinical trials based upon the rational design of MSC therapy in the future. MSCs that are derived from the placenta provide a great choice for stem cell therapy. Although targeting the microglial activation is an important approach to reduce the burden of the injury, it is not the only one. This review focuses on this specific aspect.
1 Introduction
Neuroinflammation is a hallmark of brain injury
Inflammation is a hallmark of stroke (Lambertsen, Biber, & Finsen, 2012), traumatic brain injury (TBI) (Mannix & Whalen, 2012), and heatstroke pathology (Chen, Lin, & Chang, 2013). The cytokines that modulate tissue injury in ischemic stroke, TBI, spinal cord injury (SCI), or heatstroke, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-6, are potential targets for future therapy. The production of these cytokines in greatly increased by microglia in the brain the first 24 hours after experimental stroke (Clausen, Lambertsen, Meldgaard, & Finsen, 2005; Clausen et al., 2008; Hill et al., 1999; Lambertsen, Meldgaard, Ladeby, & Finsen, 2005). Interleukin-1β and TNF-α are produced by a largely segregated population of microglia and infiltrating macrophages after ischemic stroke in mice (Clausen et al., 2008). This has promoted the hypothesis that inhibiting proinflammatory cytokine production may be a therapeutic approach in treating brain injury (Barone & Parsons, 2000). Indeed, according to an observational study that involved 629 consecutive patients with chronic neurological, neuropsychiatric, and clinical impairment after stroke and TBI, the perispinal administration of etanercept produces clinical improvement (Tobinick, Rodriguez-Romancce, Levine, Ignatowski, & Spengler, 2014). In addition, various drugs or strategies improve outcomes of experimental heatstroke by reducing the overproduction of these proinflammatory cytokines resulting from heat stress (Chen et al., 2013).
Microglial activation is involved in brain injury pathology
In contrast to their well-known deleterious roles, TNF-α and IL-6 have also been shown to exhibit neuroprotective properties. In both TNF-deficient mice (Bruce et al., 1996; Gary, Bruce-Keller, Kindy, & Mattson, 1998; Lambertsen et al., 2009; Taoufik et al., 2007) and IL-6-deficient mice (Herrmann et al., 2003), infarct sizes were significantly increased following cerebral injury. In addition, TNF-α and IL-6 double-receptor knockout mice had higher mortality rates than did their wild-type controls following heatstroke collapse (Leon, Blaha, & DuBose, 2006). Adult IL-6 knockout mice have also shown to compromise neurogenesis (Bowen, Dempsey, & Vemuganti, 2011). A complete lack of TNF-α or IL-6 might be detrimental to neurogenesis in the adult brain (Monje, Toda, & Palmer, 2003; Vallières, Campbell, Gage, & Sawchenko, 2002). This can be concluded by previous studies that show that an appropriate baseline level of TNF-α or IL-6 is necessary and essential for neurogenesis or host defense, whereas higher levels of TNF-α or IL-6 are detrimental to neurogenesis or host defense.
Microglia are activated rapidly in response to central nervous system injury and produce proinflammatory cytokines, growth factors, reactive oxygen species, nitric oxide, and glutamate (Block & Hong, 2005; Jin, Yang, & Li, 2010; Stolp & Dziegielewska, 2009). An appropriate state of microglial activation is necessary and crucial for host normal neurogenesis and defense; however, microglial overactivation results in deleterious and neurotoxic consequences. Proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, which are increasingly expressed during experimental stroke, have a crucial role in the progression of neuronal loss and brain injury (Banati, Gehrmann, Schubert, & Kreutzberg, 1993; Barone et al., 1997; Rothwell, Allan, & Toulmond, 1997).
Recent developments in magnetic resonance (MR) and positron emission tomography (PET) imaging techniques have demonstrated that increased binding of the peripheral benzodiazepine receptor (PBR) PET ligand 11C-RK11195 is interpreted as a marker of microglial activation and hence neuroinflammation in several brain diseases (Denes et al., 2010). Increases in 11C-PK11195 binding are found 30 days after stroke in patients, which suggests a contribution of microglial activation to ongoing processes in the ischemic brain (Price et al., 2006). In a rat stroke model, evidence supports a role for microglia as a central mediator in the ongoing processes of stroke damage (Gelosa et al., 2014). In addition, microglial activation is involved in other neurodegenerative disease models, such as Alzheimer's and Parkinson's disease (Mosher & Wyss-Coray, 2014; Walker et al., 2014), traumatic brain injury (Chio, Lin, & Chang, 2015), and heatstroke (Chen et al., 2013).
Tumor necrosis factor-alpha levels in both serum and cerebrospinal fluid are found to be significantly elevated in ischemic stroke, traumatic brain injury, and heatstroke (Chen et al., 2013; Chio et al., 2015; Gelosa et al., 2014). Activation of TNF receptor 1 (TNF-R1) is believed to promote proinflammatory and proapoptotic action, astrogliosis, leukocyte extravasation, and disrupted blood–brain barrier (BBB) permeability (McCoy & Tansey, 2008). However, other results have demonstrated that TNF-R1 is required for erythropoietin receptor and vasculoendothelial growth factor expression and protective effects in primary cortical neurons after ischemic and excitotoxic injury (Taoufik et al., 2008).
MSC therapy may improve outcomes of brain injury by modulating microglial activation
Mesenchymal stem cells (MSCs) can be derived from different sources, including bone marrow, adipose tissue, the umbilical cord, and the placenta. Currently, clinical trials are being conducted to investigate the therapeutic effects of human MSCs in many cardiovascular and neurodegenerative disorders (Kalladka & Muir, 2014; Mastri, Lin, & Lee, 2014). In addition to their multilineage differentiation potential, MSCs may exert their regenerative effect via the production of multiple paracrine factors (Kalladka & Muir, 2014; Mastri et al., 2014). Production of IL-6, vascular endothelial growth factor (VEGF), hepatocytes growth factor (HGF), brain-derived neurotrophic factors (BDNF), glial-derived neurotrophic factor (GDNF), neurotrophin-3 (NT3), fibroblast growth factor (FGF), and thrombospondins can be promoted by MSCs. It is well known that neural injury results in BBB breakdown and the infiltration of tissue neutrophils and macrophages into damaged brain tissue, which causes microglial activation. In addition, microglia have been promoted as a compelling target for treating infectious and inflammatory diseases of the brain (Chio et al., 2015; Denes et al., 2010; Rock & Peterson, 2006). It is likely that MSC therapy may improve outcomes of brain injury by modulating microglial activation. Although targeting the microglial activation is an important approach to reduce the burden of the injury, it is not the only one.
MSCs fulfill the criteria that have been established by the international society of cellular therapy
Mesenchymal stem cells are multipotent, self-renewing cells (Friedenstein, Petrakova, Kurolesova, & Frolova, 1968). They fulfill the following criteria that have been established by the International Society of Cellular Therapy (Dominici et al., 2006): (i) adherence to plastic, (ii) expression of CD105, CD73, and CD90; lack of expression of CD45, CD34, CD14, CD116, CD79a, CD19, and HLA11; and (iii) ability to differentiate into osteoblasts, adipocytes, and chondroblasts in vitro. Due to extensive self-renewal capacity, their ease of isolation, and their presence during young and fetal life, MSCs that are derived from the placenta are an appropriate source for stem cell therapy.
In this review, we collected publications that pertain to MSC therapy and cerebral injury that is caused by stroke, neural trauma, and heatstroke. In doing so, we emphasized the mechanisms of MSC therapy-related neuroprotection, which were identified using an electronic search (e.g., using PubMed). It reports the feasibility of MSCs to improve neurological function after injury. It focuses on adult injuries such stroke, TBI, and heatstroke. It summarizes the pathophysiology of the injury briefly and offers an overview of MSCs therapeutic approaches.
2 Therapeutic Effects of MSCs in Ischemic Stroke
Neonatal stroke rats or mice
Neonatal stroke occurs frequently in live birth and presents motor dysfunction, cognitive deficits, and epilepsy (Ferriero, 2004; Kirton & de Veber, 2009). However, treatment options are not currently available. The transplantation of MSCs into neonatal animal models of ischemic stroke promotes functional recovery by stimulating neurogenesis, oligodendrogenesis, and axonal remodeling (van Velthoven, Kavelaars, van Bel, & Feijene, 2010a,b; Yasuhara et al., 2008). The beneficial effect of MSC transplantation might involve the augmentation of the secretion of growth and differentiation factors and the fostering of an environment that stimulates both angiogenesis and neurogenesis (van Velthoven et al., 2010b, 2012, 2013) (Table 1). The secretome that has been obtained from MSCs contains several neurotrophic factors, including insulin-like growth factor-1 and brain-derived neurotrophic factor, which are responsible for the protective effects of MSCs that were observed in studies with in vitro and in vivo neuronal injury models (Wei et al., 2009). When compared with adults, it is believed that newborns benefit more from cell therapy because newborns have an increased brain plasticity as well as a different pathophysiology of the injury. In addition, in newborns the microglial activation is more pronounced as microglial activation is present during physiological brain development as well.
| Treatment regimens | Main results | References no. |
|---|---|---|
| 1. Neonatal stroke rats or mice received intranasal or intracerebral injection of MSCs | Decreasing cerebral damage by reducing both overproduction of IL-6 and TNF-α and microgliosis, but stimulating neurogenesis (e.g., increased production of HGF, VEGF, IGF, EGF, 6FGF, IL-10, GDNF, BDNF, NF3, angiopoietin, TGF, and I-CAM 1 | van Velthoven et al. (2010a,b), Yasuhara et al. (2008), van Velthoven et al. (2012, 2013), Wei et al. (2009) |
| 2. Adult stroke rats received intravenous or intracerebral injection of MSCs | Decreasing cerebral damage by stimulating synaptogenesis and vessel density, reducing apoptosis in the ischemic boundary zone, and increasing proliferation of progenitor cells in the subventricular zone. | Wakabayashi et al. (2010), Xu et al. (2010); Bao et al. (2011), Lin et al. (2011); Walker et al. (2010), Wei et al. (2012), Ma et al. (2013), Tang et al. (2014a,b), Cheng et al. (2015) |
| 3. Adult stroke monkeys received intracerebral injection of MSCs | Reducing cerebral damage by stimulating production of IL-10 | Li et al. (2010) |
| 4. Adult stroke patients received intravenous injection of MSCs | Reducing cerebral damage by promoting nerve cell proliferation | Weimann et al. (2003) Bang et al. (2005) Lee et al. (2010) |
- MSCs, mesenchymal stem cells; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; IL-10, interleukin-10; VEGF, vascular endothelial growth factor; HGF, hepatocytes growth factor; BDNF, brain-derived neurotrophic factor; GDNF, glial-derived neurotrophic factor; NT3, neurotrophin-3; FGF, fibroblast growth factor; IGF-1, insulin-like growth factor; EGF, epidermal growth factor; TGF, transforming growth factor; ICAM-1, intercellular adhesion molecule-1.
Adult ischemic stroke models
2.2.1 MSC therapy improves outcomes of stroke mainly by secreting paracrine factors
Mesenchymal stem cells have the potential to differentiate into osteoblasts, chondrocytes, adipocytes, hepatocytes, and neurons (Sanchez-Ramos et al., 2000). Although, MSCs are able to pass through the BBB (Kopen, Prockop, & Phinney, 1999), MSCs that are transplanted by intracerebral or intravenous routes minimally and selectively migrate to the ischemic boundary sites (Li et al., 2002; Zhao et al., 2002). Considering the small number of MSCs in injured brain tissue, the presence of therapeutic neurotrophic factors that are secreted by MSCs apparently confers neuroprotection. This suggests that providing the therapeutic molecules that are secreted by these cells can be neuroprotective (Borlongan, Hadman, Sanberg, & Sanberg, 2004). Although MSCs have been shown to localize only to the injured brain using immunohistochemistry (Chen et al., 2001; Vendrame et al., 2004), intravenously transplanted human MSCs are functionally involved in repair in ischemic stroke rats, possibly by providing human insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic fibroblast growth factor (FGF), and neurotrophic neurotrophic factors to the host brain (Wakabayashi et al., 2010). Xu and colleagues (Xu et al., 2010) further suggested that the transplantation of neuronal cells induced from human MSCs improves neurological function after stroke without cell fusion.
2.2.2 MSC therapy improves outcomes of stroke by stimulating angiogenesis, neurogenesis, and synapse formation
The mechanisms that underlie the beneficial effects of transplanted MSCs include transdifferentiation into the neural lineage as well as the induction of neurogenesis, angiogenesis, and synapse formation in rodents (Kurozumi et al., 2005; Li et al., 2002; Shen et al., 2006; Wislet-Gendebien et al., 2005). Transplantation of MSCs protects against cerebral injury and upregulates IL10 expression in Macaca fascicularis (Li et al., 2010), thereby suggesting the activation of endogenous neurotrophins. Angiogenesis that is induced by MSC transplantation promotes endogenous neurogenesis, which may produce functional recovery after cerebral injury in rats with ischemic stroke (Bao et al., 2011). Both histology and MRI reveal that human umbilical MSCs promote recovery after ischemic stroke in rats (Lin et al., 2011). The beneficial effects of MSC therapy are associated with improved revascularization in ischemic injured tissues.
2.2.3 MSC therapy attenuates neuronal death by suppressing activated microglia
During the acute phase of cerebral injury, the expression of neuronal and microglial IL-6 is elevated in the injured penumbra (Berti et al., 2002; Block, Peters, & Nolden-Koch, 2000). Direct intrathecal implantation of MSCs results in enhanced neuroprotection. The implantation of MSCs into the injured brain activates resident stem cells niches via an NF kappa B-mediated increase in IL-6 production (Walker et al., 2010). Microglia have also been implicated in the pathogenesis of a number of neurodegenerative diseases, such as stroke, Alzheimer's disease, dementia, and multiple sclerosis (Danton & Dietrich, 2003). Microglia can defend against brain damage, but excessive or sustained microglia activation can contribute to apoptotic cell death (Ohmi et al., 2003). Bone marrow MSCs result in the suppression of activated microglia and to a delay of neuronal death (Ohmi et al., 2003; Wei, Fraser, Lu, Hu, & Yu, 2012). Human MSCs also stimulate angiogenesis in focal cerebral injury by increasing expression of α-tubulin and angiopoietin 1 and 2 (Ma et al., 2013). MSC treatment reduces the expression of inflammatory cytokines in lipopolysaccharide-activated microglia and subsequently reduces aquaporin-4 expression and apoptosis of astrocytes after cerebral injury (Tang, Cai, et al. 2014a, Tang, Liu, et al., 2014b). In addition, the survival and function of transplanted MSCs after focal cerebral injury can be enhanced by melatonin pretreatment (Tang et al., 2014b). Both neurological deficit and brain edema and infarct volume are significantly decreased postischemic stroke with MSC treatment via the tail vein (Tang et al., 2014a). MSCs also protect against brain injury in the mouse by stimulating the production of TGF-β (transforming growth factor), but reduce proinflammatory cytokines (e.g., IL-1, TNF-α) (Cheng et al., 2015). Thus, it appears that MSCs improve outcomes of ischemic stroke in animal models by stimulating neurotrophic factors production and endogenous neurogenesis and modulating neuroinflammation.
Stroke patients
Systemic delivery of MSCs has also been shown to be a feasible and safe therapy for treating ischemic stroke patients (Tang et al., 2014b). Long-term follow-up data further indicate a contribution of transplanted MSCs to Purkinje neurons in human adult brains (Bang, Lee, Lee, & Lee, 2005; Lee et al., 2010; Weimann, Charlton, Brazelton, Hackman, & Blau, 2003). Both clinical (Bang et al., 2005; Cheng et al., 2015; Tang et al., 2014a) and experimental (Lee et al., 2015) studies demonstrate that the outcomes of ischemic stroke in patients and rodents are greatly improved by MSC therapy. Furthermore, earlier administration of MSCs produces an improved functional recovery, survival rate, stroke recurrences, or adverse effects.
A more recent report has shown that CD4+ CD28- T cells (also called CD28 null cells) are increased in the clinical setting of acute ischemic stroke (Tuttolomondo et al., 2015). Among these T cells, CD28 null cells produce high amounts of γ-interferon and TNF-α and thus may have a direct pathogenetic role in neuronal damage. It is not known whether the peripheral frequency of CD28 null cells in acute ischemic stroke can be affected by MSC therapy.
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