Three-Dimensional Spheroid-Cultured Mesenchymal Stem Cells Devoid of Embolism Attenuate Brain Stroke Injury After Intra-Arterial Injection

Guo, Ling; Ge, Jianfeng; Zhou, Ying; Wang, Shan; Zhao, Robert C.H.; Wu, Yaojiong

doi:10.1089/scd.2013.0338

Cited by 51 publications

(56 citation statements)

References 39 publications

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“…As a result, the size of MSCs significantly reduced (Fig. A, B), consistent with our earlier findings . Measurements of the diameter of single MSCs derived from the spheroids at different times showed that the cell size decreased progressively in the first 36 hours of hanging drop culture (Fig.…”

Section: Resultssupporting

confidence: 91%

Three-Dimensional Culture Reduces Cell Size By Increasing Vesicle Excretion

Zhou

et al. 2017

Stem Cells

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Our previous study has shown that three-dimensional (3D) culture decreases mesenchymal stem cell (MSC) size, leading to enhanced trafficking ability and reduced lung vascular obstructions. However, the underlying mechanisms are unclear. In this study, we proposed that 3D culture reduces MSC size by increasing vesicle excretion. Scanning electron microscope showed that 3D culture markedly increased the amount of membrane-bound vesicles on the cell surface. In consistence, tunable resistive pulse sensing quantifying analysis of vesicles in the culture medium indicated that there were higher levels of vesicles in the 3D culture MSC medium. 3D culture significantly lowered the level of actin polymerization (F-actin), suggestive of lowering actin skeleton tension may facilitate vesicle excretion. Indeed, treatment of MSCs with Cytochalasin D or functional blockade of integrin β1 caused increased vesicle secretion and decreased cell sizes. Thus, our results suggest that 3D culture reduces MSC size by increasing vesicle excretion which is likely mediated by lowering cytoskeleton tension. Stem Cells 2018;36:286-292.

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Section: Resultssupporting

confidence: 91%

Three-Dimensional Culture Reduces Cell Size By Increasing Vesicle Excretion

Zhou

et al. 2017

Stem Cells

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“…Our findings were supported by a previous study, where suspension culture was able to maintain the low expression level of integrin a5 in a CD45 2 /integrin a5 low bone marrow MSC subpopulation, whereas adherent culture quickly upregulated the expression of integrin a5 [30]. Interestingly, in our previous studies, we found that 2-3 days of 3D spheroid culture dramatically reduced the vascular obstruction of MSCs that had been culture expanded in monolayers for several passages [22]. In this study, we found that 3D spheroid culture substantially reduced the surface protein and mRNA expressions of most integrins analyzed; importantly, spheroid culture profoundly decreased the level of activated integrin b1 in MSCs.…”

Section: Discussionsupporting

confidence: 91%

Excess Integrins Cause Lung Entrapment of Mesenchymal Stem Cells

Wang

Guo

et al. 2015

Stem Cells

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Mesenchymal stem cells (MSCs) are largely entrapped in the lungs after intravenous delivery. The underlying mechanisms have been poorly understood. Flow cytometry and Western blot analysis showed that the expression levels of many integrins such as b1, a5, and aVb3 in MSCs increased markedly upon cultured expansion in 2D monolayers, whose ligands fibronectin and vitronectin were detected on the surface of vascular endothelial cells in the lungs by immunostaining and flow cytometry. Blockade of integrin b1, integrin a5, or integrins aVb3 with functional blocking antibodies significantly decreased the amount of MSCs entrapped in the lungs following intravenous infusion as determined by real-time PCR and histological analysis; meanwhile, corresponding increases in the levels of circulating MSCs in the blood and MSCs homed to the ischemic myocardium and inflamed ear were found. Intriguingly, a short period of 3D spheroid culture of MSCs, which had been expanded for several passages in monolayers, substantially reduced the expression levels of many integrins and the number of MSCs entrapped in the lungs. Our results indicate that the excess expression and activation of integrins is a significant cause of lung entrapment of MSCs. STEM CELLS 2015;33:3315-3326 SIGNIFICANCE STATEMENTMesenchymal stem cells (MSCs) have shown profound therapeutic potential in tissue repair=regeneration, and intravenous infusion has been a popular translation route of the cells for its convenience and safety. However, recent studies indicate that MSCs are largely entrapped in lungs after intravenous delivery and die shortly. The underlying mechanisms have been poorly understood. In this study, we provide evidence to show that excess expression and activation of integrins in MSCs that are developed during conventional monolayer culture is a critical cause of MSC entrapment in the lungs. Our study suggests a novel approach to increase MSC homing and engraftment to sites of tissue injuries by reducing the ECM binding activity of surface integrins.

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“…However, one possible explanation may relate to the size of cells that were injected into the bone cavity. A recent study evaluating the therapeutic potential of human placenta-derived mesenchymal stem cells (hMSCs) in ischemic stroke, demonstrated high incidences of embolism and neurological abnormalities following the intra-carotid injection of hMSCs previously cultured as monolayers [38]. By contrast, the injection of hMSC suspensions derived from 3-D microtissue spheroids, led to a subsequent improvement in neurological function with no reports of vascular obstruction.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic potential of adipose-derived stromal cells in age-related osteoporosis

et al. 2014

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a b s t r a c tAdipose-derived stromal cells (ASCs) are increasingly being used for orthopedic-based tissue engineering approaches due to their ability to readily undergo osteogenic differentiation. In the present study, we used in vitro and in vivo approaches to evaluate the use of ASCs as a treatment strategy for age-related osteoporosis. Molecular, histological and micro-computed tomography (micro-CT) based approaches confirmed that ASCs isolated from 18-week-old osteoporotic senescence-accelerated mice (SAMP6) were capable of undergoing osteogenesis when cultured in either silk fibroin (SF) scaffolds or scaffold-free microtissues (ASC-MT). A single intratibial injection of CM-Dil-labeled isogeneic ASCs or ASC-MT into SAMP6 recipients significantly improved trabecular bone quality after 6 weeks in comparison to untreated contralateral bones, as determined by micro-CT. Injected ASCs could be observed in paraffin wax bone sections at 24 h and 6 weeks post treatment and induced a significant increase in several molecular markers of bone turnover. Furthermore, a significant improvement in the osteogenic potential of osteoporotic patient-derived human bone marrow stromal cells (BMSCs) was observed when differentiated in conditioned culture media harvested from osteoporotic patient-derived human ASCs. These findings therefore support the use of ASCs as an autologous cell-based approach for the treatment of osteoporosis.

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Three-Dimensional Spheroid-Cultured Mesenchymal Stem Cells Devoid of Embolism Attenuate Brain Stroke Injury After Intra-Arterial Injection

Cited by 51 publications

References 39 publications

Three-Dimensional Culture Reduces Cell Size By Increasing Vesicle Excretion

Three-Dimensional Culture Reduces Cell Size By Increasing Vesicle Excretion

Excess Integrins Cause Lung Entrapment of Mesenchymal Stem Cells

Therapeutic potential of adipose-derived stromal cells in age-related osteoporosis

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