The prospective role of mesenchymal stem cells exosomes on circumvallate taste buds in induced Alzheimer’s disease of ovariectomized albino rats: (Light and transmission electron microscopic study)
Introduction
Taste buds are intra-epithelial structures scattered on the dorsal surface of the mammalian tongue (fungiform, circumvallate, and foliate papillae), in addition to the oral side of the soft palate, and oropharyngeal areas (Chandrashekar, Hoon, Ryba, & Zuker, 2006; Kobayashi et al., 2005). The taste buds are controlled by the cranial nerves (VII, IX, X, XI) via the thalamus (Suto et al., 2014).
Mammalian taste buds consist of different populations of mature, elongated cells that are classified into three main types; (type I, II and III), beside basal cells (type IV). The elongated cell possesses a bipolar shape that fill the entire epithelium thickness. It has an apical process that extends into an opening in the epithelium surface (taste pore) and has also a basal process that reaches the basal lamina (Chaudhari & Roper, 2010; Finger, 2005).
Each type of cells has an exclusive function. Type I cells are supporting cells that surround other elongated cells (Bartel, Sullivan, Lavoie, Sevigny, & Finger, 2006; Zimmermann, Zebisch, & Strater, 2012). Type II (receptor) cells are responsible for sweet, bitter and umami tastes. They express metabotropic taste receptor proteins coupled with G-protein (G-protein-coupled receptors) which are required to perform their transduction function (Chandrashekar et al., 2006; Clapp, Yang, Stoick, Kinnamon, & Kinnamon, 2004). Type III (synaptic) cells express the channels responsible for the transduction of different taste sensations mainly sour and possibly salty taste (Huang, Maruyama, Stimac, & Roper, 2008; Kataoka et al., 2008). Type IV (basal) cells are proliferative cells that can differentiate into the previously mentioned types of mature cells. The basal cells appear as round or ovoid shaped cells resting on the base of the taste buds (Chaudhari & Roper, 2010; Finger, 2005).
Disturbance in taste sensation “related to aging, diseases or drugs side effects” defiantly affects the life’s quality as aberrations in taste homeostasis influence food intake which leads to anorexia, malnutrition and therefore weight loss (Cohn, Kim, Huang, Brand, & Wang, 2010; Shin et al., 2012).
Failure to recognize different tastes warns of clinical symptoms of several neurodegenerative and neuropsychiatric diseases that require immediate intervention (Huttenbrink, Hummel, Berg, Gasser, & Hahner, 2013; Stamps, Bartoshuk, & Heilman, 2013).
Alzheimer’s disease is one of age-related diseases. It is considered as a common chronic progressive neurodegenerative disorder that leads to deficiency of perception-related functions due to selective loss of neurons in the central nervous system (Anand, Gill, & Mahdi, 2014; Bossy-Wetzel, Schwarzenbacher, & Lipton, 2004). Moreover, it was reported that Alzheimer’s disease is one of neurological diseases that are associated with taste dysfunction and disturbance of different taste perception (sweet, salt, bitter and sour) (Epstein, Smutzer, & Doty, 2016).
95% of Alzheimer’s disease suffering people are aged 65 or older (late-onset, or sporadic), while the remaining 5% are developed before age 65 due to genetic mutations (early onset, non-sporadic, or familial), (Holtzman, Morris, & Goate, 2011). It was found that constant exposure to aluminum leads to pathogenesis of Alzheimer’s disease (Zaky, Mohammad, Moftah, Kandeel, & Bassiouny, 2013).
Patients with mild to moderate degree of Alzheimer’s disease depend on drugs that treat only the symptoms or assist in maintaining the symptoms from getting worse for a restricted time (Beheshti & Aghaie, 2016). However, the used drugs are linked with many side effects such as bradycardia, agitation, confusion, dyspepsia, increased sweating, and tremors (Birks & Flicker, 2006).
Recently it was proved that, the exosomes derived from mesenchymal stem cells have the ability to regenerate the functions of many tissues through their paracrine effect by secretion of growth factors, cytokines, or chemokines (Nakamura et al., 2015; Sabin & Kikyo, 2014).
Exosomes are released by almost all eukaryotic cells (Kosaka et al., 2010; Yanez-Mo, Siljander, & Andreu, 2015). The expression “exosomes” refers to intraluminal vesicles of multivesicular bodies produced by reverse budding of endosomal membrane. Intraluminal vesicles are secreted upon fusion of multivesicular bodies with the plasma membrane (van Niel, D’Angelo, & Raposo, 2018).
The exosomes exerted their functions through fusion with the target cell and release of active small molecules like messenger-RNA, micro-RNA, lipids and proteins from their cell of origin into the membranes and cytosol of the target cell. This consequently stimulates the surface receptors and thus regulates the target cell (Valadi et al., 2007; Yanez-Mo et al., 2015).
From the preceding facts, this study was conducted in an attempt to explain the histological changes in circumvallate taste buds that occurs in Alzheimer’s disease and the potential effect of exosomes obtained from bone marrow mesenchymal stem cells (BM-MSCs) on such changes.
Section snippets
Isolation and culture of BM-MSCs
BM-MSCs were obtained from four male albino rats 10 weeks old at the Biochemistry and Microbiology Unit, Faculty of Medicine, Cairo University.
Bone marrow was flushed out from tibias of the rats using phosphate buffered saline (GIBCO™/Invitrogen, Grand Island, New York, USA) then centrifuged at 1000 rpm for 5 min. The upper layer was discarded leaving mononuclear cell layer which was washed in phosphate buffered saline twice then centrifuged at 200 × g for 10 min at 10 °C. The isolated BM-MSCs
Group I (Control)
Histological examination of Group I showed the characteristic inverted cone shape of circumvallate papilla. It was marked out by a deep furrow or trench. The papilla was covered by apparently thin stratified squamous epithelium with noticeable regular thin keratin layer. On its lateral surface, the epithelium lining the furrow contained obviously numerous taste buds. The papilla consisted of a central core of connective tissue “the lamina propria” with numerous secondary papillae projecting
Discussion
Alzheimer’s disease is neurodegenerative disorder characterized by microglia-triggered inflammation, over activation of glutamate receptors, increased intracellular calcium levels, production of nitric oxide species, release of free radicals, mitochondrial dysfunction and synaptic dysfunction (Bossy-Wetzel et al., 2004). Development of dysgeusia is mediated by activation of inflammatory pathways that disturbs the homeostasis of the taste buds (Wang, Zhou, Brand, & Huang, 2009). MSC-derived
Conclusions
Alzheimer’s disease has degenerative effects on circumvallate taste buds and the gustatory nerve fibers. BM-MSC-derived exosomes have the ability to improve the destructive changes in the taste buds and their innervations induced by Alzheimer’s disease.
Ethical Approval
This research follows the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978)
Financial support
This research did not receive any specific grant from funding agencies.
Declaration of Competing Interest
None declared.
References (81)
- et al.
Therapeutics of Alzheimer’s disease past, present and future
Neuropharmacology
(2014) Oxidative damage as an early marker of Alzheimer’s disease and mild cognitive impairment
Neurobiology of Aging
(2005)- et al.
Treatment of neural injury with marrow stromal cells
The Lancet Neurology
(2002) - et al.
Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria
The Journal of Biological Chemistry
(2004) - et al.
Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis
The Journal of Biological Chemistry
(2004) - et al.
Secretory mechanisms and intercellular transfer of microRNAs in living cells
The Journal of Biological Chemistry
(2010) - et al.
Homing and restorative effects of bone marrow-derived mesenchymal stem cells on cisplatin injured ovaries in rats
Molecules and Cells
(2014) - et al.
Sex hormones and adult hippocampal neurogenesis: Regulation, implications, and potential mechanisms
Frontiers in Neuroendocrinology
(2016) - et al.
Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration
FEBS Letters
(2015) - et al.
Microvesicles as mediators of tissue regeneration
Translational Research
(2014)
A brief olfactory test for Alzheimer’s disease
Journal of the Neurological Sciences
Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2Dand 3D conditions improves functional recovery in rats after traumatic brain injury
Neurochemistry International
Synaptophysin as a probable component of neurotransmission occurring in taste receptor cells
Journal of Molecular Histology
A method for detecting abasic sites in living cells: Age-dependent changes in base excision repair
Proceedings of the National Academy of Sciences of the United States of America
Nucleoside triphosphate diphosphohydrolase-2 is the ecto-ATPase of type I cells in taste buds
The Journal of Comparative Neurology
The effects of ceftriaxone on cue-primed reinstatement of cocaine-seeking in male and female rats: Estrous cycle effects on behavior and protein expression in the nucleus accumbens
Psychopharmacology (Berl.)
Therapeutic effect of frankincense in a rat model of Alzheimer’s disease
Avicenna Journal of Phytomedicine
Donepezil for mild cognitive impairment
The Cochrane Database of Systematic Reviews
Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents
International Journal of Molecular Sciences
Molecular pathways to neurodegeneration
Nature Medicine
Exosomes: A novel therapeutic target for Alzheimer’s disease?
Neural Regeneration Research
The receptors and cells for mammalian taste
Nature
The cell biology of taste
The Journal of Cell Biology
Mesenchymal stem cells deliver exogenous miR-21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration
Journal of Cellular and Molecular Medicine
Morphologic characterization of rat taste receptor cells that express components of the phospholipase C signaling pathway
The Journal of Comparative Neurology
Lipopolysaccharide induced inflammation attenuates taste progenitor cell proliferation and shortens the life span of taste bud cells
BMC Neuroscience
Exosome and microvesicle-enriched fractions isolated from mesenchymal stem cells by gradient separation showed different molecular signatures and functions on renal tubular epithelial cells
Stem Cell Reviews
Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression
Stem Cells Translational Medicine
Understanding the impact of taste changes in oncology care
Supportive Care in Cancer
Therapeutic potential of bone marrow-derived mesenchymal stem cells on experimental liver injury induced by Schistosoma mansoni: A histological Study
International Journal of Stem Cells
Cell types and lineages in taste buds
Chemical Senses
ATP signaling is crucial for communication from taste buds to gustatory nerves
Science
Cell biology of taste epithelium
Oligomeric amyloid decreases basal levels of brain-derived neurotrophic factor (BDNF) mRNA via specific downregulation of BDNF transcripts IV and V in differentiated human neuroblastoma cells
The Journal of Neuroscience
Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury
Nephrology Dialysis Transplantation
Effects of progesterone derivatives, dihydroprogesterone and tetrahydroprogesterone, on the subependymal layer of the adult rat
Journal of Neurobiology
Current trends in regenerative medicine: From cell to cell-free therapy
BioNanoScience
Preemptive analgesic effects of midazolam and diclofenac in rat model
Bosnian J. Basic Med. Sci.
Alzheimer disease in the United States (2010–2050) estimated using the 2010 census
Neurology
Alzheimer’s disease: The challenge of the second century
Science Translational Medicine
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