01 October 2016
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Established in 2011,  Stem Cell Research Center (SCRC), a 400-square-meter facility, is currently located in Tabriz University of Medical Sciences, Daneshgah St., Tabriz - Iran. Since its establishment, the center has tried to play a key role in efforts to establish a research framework for the discovery of novel approaches in stem cell lineage commitment, underlying mechanism, and fundamental biology as well as in the development of therapeutics to be used in the treatment of diseases. The center's broad expertise contributes to a greater understanding of fundamental biology of either adult or embryonic stem cells which lead to develop pre-clinical models of stem cell therapeutics. Our center targeted research includes embryonic, adult (including hematopoietic, neural, marrow- and tissue-derived), and cancer stem cells.  Some kind of diseases targeted for stem cell therapeutics include hematological disorders, cardiovascular diseases, angiogenesis-related pathologies, diabetes, neurodegenerative diseases, dental problems, and regenerative medicine. 12 Faculty members currently reside within the center.

 

 
 

Parkinson’s disease (PD) is considered as a high prevalence neurodegenerative disorders worldwide. Pathologically, the demise of dopamine-producing cells, in large part due to an abnormal accumulation of the α-synuclein in the substantia nigra, is one of the main causes of the disease. Up until now, many de novo investigations have been conducted to disclose the mechanisms underlying in PD. Among them, impacts of non-coding RNAs (ncRNAs) on the pathogenesis and/or progression of PD need to be highlighted. microRNAs (miRNAs) and long ncRNAs (lncRNAs) are more noteworthy in this context. miRNAs are small ncRNAs (with 18–25 nucleotide in length) that control the expression of multiple genes at post-transcriptional level, while lncRNAs have longer size (over 200 nucleotides) and are involved in some key biological processes through various mechanisms. Involvement of miRNAs has been well documented in the development of PD, particularly gene expression. Hence, in this current review, we will discuss the impacts of miRNAs in regulation of the expression of PD-related genes and the role of lncRNAs in the pathogenesis of PD.

Molecular Biology Reports pp 1–12


 
 
A reversal of age-dependent proliferative capacity of endothelial progenitor cells from different species origin in in vitro condition

Mehdi Hassanpour, Omid Cheraghi, Vahid Siavashi, Reza Rahbarghazi, Mohammad Nori

A large number of cardiovascular disorders and abnormalities, notably accelerated vascular deficiencies could be related to aging changes and increased length of life. During the past decades, the discovery of different stem cells facilitates ongoing attempts for attenuating many disorders, especially in vascular beds. Endothelial progenitor cells (EPCs) are a subtype of stem cells that have potent capacity to differentiate into mature endothelial cells (ECs). However , some documented studies reported an age-related decline in proliferation and function of many stem cells. There is no data on aging effect upon proliferation and morphological feature of EPCs .To show aging effect on EPCs proliferation and multipotentiality, bone marrow samples were provided from old and young cases in three different species; human, mouse and dog. After 7 days of culture, the cell morphology and clonogenic capacity were evaluated. We also calculated the mean number of colonies both in bone marrow samples from old and young subjects. To confirm the cell phenotype, isolated cells were immune-phenotyped by a panel of antibodies against Tie-2, CD133 and CD309 markers . Our results showed that EPCs exhibited prominent spindle form in all bone marrow samples from young cases while the cell shape became more round by aging. Notably, the number of colonies was reduced in aged samples as compared to parallel young subject samples (P < 0.05) . We also detected that the expression of endothelial related markers diminished by aging . The results of this study suggest that the age-related vascular abnormalities could be presumably related to the decline in stemness capacity of EPCs.                                                                                                                                                                                Available: Journal of Cardiovasc Thorac Res, 2016, 8

 
 

Potent anti-angiogenic and cytotoxic effect of conferone on human colorectal adenocarcinoma HT-29 cells

Cancer is one of the leading causes of death worldwide, both in developed and developing countries. Of note, colorectal adenoma encompasses a high rate of gastrointestinal-associated cancer death in human being. Today, different strategies, including surgery approaches, photodynamic therapy, radiation and particularly natural compounds have been extensively used to manage tumor behavior in human body . The objective of the present study was to elucidate the multilateral effect of conferone on HT-29 cell lines. In addition to cell cytotoxicity analysis, the extent of lipid peroxidation, MDA formation, catalase, superoxide dismutase and intracellular ROS levels, as markers of oxidative stress, were also studied. P-glycoprotein-mediated cellular efflux effectiveness, anti-angiogenic and finally anti-migratory capacities of conferone-exposed HT-29 cells were monitored over a course of 72 h . It was found that, conferone mediated cell proliferation arrest and induced cell death through both apoptosis and necrosis phenomena. HT-29 cells, exposed to 20 µM conferone, under gone oxidative stress and total content of reactive oxygen species was increased in a time-dependent manner. Intracellular accumulation of rhodamine 123 and cell's swelling under iso- and hypo-osmotic conditions could be related to P-glycoprotein incorrect performance in the presence of conferone. A significant reduction in CD31 positive cells population and in vitro tubulogenesis of endothelial cells was also observed after incubation with conditioned medium collected from 72 h conferone-treated HT-29 cells. Conferone also precluded angiogenesis capability of treated HT-29 cells through an altered secretome profile, including vascular endothelial growth factor, Angiopoietin-1 and -2 factors. In addition to anti-angiogenic properties of conferone, a profound decrease in migration capability of HT-29 cells was also evident.

Source: Omid Cheraghi et al. Phytomedicine 21 February 2016 

 
 
Morphine Inhibited the Rat Neural Stem Cell Proliferation Rate by Increasing Neuro Steroid Genesis.

In accordance to experimental work by Feizy et al. it was found that morphine exerts adverse effects on neural stem cells. They previously acclaimed that: 

Up to present, a large number of reports unveiled exacerbating effects of both long- and short-term administration of morphine, as a potent analgesic agent, on opium-addicted individuals and a plethora of cell kinetics, although contradictory effect of morphine on different cells have been introduced until yet. To address the potent modulatory effect of morphine on neural multipotent precursors with emphasis on endogenous sex-related neurosteroids biosynthesis, we primed the rat neural stem cells isolated from embryonic rat telencephalon to various concentrations of morphine including 10, 20, 50 and 100 µM alone or in combination with naloxone (100 µM) over period of 72 h. Flow cytometric Ki-67 expression and Annexin-V/PI based necrosis and apoptosis of exposed cells were evaluated. The total content of dihydrotestosterone and estradiol in cell supernatant was measured by ELISA. According on obtained data, both concentration- and time-dependent decrement of cell viability were orchestrated thorough down-regulation of ki-67 and simultaneous up-regulation of Annexin-V. On the other hand, the addition of naloxone (100 µM), as Mu opiate receptor antagonist, could blunt the morphine-induced adverse effects. It also well established that time-course exposure of rat neural stem cells with morphine potently could accelerate the endogenous dihydrotestosterone and estradiol biosynthesis. Interestingly, naloxone could consequently attenuate the enhanced neurosteriodogenesis time-dependently. It seems that our results discover a biochemical linkage between an accelerated synthesis of sex-related steroids and rat neural stem cells viability.

This research was further published on Journal of Neurochemical Research. 2016 Jan 30 



 
 

CD26+ Cord Blood Mononuclear Cells Significantly Produce B, T, and NK Cells.

ABSTRACT

Background: Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cell transplantation (HSCT), used in Leukemia treatment. CD26+ cells, a fraction of CD34+cells, are a major population of UCB cells which negatively regulate the in vivo homing and engraftment of HSCs. CD26 is highly expressed in various cells such as HSCs, immune cells, fibroblasts, and epithelial cells. It has been shown that the inhibition of the CD26 on CD34+ cells improves the efficiency of Hematopoietic Stem and Progenitor Cell (HPC) transplantation.

 Objective: To evaluate the relationship between the production of B, T, and NK cells from the CD26 positive fraction of cord blood mononuclear cells.

Methods: Cord blood mononuclear cells were cultured for 21 days using different combinations of stem cell factors (SCF), Flt3 ligand (FL), IL-2, IL- 7, and IL-15. The harvested cells were then analyzed by flowcytometry every week for 21 days.

 Results: T cell differentiation from CD26 subset of cord blood mononuclear cells increased by using IL-2 and IL-7. Our data showed that IL-2 and IL-7 significantly affected the generation of B cells from CD26+ cord blood mononuclear cells. On the other hand, NK (NKp46+) derived CD26+ cells increased by IL-15 and IL-2.

Conclusion: Taking all into account, we conclude that B, T, and NK cells can differentiate from the CD26+ subset of mononuclear cord blood cells by using key regulatory cytokines 

By: Dr. H. Nozad charoudeh

To see more please click following link

a_2ndiji_vol12_no1_2015.pdf

 
 ERK pathway and hepatocellular carcinoma complications

      Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer and the third cause of cancer related death all over the world. It goes without saying that hepatic-related cancers have become a big problem in individual's health so that approximately 500000 new cases are recognized annually worldwide. Furthermore, HCC is however recognized as one of the most chemo-resistant solid cancers. Recently, molecular targeted therapies are considered as new strategies for treatment of this invasive cancer and may be a good candidate for traditional chemotherapies.

      Among the enormous cellular pathways, ERK pathway couples the obtained signals from cell surface receptors with controlling gene expression transcriptional factors and regulates the activity of modulating proteins involved in proliferation, cell cycle and apoptosis process through central role of ERKs. ERK-related signaling proteins are a subfamily of serin-threonine kinases and contribute to activation of several members which among them ERK1 (MAPK3) and ERK2 (MAPK1) are mostly studied. These kinases are often up-regulated in human tumors and are considered as a new therapeutic target in cancer therapy. Over past decades, scientists deciphered the role of ERK1/2 pathway in cancer chemoresistance including HCC. Suppression of ERK1/2, which is central kinases of pathway, seems to be more logical. Methods for achieving this aim are under heavy studies. There are about 15 drugs approved by FDA as chemical inhibitors of ERK pathway but recommended compounds for ERK1/2 are not still clinically useful. Combination therapy of HCC through genetic and chemical inhibitors is a scope that seems to be more effect in comparison to traditional methods of HCC treatment

By: Dr. A. Mehdizaheh

 
 Autophagy as pro- or anti-death pathway

      The term Autophagy, originated from Greek defined as self-eating, as basic catabolic mechanism of cell, is an intracellular degradation process by selective and nonselective manners, in which cytoplasmic dysfunctional components including damaged organelles, defected proteins and invasive microbes are degraded and recycled through lysosome in mammalian or in form of vacuole in yeast. Following degradation process, the breakdown products are released back into the cytoplasm in order to recycle the macromolecular constituents and keep cell viability during stress conditions e.g. nutrient starvation by maintaining cellular energy levels. During this process, targeted cytoplasmic components are sequestered from the rest of the cell within a cup-shaped double-membraned vesicle known as an autophagosome. The outer layer of autophagosome then fuses with a lysosome and its cargo is degraded by lysosomal enzymes.

      Two key protein degradation and recycling pathways are defined in eukaryotic cells; the UPS (ubiquitin-proteosome system) and the autophagy –lysosome pathways. The UPS regulates levels of short-live proteins whereas autophagy is responsible for the degradation of long lived proteins and organelles. Up to present time, there three main types of autophagy accepted in underlying-related mechanisms that are described as following: macroautophagy, microautophagy and chaperone-mediated autophagy.

Macroautophagy (usually referred to autophagy) is characterized by double membrane vesicle around cytoplasmic cargos resulting in autophagosome formation which is induced by class 3 phosphoinositide-3-kinase (PI3K), Beclin-1 (also known Atg6) and ubiquitin-like conjugation reactions. Other autophagy-related proteins such as Atg4, Atg5, Atg12, and Atg16 are also involved in the regulation of autophagosome formation. In contrast to other types, macroautophagy allows the delivery of bulk of different cargo molecules into the lysosome to degrade by lysosomal acidic enzymes.

Microautophagy (lesser known self-eating) is the randomly engulfment of cytoplasmic materials and translocates them into the lysosome/vacuole for further degradation by either direct invagination, protrusion of the lysosomal or vacuolar membrane. The only cellular function that has been assigned to microautophagy is the turnover of peroxisomes under specific conditions in fungi.

Chaperone-mediated autophagy (CMA) is a very complex and specific process which has been characterized in higher eukaryotes but not usual in yeast. CMA targets only single proteins and a chaperone protein (heat shock protein; hsc70) binds to its cytosolic targets and unfolding of the protein eventually occurs which resulted in the CMA/chaperone complex forming. Further, the unfolded cytosolic target protein is subsequently translocated directly into the lysosome for its degradation.


Photo credit: Clin Sci (Lond). 2009 May; 116(9):697-712. doi: 10.1042/CS20080508.

In addition, autophagy plays a key role in adaptive responses in different forms cellular insults including stress, homeostasis, cellular differentiation and development. Under normal conditions, this process occurs at low levels to achieve housekeeping functions such as degradation of defected proteins or dysfunctional organelles. Moreover, in the presence of stress conditions e.g. starvation, oxidative stress, hormonal imbalance or removal of protein aggregated (as internal needs); the process of autophagy is up-regulated. In contrary, autophagy may also have essential role in stress-induced cell death. With regarding to critical role of autophagy pharmacological approaches represent a major challenge for clinicians to treat diseases in human pathology such as cardiovascular diseases, neurodegenerative disorders, nephropathies, cancers, and aging.

 

By: Dr. A. Rezabakhsh

 
 
Best article of Stem Cell and Regenerative Medicine was achieved by academic member of Stem Cell Research Center of Tabriz University of Medical Sciences on 4th of top article competition held by Iranian Council of Stem Cell Technology (ICST). This article focused on the application of marrow Mesenchymal Stem Cells (MSCs) in rabbit model of experimental infarction. In addition, authors explained the dynamic balance of pro-angiogenic factors after transplantation of MSCs into myocardial niche. The result of this article published on Internal Journal of Cardiology.



     Abstract:

Background: Cell-based pro-angiogenic therapy by bone marrow Mesenchymal stem cells (MSCs) has been touted as a means to reducing the adverse effects of cardiac remodeling after myocardial infarction (MI). Milieu-dependent regulation of pro-angiogenic potential of MSCs after infarction remains to be elucidated. In this study, the effects of marrow-derived MSCs on the kinetics of angiogenesis signaling factors were investigated in a rabbit model of MI.

Methods: MI was induced in rabbits, and the animals were randomized into two groups (cell transplantation and control, each group with 21 animals). 1 × 106 autologous marrow-derived MSCs were injected into the myocardium of the border zone after transfection with a green fluorescent protein (GFP) lentiviral reporter vector. Control animals received PBS vehicle only. Effect of the transplanted cells on the hearts was evaluated over time by pathological, immunofluorescence, western blotting, immuno-electron microscopy, and echocardiographic analyses.

Results: Transplanted GFP-positive MSCs were enriched with time in the peri-infarct border zone with differentiation potential into threemajor cell types of the heart, including cardiomyocytes, endothelial cells, and smooth muscle cells, and there was significant augmentation of microvascular density. The transplanted cells could change the milieu of the injured myocardium to increase the expression levels of VEGF as well as the ratio of Ang-2 to Ang-1, and to reduce the ratio of phosphorylated Tie2 to Tie2.

Conclusion: An angiogenesis-promoting milieu was induced after the transplantation of marrow MSCs in the injured myocardium. Compared with the resident cells, the transplanted cells had a greater rate of cellular kinetics in the infarcted myocardium.

 

To see more please click following link

Int Cardio J.pdf


 
 Galnt-11 as new signaling pathway in cellular mechanisms

Glycosylation or addition of sugar chains to protein is a highly conserved form of protein modifications cellular metabolism. There are two major abundant and well-known forms of glycosylation that occur on the many proteins; N-linked and mucin-type O-linked. Mucin-type O- glycosylation is a conserved protein modification present on membrane-bound and secreted proteins.  One of the most important molecular alterations in cancer cells is the aberrant expression of antigens resulting from an incomplete O-glycosylation. It was well-established that an abnormal Mucin-type O-glycan associated with cancer and several human disorders is Tn-antigen.  This glycan has a simple structure composed of N-acetyl-d-galactosamine with a glycosidic α linkage to Serine/Threonine residues in glycoproteins. This type of glycosylation is initiated with a large family of enzymes called UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferases (GALNTs) in mammals. Each member of the family is capable of catalyzing the addition of GalNAc to the hydroxyl group of Serines or Threonines in protein substrate. There are 20 ppGalNAc-Ts in humans that all family members are type II- transmembrane proteins that have a short N-terminal cytoplasmic tail and a hydrophobic region that spans the Golgi membrane, and a conserved catalytic region that lies within the Golgi lumen. In addition, in vitro studies have demonstrated that certain members of this family have unique protein substrate preferences as well as specific sites of GalNAc addition within those substrates. The following scheme illustrates mucin-type O-glycan biosynthesis:

  In one of the recent studies the expression of 14 GALNT genes were analyzed in normal and cancerous B and C lymphocytes of either in patients with AML or CLL. In conclusion, it was found that GALNT11 was expressed in Jukart, T and CLL cells while little or no expression was found in normal B and Daudi cells. Conclusively, GALNT11 enzyme is presumably introduced as a new marker in Chronic Lymphocytic Leukemia. It reasonable to focus about the possible role of this enzyme during maturation of hematopoietic stem cell into end stage cells like lymphocyte.


1.       Gene. 2014 Jan 1; 533(1):270-9. doi: 10.1016/j.gene.2013.09.052. Epub 2013 Sep 27.

2.       Angew Chem Int Ed Engl. 2011 Feb 18; 50(8):1770-91.

3.       Mucin-type O-glycosylation during development." Journal of Biological Chemistry 288.10 (2013).

 

                                                                                                                                                                                            By: Sh. Mozaffari

 
 

Cancer Stem Cell Hypothesis, History and its Implications

In the cancer stem cell model of tumors, there is a small subset of cancer cells, the cancer stem cells, which establish a reservoir of self-sustaining cells with the exclusive ability to self-renew and maintain the tumor. These cancer stem cells have the capacity to both divide and expand the cancer stem cell pool and to differentiate into the heterogeneous non-tumorigenic cancer cell types that in most cases appear to constitute the bulk of the cancer cells within different tumors. Cancer stem cells were initially isolated from blood cancers and were first identified using Tritium-labeling studies by John Dick et al. in acute myeloid leukemia in the late 1990s. They showed the existence of a subset of primitive-appearing cells with cycling properties different from the majority of tumor cells. These early tritium-labeling studies, coupled with genetic studies suggesting that much leukemia contained an immature cell population capable of generating post-mitotic progeny, predicted the existence of a leukemic stem cell. The definition of a cancer stem cell is a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. Cancer stem cells are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients, especially for patients with metastatic disease.

 

Cancer Stem cell specific and conventional cancer therapies (A); (Peter Znamenskiy May 30, 2006). Cancer stem cells (grey) self-renew and differentiate within tumors to form additional cancer stem cells as well as non-tumorigenic cancer cells (orange), which have limited proliferative potential. As the tumor grows, these cells can either undergo limited benign growth or form disseminated malignancies. Therapies that kill, induce differentiation or prevent the metastasis of cancer stem cells represent potential cures. Therapies that kill primarily non-tumorigenic cancer cells can shrink tumors, but will not cure the patient because the cancer stem cells will regenerate the tumor. (Ricardo Pardal, Michael F. Clarke & Sean J. Morrison Nature Reviews Cancer 3, 895-902 (December 2003)).

By: Dr. M. Mohammadi

 
 New publication

 

          Up to now, many efforts have been undertaken to relief the degenerative changes after injury or disease in different tissues especially in brain and spinal cord, i.e. central nervous system. Unlike the peripheral nerves, central nervous system neurons are restricted by physical and chemical conditions that prevent proper healing and restoration of function. The CNS is vital to bodily function, and malfunction of any section of it can profoundly and permanently alter a person’s quality of life. Tissue engineering, as new emerging method, could offer many adequate solutions to regenerate or replace damaged central nervous system tissue. This book will further discuss the current central nervous system tissue engineering approaches integrating scaffolds, cells and stimulation techniques. For example, hydrogels are commonly used in engineering scaffolds to stimulate and enhance regeneration and reconstitution and angiogenesis, but fiber meshes and other porous structures show specific utility depending on application. Central nervous system relevant cell sources have also focused on implantation of exogenous cells or stimulation of endogenous populations. Somatic cells of the central nervous system are rarely utilized for tissue engineering; however, glial cells of the peripheral nervous system may be alternatively used to myelinate and protect spinal cord damage. Pluripotent and multipotent stem cells also offer alternative cell sources due to continuing advancements in identification and differentiation of these cells. Finally, physical, chemical, and electrical guidance cues are extremely important to neural cells, serving important roles in development and adulthood. These guidance cues are being integrated into tissue engineering approaches. Of particular interest is the inclusion of cues to guide stem cells to differentiate into CNS cell types, as well to guide neuron targeting. This book was translated recently by a group of stem cell researchers to conducted Iranian students, researchers to better understanding of tissue engineering in central and peripheral nervous system.   

 
 Regulator mechanisms in adult neural stem cells and neurogenesis

Neural stem cells (NSCs), nestin and SOX2 positive populations, have capability to differentiate into neurons or glial cells such as astrocyte, oligodendrocyte, etc. These cells actively participate in neurogenesis a process in mammalian brain that result in proliferation, differentiation, migration and functional integration of new neurons in the brain neuronal circuitry. This phenomenon commonly takes place in two distinct regions of adult brain: subventricular zone (SVZ) of lateral ventricle and dentate gyrus (DG) of hippocampus. The neurogenesis is controlled by intrinsic and extrinsic factors which plays key role under normal or disease conditions. These endogenous extrinsic factors in microenvironment of neurogenic zones orchestrate “neurogenic niche” or “stem cell niche”. Various factors and intracellular signaling pathways provide microenvironment of neurogenic niche such as Wnt, sonic hedgehog, Notch, bone morphogenic proteins (BMPs), neurotrophins, and neurotransmitters. Recently intrinsic mechanisms such as transcription factors and epigenetic regulators have been shown for their role in adult neurogenesis regulation. Here we describe main regulators of neurogenesis.

Wnt-signaling intervenes in neuroblast proliferation and neuronal differentiation of hippocampal progenitor cells by beta-catenin pathway. Wnt signaling pathway increases neurogenesis in adult brain. Wnt signaling pathway has a prominent role in nervous system development. Notch maintains adult NSCs by retaining cell cycle. In this regard, inhibiting notch pathway causes differentiation of NSCs to neurons, which results in NSCs loss in niche finally. Notch signaling helps to niche characteristics and stemness to remain. Sonic hedgehog protein has an important role in NSCs proliferation in neurogenic areas. Inhibition of this pathway weaken proliferation on NSCs. Sonic hedgehog has a role in neuroblast migration. Four neurotrophic factors in mammals has been identified: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5). Generally BDNF and NT-3 does not affect NSCs proliferation. Also in previous studies NGF administration didn’t increase NSCs proliferation but it increases neuronal viability in DG of hippocampus. Prominent growth factors in adult brain include of Fibroblast growth factor-2 (FGF-2), Insulin-like growth factor-1 (IGF-1), and Vascular endothelial growth factor (VEGF). Mainly growth factors increase neurogensis in adult brain. They enhance glial differentiation and they restrain neuronal differentiation in neurogenic regions. BMPs are important for survive of migrating neuroblasts in rostral migratory stream (RMS). Glutamate increases cell proliferation in DG of hippocampus by its counter kainate and AMPA receptors. GABA inhibits neural progenitor cell proliferation so prepares a feedback mechanism. Also it inhibits neuroblast migration in RMS.   





A: Representative image of adult neural stem cell and differentiation capacity into oligodendrocytes (green) and astrocytes (red). Blue= nucleus (available in website; http://bobkleinpublicpolicyprofile.com/photos-of-stem-cells/. B: BMP signaling maintains neural stem cells in the hippocampus, in a quiescent state for required condition. Blue= cell nuclei, green= neural stem cells nuclei, red = radial stem cells (photo credit: Dr. Helena Mira, Carlos III Health Institute, Madrid).


                                                                                                                                                        By: Dr. M. H.  Geranmayeh

 
 Exosomes as emerging opportunities in stem cells therapeutic intervention

To date, it has been well established extracellular vesicles, as important mediators of intercellular communication, are released by nearly all mammalian cell types, especially stem cells. These vesicles harbor numerous biological signaling molecules such as proteins, lipids and nucleic acids. Exchanging information through the secretion of soluble factor in vesicles could affect neighboring or distant cells. Based on their biogenesis and cellular origin, three main classes of extracellular vesicles have been introduced until this moment; exosomes, microvesicles and apoptotic bodies. All of them are enclosed by a lipid bilayer and ranging from 30 nm to 2,000 nm in diameter.

ESCRT, endosomal sorting complex required for transport, MFGE8, milk fat globule-EGF factor 8 protein; PDCD6IP, programmed cell death 6 interacting protein (also known as ALIX); TSG101, tumour susceptibility gene 101 protein; TSPAN29, tetraspanin 29 (Samir EL Andaloussi et al., Nature Reviews Drug Discovery 2013 (12) 347-357).

 
Transmission electron micrograph of exosomes derived from human umbilical cord-mesenchymal stem cells (Tingfen et al., Stem Cell and Development 2013 (22) 845-854).

In addition, an alternative classification of extracellular vesicles has also been categorized on the basis of their biogenesis pathways. For example, Ectosomes (released by neutrophils or monocytes), Microparticles (shed from platelets in blood or endothelial cells), Tolerosomes (in serum of antigen-fed mice), Prostatosomes (in seminal fluid), Cardiosomes (cardiomyocytes-derived vesicles) and Vexosomes (adeno-associated virus vectors) have been elucidated. It is assumed that exosomes, as a member of extracellular vesicles, ranging from 40-100 nm, are a homogeneous population of vesicles of endocytic origin that formed by the inward budding of the multivesicular body (MVB) membrane. Many authorities also showed the existence of exosome in mesenchymal stem cells (MSCs) conditioned media. The positive expression of exosomal markers, such as CD9, CD63 and CD81 identified in MSC-derived exosomes. It was demonstrated that MSC-derived exosomes could alleviate collagen deposition and hepatic inflammation after exposure to hepatotoxic agents. The potency of MSC associate exosomes in amelioration of acute tubular injury, myocardial ischemia, and immune mediate disorders was determined previously. In this set of materials, some articles pointed that MSCs might perform their therapeutic roles through paracrine activity especially by exosomes. As a result, it seems that MSC-derived exosomes play a fundamental biological role in the regulation and mediating tissue regeneration under certain conditions. Increasing attempts will be made in the coming years to better understand their biology and function. 


 (Samir EL Andaloussi et al., Nature Reviews Drug Discovery 2013 (12) 347-357). 
                                                                                                                   
By: Dr. R. Rahbarghazi

 
 Endometrial Stem Cells

Recently, a small population of clonogenic endometrial stromal cells with typical adult stem cell properties of self renewal, high proliferative potential and multi-lineage mesodermal differentiation capacity was identified in human endometrium. These were defined as endometrial Stem Cells (EnSCs) that are positive for CD146 and w5c5 markers. The EnSCs can be easily obtained by uterine biopsy with access via the cervix or menstrual blood. In contrast, the procurement of bone marrow MSCs and adipose MSCs requires at least local anesthesia, while the endometrium is one source of human MSCs that does not require an anesthetic. The endometrium undergoes regular cycles of shedding and regeneration for up to 500 times during a woman’s reproductive years. The EnSCs were found in both reproductive age and postmenopausal women and in the endometrium of women on oral contraceptive therapy indicating that EnSCs can be harvested from women of all ages irrespective of hormonal status or treatments. The EnSCs are clonogenic and self-renew as demonstrated by serial cloning in culture. They are also highly proliferative, undergoing 30 population doublings with a total cellular output of several billion cells from a single cell, indicating their capacity for ex vivo expansion and potential utility in cell-based therapies. The EnSCs also differentiate into ectodermal and endodermal lineages, including neural cells in vitro and in vivo and insulin-producing cells in vitro, thus making them a possible source for use in neurodegenerative diseases, such as stroke, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, epilepsy, trauma and intoxications, and for treatment of diabetes.

                                                                                                                   By: Dr. S. Ebrahimi

Schematic representation showing isolation procedures for obtaining endometrial stem/progenitor cells from human uterus and menstrual blood. Photo credit: Ulrich D., et al., (EXPERT OPINION, 2013)

 
 Adult Neural Stem Cells (NSCs) in Central Nervous System

Stem cells niches throughout the postnatal body retain populations of multipotent cells into adulthood. In 1989, Sally Temple described multipotent, self-renewing progenitor and stem cells in the subventricular zone of the mouse brain. For the first time, Reynolds and Weiss were isolated and expanded cells as “neurosphers” from the CNS of adult and embryonic mice in the presence of epidermal growth factor (EGF). NSCs are generated throughout an adult's life via the process of neurogenesis. Two germinal regions within the adult mammalian brain have been shown to contain neural progenitor cells: subventricular zone (SVZ) of the lateral ventricles, the dentate gyrus (DG) of the hippocampus. Physiological neurogenesis in the DG takes place in the innermost region of the subgranular zone of the hippocampus, quickly becoming neurons with mature phenotype that incorporate into the granule layer. Cells from the SVZ naturally migrate along a track lined by astrocytes to the olfactory bulb where they differentiate into granule cells. EGF and basic fibroblast growth factor (bFGF) are mitogens that promote neural progenitor and stem cell growth in vitro, though other factors synthesized by the neural progenitor and stem cell populations are also required for optimal growth. SVZ-derived adult NSCs can be induced to differentiate into neurons and glial associate cells by a variety of factors including Insulin-like growth factor (IGF-I), Neural growth factor (NGF), Brain-derived neurotrophic factor  (BDNF), angiopoietin-1, cAMP, BMP-2, platelet derived growth factor (PDGF-AA), and the cytokine such as interferon gamma (IFN-γ) in in vitro models. The role of NSCs during diseases is now being elucidated by several research groups around the world. NSCs have shown promising results in preclinical regenerative medicine studies on traumatic brain injury, stroke, multiple sclerosis and Parkinson’s disease either in humans or animal models. The results of theses ongoing investigations may have future applications to treat human neurological diseases. The NSCs can contribute to adult neurogenesis when they are appropriately stimulated by its neurogenic environment, thus making them excellent tool in regenerative medicine.

                                                                                                                                                                     By: Dr. S. Ebrahimi

 
 Cellular reprogramming as a new approach in biomedicine studies

Recent attempts by different scientific groups have shed lights on human ability in changing cell phenotype. Cellular reprogramming refers to the conversion of one specific cell type to another via genetic manipulation. In recent years, many efforts have been taken to securitize the epigenetic and molecular changes during reprogramming process. Many authorities has focused on this recently provided technique to transform terminally differentiated or end-staged cells into pluripotent state entitled as induced pluripotent stem cells (iPSCs) that could give rise to the three germ layers especially by simultaneous overexpression of OSKM (Yamanaka factors) including Oct4, Sox2, Klf4, and c-Myc. Therefore, both epigenetic and transcriptional changes immediately occur in cells which undergo reprogramming. Moreover, the reprogramming induction efficiency is confirmed by up-regulation of target proliferative genes and de-differentiation process as hallmarks of pluripotency. The programmed cells resemble embryonic stem cells respectively in morphology, antigen marker and gene expression. In spite of the tremendous achievements, low efficacy of reprogramming the cells, and the costs and time involved in their creation are some of the main obstacles for pluripotency induction. Overall, reprogramming approach opens a new door to patient specific therapeutic application.
                                                                                                                                                                                          By: Dr. R. Rahbarghazi   

 

The potency of iPSCs in clinical application.  Jiang, Z., Y. Han, et al. (Cellular & Molecular Immunology, 2014).
This
image is accessible on
http://www.nature.com/cmi/journal/v11/n1/fig_tab/cmi201362f2.html#figure-title

                                                                                                                                                               

 
 Cancer Stem Cells

Cancer stem cells (CSCs), presenting in a variety of different cancer types, constitute a tiny fraction of the total cells population within tumor masses. They possess stemness potency that enables them to give rise to all cell types within tumor parenchyma. It seems that CSCs are like stem cells counterparts and share many features, but in distorted way. In addition, self-renewal and differentiation into multiple cell types proposed presumably enable tumors to withstand the constant attack of the immune system. However, some authorities cast doubts over CSCs existence in all tumors. Today, a number of cell surface markers, for example CD133, CD44, CD24, and EpCAM, have been considered to isolate CSCs from different kinds of solid and hematological tumors. It is also thought that CSCs could enter epithelial-mesenchymal transition (EMT) which is crucial for metastasis and invasion. Therefore, CSCs must be considered as a key point in ongoing cancer therapy and treatment. Many authorities announced that CSCs like their normal counterparts, stem cell, are resistant to routine chemotherapeutic agents. A slow rate of cell turnover, pumping out drugs and DNA repair associate proteins are tools that make these cells became different from other cancer derived cells. On the whole, by deciphering CSCs identity and providing directed therapies against them, it would be presumably possible to control the metastasis and relapse of many malignant tumors in future.

                                                                                                                                                       By: Dr. R. Rahbarghazi 

 
 Stem Cells and Angiogenesis

Cell transplantation is one of the most promising approaches for tissue regeneration and engineering. Angiogenesis or new-capillary formation is underlying process especially in recently-formed tissues. Over decades, many efforts have been made to maintain vascularization in appropriate level to regulate the growth of manipulated tissues. Recent studies have also brought new insight into stem cells role and their importance in biomedical and tissue engineered-based studies. In addition to trans-differentiation capacity of stem cells to different lineages, paracrine activity for angiogenesis induction either via micro-vesicles or exosomes, in addition to stem cell-derived endothelial and smooth muscle cell differentiation, has been determined. Interestingly, it is worthy to notify that both anti- and pro-angiogenic properties of stem cells obtained by many authorities, for example stem cell-derived angiogenesis induction on infarcted areas or angiogenesis inhibition on cornea. Understanding and revealing the different aspects of the underlying mechanisms at molecular level, which are driven by stem cells, will shed lights into angiogenesis pathways and help us to consider as much related phenomena as possible during the development of new methods for angiogenesis-oriented therapy. Endothelial cells are at the center of attention during angiogenesis and thereby stem- endothelial cell interactions seem to be pivotal. However, there is a controversy on the mechanistic basis of stem cell-derived effects on endothelial cell. So, many scientists and especially Umbilical Cord Stem Cell Research Center (UCSCRC) in accordance with other research institutes are seeking to unveil the kinetics of angiogenesis signaling molecules and their cognate receptors are involved in angiogenesis molecular process after cell transplantation.

Stem cells have ability to secret soluble factors that could induce or inhibit angiogenesis in in vitro models (courtesy by Dr. R. Rahbarghazi).

 
  The application of transgenic animals in stem cells studies

 After emergence of first transgenic mouse in 1982, a wide variety of transgenic animals with specific traits have been created due to breakthroughs in molecular biology. Since then, genetically modified or transgenic animal models are playing a more important role in the discovery and development of biomedical research and disease treatments. Some examples of these are: silk-producing goats, sheep with more wool, milkier cows, healthier pigs, Glofish, Umbuku lizard, and Dolion. In addition, different models of transgenic animals on behalf of human medicine, including cancers types, Down syndrome, Alzheimer’s disease, Huntington’s disease, and many other diseases are more widely used at current experiment. In spite of ethical issues surrounding transgenesis, some pros of transgenic animals however include role in the creation of a new medicines, recombinant protein therapeutics, and benefit from transgenic animals in people with sickle cell anemia.

   DNA microinjection, retrovirus-mediated gene transfer and embryonic stem cell-mediated gene transfer are three basic methods of producing the transgenic animals. In DNA Microinjection, desired genes construct either a single gene or a combination of genes that are recombined and then cloned transfer into pronucleus of a reproductive cell. Prior to transfer to the recipient female, the manipulated cells culture in vitro to reach a specific embryonic phase. The second method is retrovirus-mediated gene transfer used as vectors to transfer genetic material into the host cell. Finally, embryonic stem cell-mediated gene transfer includes isolation of totipotent stem cells from embryos and after injection of desired DNA and incorporation into the host’s embryo it results chimeric animal.

   Today, green fluorescent protein (GFP) and mCherry (RFP) transgenic animals have been extensively used for cell marking especially in for organ transplantation research. The mice and rats are superior model of experimental animals for daily use. These proteins could be easily detected without requirement to chemical substrate for visualization. Thereby cells marked with GFP protein can be detected easily and are considered to be useful for a migration, differentiation, and viability studies after cell transplantation to recipient. In the set of this material, it appears that transgenic animals, especially laboratory animals tagged with fluorescent proteins are widely used in future stem cell-based therapy studies.
 

Image in website address; http://news.nationalgeographic.com/news/2009/05/photogalleries/glowing-animal-pictures/