Search

Among different types of mechanisms involved in neurological disorders, neuroinflammation links initial insults to secondary injuries and triggers some chronic outcomes, for example, neurodegenerative disorders. Thus, anti‐inflammatory substances can be targeted as a novel therapeutic option for translational and clinical research to improve brain disease outcomes. In this review, we propose to introduce a new insight into the anti‐inflammatory effects of mesenchymal stem cells (MSCs) as the most frequent source for stem cell therapy in neurological diseases. Our insight incorporates a bystander effect of these stem cells in modulating inflammation and microglia/macrophage polarization through exosomes. Exosomes are nano‐sized membrane vesicles that carry cell‐specific constituents, including protein, lipid, DNA, and RNA. microRNAs (miRNAs) have recently been detected in exosomes that can be taken up by other cells and affect the behavior of recipient cells. In this article, we outline and highlight the potential use of exosomal miRNAs derived from MSCs for inflammatory pathways in the context of neurological disorders. Furthermore, we suggest that focusing on exosomal miRNAs derived from MSCs in the course of neuroinflammatory pathways in the future could reveal their functions for diverse neurological diseases, including brain injuries and neurodegenerative diseases. It is hoped that this study will contribute to a deep understanding of stem cell bystander effects through exosomal miRNAs. [ABSTRACT FROM AUTHOR]

The transplantation of mesenchymal stem cells (MSCs) is of main approaches in regenerative therapy for stroke. Due to the potential tumorigenicity and low survival rate of transplanted cells, focuses have been shifted from cell replacement to their paracrine effects. Therefore, stem cell‐conditioned medium (CM) therapy has emerged as an alternative candidate. Here, we investigated the effect of CM derived from human embryonic MSCs on experimental ischemic stroke. Wistar rats underwent ischemic stroke by the right middle cerebral artery occlusion (MCAO). CM was infused either one time (1 hr post‐MCAO) or three times (1, 24, and 48 hr post‐MCAO) through guide cannula into the left lateral ventricle. Neurological functions were evaluated using Bederson's test and modified Neurological Severity Score on Days 1, 3, and 7 following MCAO. Infarction volumes and cerebral edema were measured on Days 3 and 7. growth‐associated protein‐43, synaptophysin, cAMP response element‐binding protein, and phosphorylated‐cAMP response element‐binding protein levels were also assessed in peri‐ischemic cortical tissue on Day 7 postsurgery. Our results indicated that three times injections of CM could significantly reduce body weight loss, mortality rate, infarct volumes, cerebral edema, and improve neurological deficits in MCAO rats. Moreover, three injections of CM could restore decreased levels of synaptic markers in MCAO rats up to its normal levels observed in the sham group. Our data suggest that using the CM obtained from embryonic stem cells–MSCs could be a potent therapeutic approach to attenuate cerebral ischemia insults which may be partly mediated through modulation of synaptic plasticity. [ABSTRACT FROM AUTHOR]

Umbilical cord Wharton's jelly‐derived mesenchymal stem cells (WJ‐MSCs) have recently gained considerable attention in the field of regenerative medicine. Their high proliferation rate, differentiation ability into various cell lineages, easy collection procedure, immuno‐privileged status, nontumorigenic properties along with minor ethical issues make them an ideal approach for tissue repair. Besides, the number of WJ‐MSCs in the umbilical cord samples is high as compared to other sources. Because of these properties, WJ‐MSCs have rapidly advanced into clinical trials for the treatment of a wide range of disorders. Therefore, this paper summarized the current preclinical and clinical studies performed to investigate the regenerative potential of WJ‐MSCs in neural, myocardial, skin, liver, kidney, cartilage, bone, muscle, and other tissue injuries. [ABSTRACT FROM AUTHOR]

Placenta has attracted increasing attention over the past decade as a stem cell source for regenerative medicine. In particular, the amniochorionic membrane has been shown to harbor populations of mesenchymal stromal cells (MSCs). In this study, we have characterized ex vivo expanded MSCs from the human amniotic (hAMSCs) and chorionic (hCMSCs) membranes of human full-term placentas and adult bone marrow (hBMSCs). Our results show that hAMSCs, hCMSCs, and hBMSCs express typical mesenchymal (CD73, CD90, CD105, CD44, CD146, CD166) and pluripotent (Oct-4, Sox2, Nanog, Lin28, and Klf4) markers but not hematopoietic markers (CD45, CD34). Ex vivo expanded hAMSCs were found to be of fetal origin, while hCMSCs cultures contained only maternal cells. Cell proliferation was significantly higher in hCMSCs, compared to hAMSCs and hBMSCs. Integrin profiling revealed marked differences in the expression of α subunits between the three cell sources. Cadherin receptors were consistently expressed on a subset of progenitors (ranging from 1% to 60%), while N-CAM (CD56) was only expressed in hAMSCs and hCMSCs but not in hBMSCs. When induced to differentiate, hAMSCs and hCMSCs displayed strong chondrogenic and osteogenic differentiation potential but very limited capacity for adipogenic conversion. In contrast, hBMSCs showed strong differentiation potential along the three lineages. These results illustrate how MSCs from different ontological sources display differential expression of cell-fate mediators and mesodermal differentiation capacity. J. Cell. Physiol. 227: 3234-3242, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Human placenta is an attractive source of mesenchymal stem cells (MSC) for regenerative medicine. The cell surface markers expressed on MSC have been proposed as useful tools for the isolation of MSC from other cell populations. However, the correlation between the expression of MSC markers and the ability to support tissue regeneration in vivo has not been well examined. Here, we established several MSC lines from human placenta and examined the expression of their cell surface markers and their ability to differentiate toward mesenchymal cell lineages. We found that the expression of CD349/frizzled-9, a receptor for Wnt ligands, was positive in placenta-derived MSC. So, we isolated CD349-negative and -positive fractions from an MSC line and examined how successfully cell engraftment repaired fractured bone and recovered blood flow in ischemic regions using mouse models. CD349-negative and -positive cells displayed a similar expression pattern of cell surface markers and facilitated the repair of fractured bone in transplantation experiments in mice. Interestingly, CD349-negative, but not CD349-positive cells, showed significant effects on recovering blood flow following vascular occlusion. We found that induction of PDGFβ and bFGF mRNAs by hypoxia was greater in CD349-negative cells than in CD349-positive cells while the expression of VEGF was not significantly different in CD349-negative and CD349-positive cells. These findings suggest the possibility that CD349 could be utilized as a specialized marker for MSC isolation for re-endothelialization. J. Cell. Physiol. 226: 224-235, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy is an X-linked recessive genetic disease characterized by severe skeletal muscular degeneration. The placenta is considered to be a promising candidate cell source for cellular therapeutics because it contains a large number of cells and heterogenous cell populations with myogenic potentials. We analyzed the myogenic potential of cells obtained from six parts of the placenta, that is, umbilical cord, amniotic epithelium, amniotic mesoderm, chorionic plate, villous chorion, and decidua basalis. In vitro cells derived from amniotic mesoderm, chorionic plate, and villous chorion efficiently transdifferentiate into myotubes. In addition, in vivo implantation of placenta-derived cells into dystrophic muscles of immunodeficient mdx mice restored sarcolemmal expression of human dystrophin. Differential contribution to myogenesis in this study may be attributed to placental portion-dependent default cell state. Molecular taxonomic characterization of placenta-derived maternal and fetal cells in vitro will help determine the feasibility of cell-based therapy. J. Cell. Physiol. 223:695–702, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Erythroblast cell differentiation involves self-controlled and limited nuclear proteolysis prior nucleus loss. Early evidence suggests that apoptotic-like pathways are activated during this process. The chromatin of developing erythroblasts becomes fragmented in vivo, however, the exact mechanisms and molecules involved remain elusive. In this study, erythroblasts were differentiated in culture from CD34-enriched umbilical cord blood progenitor cells and the characteristics of DNA fragmentation were examined. This analysis shows that the chromatin of differentiating erythroblasts is cleaved into discrete fragments of 50–200 kb. This process most likely involves one or several endonucleases as we detect in vivo double strand DNA cleavage. However, major players of the apoptotic DNA degradation, caspase activated DNase and apoptosis inducing factor, are not activated in these cells. Therefore, our data suggests that erythroblast chromatin degradation may involve enzymes distinct form those active in apoptotic cells. J. Cell. Physiol. 213: 490–494, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Myostatin, a secreted growth factor, is a member of the TGF-β superfamily and an inhibitor of myogenesis. Previously, we have shown that myostatin gene expression is regulated at the level of transcription and that myostatin is a downstream target gene of MyoD. Here we show that myostatin gene expression is auto-regulated by a negative feedback mechanism. Northern blot analysis indicated that there are relatively higher levels of myostatin mRNA in the biceps femoris muscle of cattle that express a non- functional myostatin allele (Belgian Blue) as compared to normal cattle. In contrast, addition of exogenous myostatin decreases endogenous myostatin mRNA. Consistent with this result, wild type myostatin protein is able to repress myostatin promoter activity via Activin type IIb receptor (ActRIIB) and ALK5 (P < 0.001). However, non-functional myostatin (Piedmontese) failed to repress the myostatin promoter suggesting that myostatin auto-regulates its promoter by negative feedback inhibition. Auto-regulation by myostatin appears to be signaled through Smad7, since the expression of the inhibitory Smad7 is induced by myostatin and the over-expression of Smad7 in turn inhibits the myostatin promoter activity (P < 0.001). In contrast down regulation of Smad7 by siRNA results in increased myostatin mRNA indicating that Smad7 is a negative regulator of myostatin gene expression. Consistent with these results, a decrease in Smad7 mRNA and concomitant increase in myostatin expression is seen in myotubes that express non functional myostatin. In addition, interference with myostatin signaling prevents the induction of Smad7 promoter activity by myostatin. Based on these results, we propose that myostatin auto-regulates its gene expression through a Smad7 dependent mechanism in myogenic cells. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Both transforming growth factor (TGF-β) and growth and development factor (GDF)-8 (myostatin) affect muscle differentiation by suppressing proliferation and differentiation of myogenic cells. In contrast, insulin-like growth factors (IGFs) stimulate both proliferation and differentiation of myogenic cells. In vivo, IGFs are found in association with a family of high-affinity insulin-like growth factor binding proteins (IGFBP 1-6) that affect their biological activity. Treatment of porcine embryonic myogenic cell (PEMC) cultures with either TGF-β1 or GDF-8 suppressed proliferation and increased production of IGFBP-3 protein and mRNA (P<0.005). An anti-IGFBP-3 antibody that neutralizes the biological activity of IGFBP-3 reduced the ability of either TGF-β1 or GDF-8 to suppress PEMC proliferation (P<0.005). However, this antibody did not affect proliferation rate in the presence of both TGFβ1 and GDF-8. These data show that IGFBP-3 plays a role in mediating the activity of either TGF-β1 or GDF-8 alone but not when both TGF-β1 and GDF-8 are present. In contrast to findings in T47D breast cancer cells, treatment of PEMC cultures with IGFBP-3 did not result in increased levels of phosphosmad-2. Since TGF-β and GDF-8 are believed to play a significant role in regulating proliferation and differentiation of myogenic cells, our current data showing that IGFBP-3 plays a role in mediating the activity of these growth factors in muscle cell cultures strongly suggest that IGFBP-3 also may be involved in regulating these processes in myogenic cells. [ABSTRACT FROM AUTHOR]