Intrathecal delivery of human ESC-derived mesenchymal stem cell spheres promotes recovery of a primate EAE model
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PROVIDER: PRJNA419161 | ENA |
REPOSITORIES: ENA
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Intrathecal delivery of human ESC-derived mesenchymal stem cell spheres promotes recovery of a primate multiple sclerosis model.
Yan Li L Jiang Bin B Niu Yuyu Y Wang Hongxuan H Li Enqin E Yan Yaping Y Sun Huiyan H Duan Yanchao Y Chang Shaohui S Chen Guokai G Ji Weizhi W Xu Ren-He RH Si Wei W
Cell death discovery 20180820
Nonhuman primate experimental autoimmune encephalomyelitis (EAE) is a valuable model for multiple sclerosis, an inflammatory demyelinating disease in the central nervous system (CNS). Human embryonic stem cell-derived mesenchymal stem cells (EMSC) are effective in treating murine EAE. Yet, it remains unknown whether the EMSC efficacy is translatable to humans. Here we induced a primate EAE model in cynomolgus monkeys and delivered EMSC in spheres (EMSCsp) to preserve the cell viability during lo ...[more]
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Project description:Nonhuman primate experimental autoimmune encephalomyelitis (EAE) is a valuable model for multiple sclerosis an inflammatory demyelinating disease in the central nervous system (CNS). Human embryonic stem cell-derived mesenchymal stem cells (EMSC) are effective in treating murine EAE. Yet, it remains unknown whether the EMSC efficacy is translatable to humans. Here we induced a primate EAE model in cynomolgus monkeys and transported EMSC in spheres (EMSCsp) to preserve the cell viability under ambient conditions. First, single cells dissociated from EMSCsp were intravenously infused into normal and EAE monkeys. The cells reached various organs including CNS but diminished rapidly. To increase the number and viability of EMSC in the CNS, we injected EMSCsp intrathecally (i.t.) into the subarachnoid cavity of EAE monkeys multiple times post-onset and upon relapses during a 3-month observation. The clinical symptoms in these animals relieved rapidly following the injections and eventually disappeared. Whereas, symptoms in a vehicle control-injected EAE monkey remained and reduced slowly. Consistently, reduced lesions and active regeneration were found in the CNS of the EMSCsp-treated monkeys compared to the control. EMSC were found in the CNS long after the i.t. injections and some of the cells had differentiated into neurons and oligodendrocytes. Supporting evidence demonstrated that EMSCsp cultured in cerebrospinal fluid from the EAE monkeys largely converted to neural cells with elevated expression of genes for neuronal markers, neurotropic factors, and neuronal myelination. Together, this study suggests that i.t. injection of ambiently transported EMSCsp can treat EAE in nonhuman primates via remyelination and transdifferentiation, which shall expedite the clinical application of EMSC in patients. Overall design: This study for the first time demonstrates that EMSCsp, following ambient transportation, can be delivered directly via i.t. injection into the subarachnoid cavity of the spinal cord, and promote recovery in a NHP model of EAE. Spheroidal formation and i.t. injection may both enhance the cell number and survival of EMSC in the CNS, compared to peripheral administration of dissociated EMSC. Transdifferentiation of EMSC into neurons and oligodendrocytes as well as neural trophic effects of the transplanted cells may contribute to the efficacy of the cells as schemed in Fig. 7. Ideally more monkeys and EMSC lines could have been used to further verify the conclusions if the costs had not been so high. Nevertheless, the present study has extended our understanding of EMSC efficacy in the EAE models from mice to primates, and shall facilitate the translation of this potential cell therapy to humans.
2018-08-30 | GSE107145 | GEO
Project description:Nonhuman primate experimental autoimmune encephalomyelitis (EAE) is a valuable model for multiple sclerosis, an inflammatory demyelinating disease in the central nervous system (CNS). Human embryonic stem cell-derived mesenchymal stem cells (EMSC) are effective in treating murine EAE. Yet, it remains unknown whether the EMSC efficacy is translatable to humans. Here we induced a primate EAE model in cynomolgus monkeys and delivered EMSC in spheres (EMSCsp) to preserve the cell viability during long-distance transportation. EMSCsp intrathecally injected into the CNS, remarkably reduced the clinical symptoms, brain lesions, and neuronal demyelination in the EAE monkeys during a 3-month observation. Whereas, symptoms in the vehicle control-injected EAE monkey remained and reduced slowly and MRI lesions in brain expanded. Moreover, EMSC could transdifferentiate into neural cells in vivo in the CNS of the treated animals. Supporting evidence demonstrated that EMSCsp cells cultured in cerebrospinal fluid from the EAE monkeys largely converted to neural cells with elevated expression of genes for neuronal markers, neurotrophic factors, and neuronal myelination. Thus, this study demonstrates that EMSCsp injected directly into the CNS, can attenuate the disease progression in the primate EAE model, highly encouraging for clinical translation.
| S-EPMC6102276 | BioStudies
Project description:Calcium bisphosphonate/calcium polyacrylate spheres were synthesized by a facile method and applied for the first time as gene vectors for transfection. The colloidal spheres of the PAA-Ca2+-H2O complex, formed by sodium polyacrylate and calcium ions in the solution, were used as template to synthesize a spherical PAA-Ca2+-BPMP composite (CaBPMP/CaPAA) in the presence of 1,4-bis(phosphomethyl)piperazine (BPMP). The CaBPMP/CaPAA composite exhibits uniform and well-dispersed spheres with a particle size of about 200 nm as expected. The cytotoxicity assays confirm that CaBPMP/CaPAA spheres are quite safe for different cells even at a high concentration of 500 ?g/mL. In vitro transfection results show that CaBPMP/CaPAA spheres serving as gene vectors are capable of transferring exogenous genes into different cells with about 25% of transfection efficiency and good reproducibility. The transfection capacity of CaBPMP/CaPAA spheres may be attributed to the controllable sphere morphology, low cytotoxicity, moderate DNA loading capacity, and bioresorbable property. The application of calcium phosphonates with adjustable surface properties derived from the different organic groups of phosphonic acid in gene delivery provides a new design idea for gene vectors.
| S-EPMC6044815 | BioStudies
Project description:Current therapies for multiple sclerosis (MS) are largely palliative, not curative. Mesenchymal stem cells (MSCs) harbor regenerative and immunosuppressive functions, indicating a potential therapy for MS, yet the variability and low potency of MSCs from adult sources hinder their therapeutic potential. MSCs derived from human embryonic stem cells (hES-MSCs) may be better suited for clinical treatment of MS because of their unlimited and stable supply. Here, we show that hES-MSCs significantly reduce clinical symptoms and prevent neuronal demyelination in a mouse experimental autoimmune encephalitis (EAE) model of MS, and that the EAE disease-modifying effect of hES-MSCs is significantly greater than that of human bone-marrow-derived MSCs (BM-MSCs). Our evidence also suggests that increased IL-6 expression by BM-MSCs contributes to the reduced anti-EAE therapeutic activity of these cells. A distinct ability to extravasate and migrate into inflamed CNS tissues may also be associated with the robust therapeutic effects of hES-MSCs on EAE.
| S-EPMC4110787 | BioStudies
Project description:The Drosophila esc-like gene (escl) encodes a protein very similar to ESC. Like ESC, ESCL binds directly to the E(Z) histone methyltransferase via its WD region. In contrast to ESC, which is present at highest levels during embryogenesis and low levels thereafter, ESCL is continuously present throughout development and in adults. ESC/E(Z) complexes are present at high levels mainly during embryogenesis but ESCL/E(Z) complexes are found throughout development. While depletion of either ESCL or ESC by RNAi in S2 and Kc cells has little effect on E(Z)-mediated methylation of histone H3 lysine 27 (H3K27), simultaneous depletion of ESCL and ESC results in loss of di- and trimethyl-H3K27, indicating that either ESC or ESCL is necessary and sufficient for di- and trimethylation of H3K27 in vivo. While E(Z) complexes in S2 cells contain predominantly ESC, in ESC-depleted S2 cells, ESCL levels rise dramatically and ESCL replaces ESC in E(Z) complexes. A mutation in escl that produces very little protein is viable and exhibits no phenotypes but strongly enhances esc mutant phenotypes, suggesting they have similar functions. esc escl double homozygotes die at the end of the larval period, indicating that the well-known "maternal rescue" of esc homozygotes requires ESCL. Furthermore, maternal and zygotic over-expression of escl fully rescues the lethality of esc null mutant embryos that contain no ESC protein, indicating that ESCL can substitute fully for ESC in vivo. These data thus indicate that ESC and ESCL play similar if not identical functions in E(Z) complexes in vivo. Despite this, when esc is expressed normally, escl appears to be entirely dispensable, at least for development into morphologically normal fertile adults. Furthermore, the larval lethality of esc escl double mutants, together with the lack of phenotypes in the escl mutant, further suggests that in wild-type (esc(+)) animals it is the post-embryonic expression of esc, not escl, that is important for development of normal adults. Thus escl appears to function in a backup capacity during development that becomes important only when normal esc expression is compromised.
| S-EPMC2266587 | BioStudies
Project description:Experimental autoimmune encephalomyelitis (EAE) is a well-characterized animal model of multiple sclerosis. During the early phase of EAE, infiltrating monocytes and monocyte-derived macrophages contribute to T cell recruitment, especially CD4+ T cells, into the CNS, resulting in neuronal demyelination; however, in later stages, they promote remyelination and recovery by removal of myelin debris by phagocytosis. Signal regulatory protein α and CD47 are abundantly expressed in the CNS, and deletion of either molecule is protective in myelin oligodendrocyte glycoprotein-induced EAE because of failed effector T cell expansion and trafficking. Here we report that treatment with the function blocking CD47 Ab Miap410 substantially reduced the infiltration of pathogenic immune cells but impaired recovery from paresis. The underlying mechanism was by blocking the emergence of CD11chiMHCIIhi microglia at peak disease that expressed receptors for phagocytosis, scavenging, and lipid catabolism, which mediated clearance of myelin debris and the transition of monocytes to macrophages in the CNS. In the recovery phase of EAE, Miap410 Ab-treated mice had worsening paresis with sustained inflammation and limited remyelination as compared with control Ab-treated mice. In summary, Ab blockade of CD47 impaired resolution of CNS inflammation, thus worsening EAE.
| S-EPMC8663579 | BioStudies
Project description:Integrating hollow silica spheres with metal nanoparticles to fabricate multifunctional hybrid materials has attracted increasing attention in catalysis, detection, and drug delivery. Here, we report a simple and general method to prepare hollow silica spheres encapsulating silver nanoparticles (Ag@SiO2) based on spherical polyelectrolyte brushes (SPB), which consist of a polystyrene core and densely grafted poly (acrylic acid) (PAA) chains. SPB were firstly used as nanoreactors to generate silver nanoparticles in situ and then used as sacrificial templates to prepare hybrid hollow silica spheres. The resulted Ag@SiO2 composites exhibit high catalytic activity and good reusability for the reduction of 4-nitrophenol to 4-aminophenol by NaBH4. More importantly, this developed approach can be extended to the encapsulation of other metal nanoparticles such as gold nanoparticles into the hollow silica spheres. This work demonstrates that SPB are promising candidates for the preparation of hollow spheres with encapsulated metal nanoparticles and the resulted hybrid spheres show great potential applications in catalysis.
| S-EPMC7221898 | BioStudies
Project description:Genetic opticospinal EAE (OSE) and MOG-induced EAE (MOG-EAE) are two experimental autoimmune encephalomyelitis (EAE) mouse models of human multiple sclerosis. For the OSE model, double-transgenic 2D2 (TCRMOG) x IgHMOG mice were used. For MOG-EAE, wildtype C57BL/6 mice were immunized with a MOG peptide consisting of the amino acids 35-55, administered in complete Freund’s adjuvant containing 5mg / ml Mycobacterium tuberculosi. The severity of EAE was rated on the scale 0: healthy animal; 1: animal with a flaccid tail; [...]; 4: animal with both hind legs paralyzed. The case groups in the experiment were: OSE1: OSE with disease score 1; OSE4: OSE with disease score 4; MOG4: MOG-EAE injected with both MOG and adjuvant, with disease score 4. The control groups in the experiment were: OSE0: OSE with disease score 0; CFA: C57BL/6 mice injected only with adjuvant (no MOG); WT: Wildtype C57BL/6 mice. The aim of the experiment was to assess gene expression differences 1) between OSE4 and OSE0, 2) between OSE1 and OSE0, and 3) between MOG4 and CFA. For control, WT was compared to OSE0 and CFA. Subsequently, differentially expressed transcripts were compared, first, between the OSE4 vs. OSE0 and the MOG4 vs. CFA contrasts (different EAE models) and, second, between the OSE4 vs. OSE0 and the OSE1 vs. OSE0 contrasts (different EAE severity).
| E-MTAB-9132 | BioStudies
Project description:Plasmacytoid dendritic cells (pDCs) exhibit both innate and adaptive functions. In particular they are the main source of type I IFNs and directly impact T cell responses through antigen presentation. We have previously demonstrated that during experimental autoimmune encephalomyelitis (EAE) initiation, myelin-antigen presentation by pDCs is associated with suppressive Treg development and results in attenuated EAE. Here, we show that pDCs transferred during acute disease phase confer recovery from EAE. Clinical improvement is associated with migration of injected pDCs into inflamed CNS and is dependent on the subsequent and selective chemerin-mediated recruitment of endogenous pDCs to the CNS. The protective effect requires pDC pre-loading with myelin antigen, and is associated with the modulation of CNS-infiltrating pDC phenotype and inhibition of CNS encephalitogenic T cells. This study may pave the way for novel pDC-based cell therapies in autoimmune diseases, aiming at specifically modulating pathogenic cells that induce and sustain autoimmune inflammation.
2016-01-01 | S-EPMC4758828 | BioStudies
Project description:Mesoporous silica nanoparticles (MSNs) have been widely studied as drug delivery systems in nanomedicine. Surface coating of MSNs have enabled them to perform efficiently in terms of bioavailability, biocompatibility, therapeutic efficacy and targeting capability. Recent studies have suggested the use of polydopamine (PDA) as a facilitative coating for MSNs that provides sustained and pH-responsive drug release, owing to the adhesive "molecular-glue" function of PDA. This further endows these hybrid MSN@PDA particles with the ability to carry large amounts of hydrophilic drugs. In this study, we expand the feasibility of this platform in terms of exploring its ability to also deliver hydrophobic drugs, as well as investigate the effect of particle shape on intracellular delivery of both a hydrophilic and hydrophobic anticancer drug. MSN@PDA loaded with doxorubicin (hydrophilic) and fingolimod (hydrophobic) was studied via a systematic in vitro approach (cellular internalization, intracellular drug distribution and cytotoxicity). To promote the cellular uptake of the MSN@PDA particles, they were further coated with a polyethylene imine (PEI)-polyethylene glycol (PEG) copolymer. Drug-loaded, copolymer-coated MSN@PDA showed effective cellular uptake, intracellular release and an amplified cytotoxic effect with both doxorubicin and fingolimod. Additionally, rods exhibited delayed intracellular drug release and superior intracellular uptake compared to spheres. Hence, the study provides an example of how the choice and design of drug delivery systems can be tuned by the need for performance, and confirms the PDA coating of MSNs as a useful drug delivery platform beyond hydrophilic drugs.
| S-EPMC6679059 | BioStudies