Abstract WP139: Intranasal Administration of Mesenchymal Stem Cell (MSC)-Derived Exosomes Confers Acute Neuroprotection After Neonatal Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Praneeti Pathipati ◽  
Joel Faustino ◽  
Matthieu Lecuyer ◽  
Jacqueline Strivelli ◽  
Donald Phinney ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Intranasal Administration ◽  
Therapeutic Option ◽  
Cell Types ◽  
Artery Occlusion ◽  
Neonatal Stroke ◽  
Beneficial Effects ◽  
The Status

Background: Brain injury caused by stroke is a surprisingly common occurrence in neonates and is associated with significant long-term disabilities. We and others have shown delayed mesenchymal stem cell (MSC)-based therapy to be beneficial after neonatal stroke. Mounting evidence suggests MSC-derived soluble factors as key mediators of their neuroprotective/regenerative effects. We wanted to test whether Exosomes (Exo) derived from MSC carry beneficial effects after neonatal stroke. Objectives: Characterize effects of intranasal administration of MSC-derived Exo after neonatal stroke. Methods: MSCs enriched from the bone marrow of C57Bl6 mice (immuno-depletion) were cultured for 3 days in Exo-free FBS and confirmed by flow cytometry to be CD44 + /CD29 + and CD11b - /CD45 - . Exo were isolated (ExoQuick, SBI), their size distribution determined (NanoSight™), and Exo labeled with CellVue® before intranasal administration. Postnatal day 9 (P9) mice were subjected to a 3h middle cerebral artery occlusion (tMCAO), Exo (5ug, 1uL in PBS) administered into the nostril ipsilateral to injury, and injury volume and cell types that uptake Exo determined. Results: By 24h after administration, labelled Exo were visible ipsilateral along the lateral ventricle, in the SVZ, corpus callosum and in the penumbra, localized largely to Glut1 + -vessels and Iba1 + -microglia (MG). By 72h, labeled Exo were predominantly localized in Iba1 + -MG peri-infarct. Very few Exo were seen contralateral. Compared to vehicle/untreated mice, intranasal Exo significantly reduced injury volume at 72h (p<0.01, n=5). Preliminary in vitro experiments using MG isolated from acutely injured neonatal brain (CD11b-conjugated beads) confirmed significantly higher Exo uptake by MG from the ipsilateral Vs. contralateral cortex (p<0.05, n=2). Summary: We demonstrate that MSC-Exo exert short-term protection against neonatal stroke and that the magnitude of Exo uptake depends on the status of MG activation after injury. We are characterizing longer-term effects of MSC-Exo on stroke outcome to further explore potential for intranasal MSC-Exo as a clinically suitable therapeutic option for neonatal stroke. Funding: CPA PG0816 (ZV); AHA Innovation Award 17IRG33430004 (ZV); R01HL139685 (ZV)

scholarly journals Human Heart Explant-Derived Extracellular Vesicles: Characterization and Effects on the In Vitro Recellularization of Decellularized Heart Valves

2019 ◽  
Vol 20 (6) ◽  
pp. 1279 ◽  
Author(s):  
Amanda Leitolis ◽  
Paula Suss ◽  
João Roderjan ◽  
Addeli Angulski ◽  
Francisco da Costa ◽  
...  
Keyword(s):  
Wound Healing ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Extracellular Vesicles ◽  
Tissue Regeneration ◽  
Human Heart ◽  
Heart Valves ◽  
Enrichment Analysis ◽  
Cell Types

Extracellular vesicles (EVs) are particles released from different cell types and represent key components of paracrine secretion. Accumulating evidence supports the beneficial effects of EVs for tissue regeneration. In this study, discarded human heart tissues were used to isolate human heart-derived extracellular vesicles (hH-EVs). We used nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) to physically characterize hH-EVs and mass spectrometry (MS) to profile the protein content in these particles. The MS analysis identified a total of 1248 proteins. Gene ontology (GO) enrichment analysis in hH-EVs revealed the proteins involved in processes, such as the regulation of cell death and response to wounding. The potential of hH-EVs to induce proliferation, adhesion, angiogenesis and wound healing was investigated in vitro. Our findings demonstrate that hH-EVs have the potential to induce proliferation and angiogenesis in endothelial cells, improve wound healing and reduce mesenchymal stem-cell adhesion. Last, we showed that hH-EVs were able to significantly promote mesenchymal stem-cell recellularization of decellularized porcine heart valve leaflets. Altogether our data confirmed that hH-EVs modulate cellular processes, shedding light on the potential of these particles for tissue regeneration and for scaffold recellularization.

scholarly journals Mesenchymal stem cell derived exosomes enhance lymphangiogenesis via exosomal transfer of Ang-2/Tie2

2018 ◽  
Author(s):  
Ting Zhao ◽  
Zhixin Yan ◽  
Jinwen Liu ◽  
Hui Sun ◽  
Yifei Chen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Lymphatic Vessels ◽  
Tube Formation ◽  
Experimental Models ◽  
Organ Injury ◽  
Human Umbilical Cord ◽  
Beneficial Effects ◽  
Membrane Bound

AbstractMesenchymal stem cell derived exosomes (MSC-Ex) are nanosized membrane-bound extracellular vesicles found in MSC conditioned medium, that have yielded beneficial effects in several experimental models of organ injury. However, the therapeutic value and mechanism of MSC-Ex in lymphedema is poorly understood. Here we find that human umbilical cord MSCs derived exosomes (hucMSC-Ex) treatment contributed to the regeneration of LYVE-1 positive lymphatic vessels and reduction of lymphedema in a mouse model of tail lymphedema. Following uptake, exosomal lymphangiogenic factors (angiopoietin (Ang)-2 and Tie2) are taken up by HDLECs and promoted HDLECs proliferation, migration, and tube formation in vitro. We also find that exosomal Ang-2 and Tie2 exert a prolymphangiogenic effect on HDLECs through upregulating Prox1 and VEGFR3/p-Akt expression. In conclusion, our result unravel a previously unappreciated prolymphangiogenic role of hucMSC-Ex in lymphedema therapy and provide a new mechanism of Ang-2 in therapeutic lymphangiogenesis.

Abstract 17277: Myocardial Rescue by Mesenchymal Stem Cell via Tunneling Nanotube Formation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Huaxiao Yang ◽  
Raymond B Runyan ◽  
Tom K Borg ◽  
Roger Markwald ◽  
Meifeng Xu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Annexin V ◽  
Cell Types ◽  
Paracrine Factors ◽  
Vitro Assay ◽  
Mitochondrial Transfer ◽  
Tunneling Nanotube

Objectives: Mesenchymal stem cell (MSC) shows promising therapeutic potentials for heart diseases in numerous animal studies and clinical trials. The cardiogenic transdifferentiation and paracrine factors delivery of MSCs are generally accepted mechanisms for myocardial rescue. Recent studies suggest that the rescue may also be achieved by direct delivery of subcellular organelles such as mitochondria. Tunneling nanotube (TNT) formation between MSCs and various damaged cell types has been observed both in vitro and in vivo for assisting organelle transfer. Based on our recent observation in a cell patterning-based in vitro assay, it is found that mitochondria are transferred from MSCs to neonatal cardiomyocytes (NCMs) through TNTs to enhance myocyte survival. Adequate investigation of hetero-paired TNTs is hampered by their random formation in standard cell culture and the difficulty of capturing them in vivo. Accordingly, a PDMS (polydimethylsiloxane) biochip-based coculture model was microfabricated to enable more consistent examination of TNT formation and mitochondrial transfer. Methods: Rat MSC (GFP tagged in green) and 3-day NCMs (w or w/0 treatment of 1 μg/ml lipopolysaccharide (LPS)) were introduced into a two-channel microfluidics-based biochip (Figure 1A) microfabricated with PDMS, and TNTs were guided to form in microchannels between the two cell types. The numbers of TNT formed between MSC and LPS treated or untreated NCM were counted per biochip after 24 hours coculturing. Then the sample was stained with annexin V to evaluate the cardiac stress of NCMs. Results and Discussion: It was observed that mitochondria were transferred unidirectionally from MSCs to NCMs via TNT (Figure 1B), irrespective of the TNT’s direction of formation. NCMs in stressed conditions triggered more TNT formation in red of annexin V staining with MSCs than the control (Figure 1C). It suggests that a rescue effect may be produced by TNT-mediated mitochondrial transfer.

scholarly journals “Empowering” Cardiac Cells via Stem Cell Derived Mitochondrial Transplantation- Does Age Matter?

2021 ◽  
Vol 22 (4) ◽  
pp. 1824
Author(s):  
Matthias Mietsch ◽  
Rabea Hinkel
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Treatment Strategies ◽  
Cardiac Cells ◽  
Aging Effects ◽  
Beneficial Effects ◽  
Micro Rnas ◽  
New Treatment

With cardiovascular diseases affecting millions of patients, new treatment strategies are urgently needed. The use of stem cell based approaches has been investigated during the last decades and promising effects have been achieved. However, the beneficial effect of stem cells has been found to being partly due to paracrine functions by alterations of their microenvironment and so an interesting field of research, the “stem- less” approaches has emerged over the last years using or altering the microenvironment, for example, via deletion of senescent cells, application of micro RNAs or by modifying the cellular energy metabolism via targeting mitochondria. Using autologous muscle-derived mitochondria for transplantations into the affected tissues has resulted in promising reports of improvements of cardiac functions in vitro and in vivo. However, since the targeted treatment group represents mainly elderly or otherwise sick patients, it is unclear whether and to what extent autologous mitochondria would exert their beneficial effects in these cases. Stem cells might represent better sources for mitochondria and could enhance the effect of mitochondrial transplantations. Therefore in this review we aim to provide an overview on aging effects of stem cells and mitochondria which might be important for mitochondrial transplantation and to give an overview on the current state in this field together with considerations worthwhile for further investigations.

scholarly journals Uptake and Distribution of Administered Bone Marrow Mesenchymal Stem Cell Extracellular Vesicles in Retina

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 730
Author(s):  
Biji Mathew ◽  
Leianne A. Torres ◽  
Lorea Gamboa Gamboa Acha ◽  
Sophie Tran ◽  
Alice Liu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Extracellular Vesicles ◽  
Time Course ◽  
Ganglion Cells ◽  
Ex Vivo ◽  
Dependent Manner ◽  
Paracrine Effects

Cell replacement therapy using mesenchymal (MSC) and other stem cells has been evaluated for diabetic retinopathy and glaucoma. This approach has significant limitations, including few cells integrated, aberrant growth, and surgical complications. Mesenchymal Stem Cell Exosomes/Extracellular Vesicles (MSC EVs), which include exosomes and microvesicles, are an emerging alternative, promoting immunomodulation, repair, and regeneration by mediating MSC’s paracrine effects. For the clinical translation of EV therapy, it is important to determine the cellular destination and time course of EV uptake in the retina following administration. Here, we tested the cellular fate of EVs using in vivo rat retinas, ex vivo retinal explant, and primary retinal cells. Intravitreally administered fluorescent EVs were rapidly cleared from the vitreous. Retinal ganglion cells (RGCs) had maximal EV fluorescence at 14 days post administration, and microglia at 7 days. Both in vivo and in the explant model, most EVs were no deeper than the inner nuclear layer. Retinal astrocytes, microglia, and mixed neurons in vitro endocytosed EVs in a dose-dependent manner. Thus, our results indicate that intravitreal EVs are suited for the treatment of retinal diseases affecting the inner retina. Modification of the EV surface should be considered for maintaining EVs in the vitreous for prolonged delivery.

Biomaterials Nano Geometry for Control of Stem Cell Differentiation

2009 ◽  
Vol 1239 ◽  
Author(s):  
Karla Brammer ◽  
Seunghan Oh ◽  
Sungho Jin
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Stem Cell Differentiation ◽  
Human Mesenchymal Stem Cell ◽  
Oxide Surface ◽  
Specific Cell ◽  
Implant Surface ◽  
Multipotent Stem Cells

AbstractTwo important goals in stem cell research are to control the cell proliferation without differentiation, and also to direct the differentiation into a specific cell lineage when desired. Recent studies indicate that the nanostructures substantially influence the stem cell behavior. It is well known that mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into stromal lineages such as adipocyte, chondrocyte, fibroblast, myocyte, and osteoblast cell types. By examining the cellular behavior of MSCs cultured in vitro on nanostructures, some understanding of the effects that the nanostructures have on the stem cell’s response has been obtained. Here we demonstrate that TiO2 nanotubes produced by anodization on Ti implant surface can regulate human mesenchymal stem cell (hMSC) differentiation towards an osteoblast lineage in the absence of osteogenic inducing factors. Altering the dimensions of nanotubular-shaped titanium oxide surface structures independently allowed either augmented human mesenchymal stem cell (hMSC) adhesion at smaller diameter levels or a specific differentiation of hMSCs into osteoblasts using only the geometric cues. Small (˜30 nm diameter) nanotubes promoted adhesion without noticeable differentiation, while larger (˜70 - 100 nm diameter) nanotubes elicited a dramatic, ˜10 fold stem cell elongation, which induced cytoskeletal stress and selective differentiation into osteoblast-like cells, offering a promising nanotechnology-based route for novel orthopaedics-related hMSC treatments. The fact that a guided and preferential osteogenic differentiation of stem cells can be achieved using substrate nanotopography alone without using potentially toxic, differentiation-inducing chemical agents is significant, which can be useful for future development of novel and enhanced stem cell control and therapeutic implant development.

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