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Exosomes

WHAT ARE EXOSOMES?

Exosomes are nano-sized extracellular vesicles with a diameter of 40 -100 nm and originate from multivesicular bodies (MVBs) and they are present in almost all biological fluids.[1,2] Exosome morphology has been revealed as cup-shaped using transmission microscopy.[3]

Exosomes are released from cells when the MVB merge with the cell membrane. This liberates intraluminal vesicles (ILVs) into the extracellular milieu and those released vesicles are called exosomes. Once released, they can either be taken up by nearby target cells or travel to other sites through the biological fluids. Most mammalian cells can generate ILVs within MVBs and hence, produce exosomes.[4,5,6,7,8,9,10,11]

Exosomes were originally assumed to be waste products and hence, were largely ignored and often dismissed until the past decade. As it turns out, exosomes were discovered to be capable of intercellular communication and of transmission of macromolecules between cells. They also are involved in the carrying and spreading of proteins, lipids, messenger RNA (mRNA), microRNA (miRNA) and DNA. They can be very useful vectors for drugs because they are composed of cell membranes, rather than synthetic polymers, and as such are better tolerated by the host. [1,4,6,7,12,13,14,15]

Studies suggest Mesenchymal stem cell (MSC)-derived exosomes contribute to the potency of the MSCs themselves for therapies due to their ability to regulate cell-to-cell communication and deliver paracrine factors during angiogenesis, tissue regeneration and diagnosis of disorders. Exosomes from MSCs extend the biological role of MSCs in that they help optimize tissue function by maintaining tissue homeostasis. Purified exosomes from MSC show similar effects to MSC-based treatment itself. Exosomes can achieve a higher dose than using MSCs on their own.

WHAT DO EXOSOMES CONTAIN?

Exosomes contain biologically active molecules such as proteins, RNAs, DNAs, lipids and miRNAs. These molecules may regulate exosomal intercellular communication and target specific cell types.[1,4,5,6,7,12,13,14,15] The delivery of these molecules may also alter the cell function.[4] These RNAs have been shown to have functional effects in recipient cells. The proportion of miRNA is actually higher in exosomes than in their parent cells.
miRNAs are a class of 17-24nt small, noncoding RNAs that mediate post-transcriptional gene silencing. They are involved in cell proliferation, cell differentiation and cell migration. They can stably exist in body fluids. Conveying information via circulating vesicles is a method of intercellular communication that is essential for cell-to-cell contact-dependent signalling and signaling via transfer of soluble molecules. [1,4,5,6,7,12,13,14,15,16]

HOW EXOSOMES WORK?

  1. The transmembrane proteins of exosomes directly interact with the signalling receptors of target cells.
  2. The exosomes fuse with the plasma membrane of the recipient cells and empty their contents into the cytoplasm of the cells.
  3. The exosomes are then internalized into the recipient cells and have 2 fates:
    • Either,  they merge with vesicles in the cells and undergo transcytosis, which will move exosomes across the recipient cells and release them into neighboring cells.
    • Or, the vesicles in the cells fuse with the engulfed exosomes and will mature into lysosomes and undergo degradation.
Exosomes can avoid issues related to the transfer of cells that already have damaged or mutated DNA. Exosomes can also be utilized to tackle toxicity and immunogenicity problems resulting from such biomaterial treatments as nanoparticles. And finally, most exosomes are small and can easily circulate through capillaries and cross the blood brain barrier.[1,4,5,6,7,8,11,12,13,14,15,16 ]

BLOOD BRAIN BARRIER

The blood-brain barrier (BBB) has been an obstacle for development of therapeutics for neurological disorders due to its highly selective permeability and thus preventing the passage of many potentially beneficial diagnostic and therapeutic agents to the brain. Exosomes may be able to overcome these problems because of their small size, which is why scientists have suggested using exosomes as a potential mode of transport across the BBB. [17] This mode of transfer using exosomes has been successfully demonstrated in preclinical research of Parkinson’s Disease.[12] Moreover, it was found that neurons and major types of glia release vesicles, which raises the possibility that extracellular vesicles such as exosomes commonly regulate communication in the CNS. This means that exosomes have the potential to treat neurodegenerative disorders.

DISEASES & CONDITIONS WHERE EXOSOMES CAN ASSIST:

WOUND HEALING [11,18,18,20]

Decreased angiogenesis leads to elevated cell death and shortage of wound nutritional supply, which contributes to the formation of chronic wounds. Exosomes mediate regenerative outcomes in injury and disease. Growth factors derived from MSCs can promote angiogenesis, cell migration, cell proliferation, and re-epithelialization. MSC-exosomes in wound environments can suppress the death of skin cells.

In combination with growth factors and MSCs, MSC-exosomes enhance proliferation and migration of fibroblasts and keratinocytes by mediating activation of several factors. They enhance wound healing and they also exhibit immunosuppressive effects by regulating proliferation and differentiation of lymphocytes. MSC-exosomes also exhibit angiogenic effects and they cause anti-vascular remodeling by suppressing HIMF. 

Exosomes derived from Mesenchymal  stem cells activate several signalling pathways associated with wound healing (Akt, ERK, STAT3) and they induce the expression of a number of growth factors (hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), nerve growth factor (NGF), and stromal-derived growth factor-1 (SDF1)).

In diabetic preclinical studies, exosomes secreted by human Mesenchymal stem cells involved in normal wound healing, exhibit in-vitro proangiogenic properties, activate diabetic dermal fibroblasts, induce the migration and proliferation of diabetic keratinocytes, and accelerate wound closure. Important components of the exosomal cargo were heat shock protein-90α, proangiogenic (miR-126, miR-130a, miR-132) miRNAs and anti-inflammatory (miR124a, miR-125b) miRNAs, and a miRNA regulating collagen deposition (miR-21). 

ISCHAEMIC STROKE AND CARDIOVASCULAR DISEASE [4,21,22,23,24,25]

Despite the advancements in acute stroke care and neurohabilitation, ischemic stroke remains the leading cause of long-term disability. Neuroprotection after ischemic stroke has become the major roadblock in stroke recovery. Several preclinical studies suggest that cell-based therapies are effective in improving post-stroke functional outcome

Treatment with exosomes overcomes the limitations associated with cell-based therapies and offer several advantages such as easy entry into the ischemic brain after their administration because of their lipophilicity, less or no immunogenicity and tumorigenicity and less incidence of occlusion in the microvasculature. Treatment with exosomes secreted from MSCs at appropriate experimental conditions attenuates the post-stroke brain damage and improves neurological outcome. 

Intravenous administration of exosomes can pass the blood-brain barrier and are taken up by endogenous brain cells. Exosomes contain microRNAs, mRNA, and proteins and they interact with target cells and transfer their RNA, miRNA and protein content by the endocytosis route, direct fusion with the plasma membrane and binding to target cells.

Exosomes communicate with endogenous brain cells and induce neurogenesis and white matter/axonal and vascular remodelling, as well as inhibit neuroinflammation, and thereby promoting neuroprotective or neurorestorative effects, as well as improving functional outcome after stroke.

Exosome treatment prevents the reduction in post-stroke body weight and actually can result in body weight gain, prevents post-stroke brain damage, facilitates recovery,  reduces the post-stroke somatosensory dysfunction and preserves motor function after ischemic stroke.  Treatment with MSCs obtained from the human umbilical cord improves survival, reduced brain damage, prevented apoptosis, suppressed inflammatory responses, downregulated the DNA damage-inducing genes, upregulated the DNA repair genes, and facilitated neurological recovery in stroke.

Stem cell-derived Exosomes  improve cardiovascular diseases largely due to their anti-inflammatory, anti-apoptotic effect and pro-angiogenic ability. A study showed that Exosomes obtained from MSCs promoted cardiac functional restoration by increasing angiogenesis, reducing infarct size, improving cardiac remodeling in vivo and enhancing VEGF expression and vessel formation.  Angiogenesis is a vital step of tissue repair because vessel support cells at the wound site with nutrition and oxygen.  MSC Exosomes improved cardiac systolic function by protecting myocardial cells from apoptosis and promoting angiogenesis.

TRAUMATIC BRAIN INJURY [26,27]

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide and no effective treatment has been identified from clinical trials. Compelling evidence exists that treatment with MSCs exerts a substantial therapeutic effect in preclinical studies.

In a proof-of-principle study, an intravenous delivery of MSC-derived exosomes was shown to improve functional recovery and to promote neuroplasticity.  Exosomes  do not replicate or induce microvascular embolisms and thus, they can be safely stored without losing function.

Exosome-based therapy for TBI as well as for stroke does not compromise efficacy associated with using complex therapeutic agents such as MSCs. For TBI, cells migrate into the lesion boundary and increase angiogenesis and expression of related neurotrophic factors in the lesion boundary zone. Post TBI, the administration of Exosomes from MSCs increased vascular density and angiogenesis.

Systematic administration of MSC-derived exosomes promote cerebral endothelial cell proliferation and also increase postischemic angiogenesis. 

NEURODEVELOPMENTAL DISORDERS
(AUTISM, CEREBRAL PALSY AND GLOBAL DEVELOPMENTAL DELAY) [28,29]

Neurodevelopmental disorders (NDD) are characterized by an abnormal development of the brain during early childhood development, leading to delayed milestones and deficits in personal and social functioning in addition to an array of other symptoms and diseases. 

The various potential causes of NDD are a nuanced combination of genetic defects, metabolic disorders, nutritional deficiencies, exposure to toxins, infections, hypoxia/asphyxia, low birth weight, perinatal complications or spinal cord injury in children.

MSC derived growth factors together with exosomes help in remyelination, synaptogenesis and angiogenesis, which can reverse cellular injury and assist the differentiation of MSCs into neuronal cells.

Recently, it has been shown through preclinical studies that treatment with exosomes derived from MSCs can result significant behavioral improvements in social interaction and reduced repetitive behavior.

ALZHEIMER’S DISEASE [9,32]

Alzheimer’s Disease (AD) is the most frequent form of dementia and is an age related neurodegenerative disease characterized by memory loss and cognitive decline. As the disease progresses, there is widespread loss of neurons and synaptic contacts throughout the Cortex, Hippocampus, Amygdala and basal Forebrain. Beta-amyloid plaques and neurofibrillary tangles are among the various pathologies of AD. There is an increased risk of developing AD with age, and the majority of AD cases are late onset, often developing after 65 years of age.

Recent evidence in preclinical research reveal that infusion of neuronal exosomes into the brain decrease generation and deposition of beta amyloid plaques. Intracerebrally administered exosomes can act as potent beta-amyloid scavengers by binding beta-amyloids on the exosome surface, suggesting a role for exosomes in beta-amyloid clearance.

Exosomes can also be used as biomarkers to predict AD development before clinical onset.  Several studies have suggested that exosomes derived from MSCs play a neuroprotective role by promoting functional recovery, neurovascular plasticity, and repairing injured tissue in TBI and neurodegenerative disorders like AD and PD.

PARKINSON’S DISEASE [30,31]

Parkinson’s Disease (PD) is a slowly progressing motor system neurodegeneration disease characterized by the following clinical manifestations: Akinesia, rigidity and resting tremor, muscular rigidity, postural instability and bradykinesia.  PD is the second most common neurodegenerative disease after Alzheimer’s Disease and affects  approximately 2% of the population aged over 65 years. At present, there is no cure for PD, and the goals of treatment are only to alleviate the symptoms for the comfort of patients.

The principal cause of PD is the death of dopaminergic cells in the substantia nigra of the brain. This leads to an imbalance of excitatory (Acetylcholine) and inhibitory (Dopamine) neurotransmitters, which causes the motor symptoms.

Other mechanisms that induce the degeneration of dopaminergic neurons  include Lewy bodies, reactive oxygen species, neuroinflammation, excitotoxicity, apoptosis, and loss of trophic factors. Molecular pathways often act synergistically to induce degeneration of dopaminergic neurons rather than a single cause. 

Biomarkers of PD have gained increasing attention, and the discovery of disease-related proteins in exosomes isolated from PD patients has inspired research into the use of exosomes as biomarkers. As naturally-occurring nano-sized vesicles, exosomes can cross the BBB and thus have attracted considerable attention as drug-delivery vehicles and they can assist in the differentiation of MSCs into dopaminergic neurons and also reduce and provide neuroprotection in PD by transferring DNA and RNA and proteins. 

REFERENCES

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