Intraluminal Injection of Mesenchymal Stromal Cells in Spheroids Attenuates Experimental Colitis

Molendijk, Ilse; Barnhoorn, Marieke C.; Jonge‐Muller, Eveline S. M. de; Mieremet-Ooms, Marij A C; Reijden, Johan J. van der; Helm, Danny van der; Hommes, Daniël W.; Jong, Andrea E. van der Meulen–de; Verspaget, Hein W.

doi:10.1093/ecco-jcc/jjw047

Cited by 23 publications

(23 citation statements)

References 54 publications

(61 reference statements)

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“…Several previous reports showed histopathological improvements particularly at the distal colon [ 33 , 49 ], which were not reproduced in our study, implying that the beneficial effects of TMSC injection on colitis may not be associated with improved histology. In some respects, however, our findings do agree with the most recent study, which showed that direct intraluminal injection with murine BM-MSC spheroids did not significantly decrease mucosal lesions in the distal colon or endoscopy score, although it significantly alleviated DSS-induced colitis, as evidenced by body weight and DAI scores [ 35 ]. Furthermore, our current data also reproduce those from human IBD; clinical remission by definition cannot be solely explained by histopathological remission, as evidenced in one clinical study showing that most of patients with IBD exhibited mucosal inflammation despite clinical remission [ 50 ].…”

Section: Discussionsupporting

confidence: 91%

“…Although injection with TMSC[x2] also exhibited some advantages, in this study, injection with TMSC[x4] yielded statistically greater therapeutic effects based on several assays. This dose-dependent increase in therapeutic effects of TMSC on colitis are largely consistent with results from a previous study using murine BM-MSC in an experimental murine colitis model [ 35 ]. However, at the beginning of this study, injection with a double dose of TMSC (i.e., 2 x 10 6 cells) twice did not increase the effect of TMSC on DAI scores compared to a single dose (i.e., 1 x 10 6 TMSC) twice ( S1 Fig ).…”

Section: Discussionsupporting

confidence: 90%

“…A previous study reported that intraperitoneally injected MSC form aggregates [ 36 ]. In this regard, one recent study demonstrated that in vitro three-dimensional (3D) spheroid culture of murine BM-MSC enhanced the efficiency of MSC to attenuate experimental colitis [ 35 ]. Based on these results, it is now anticipated that constructing TMSC spheroids may increase their beneficial effects on colitis.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic potential of tonsil-derived mesenchymal stem cells in dextran sulfate sodium-induced experimental murine colitis

Song

Lee

et al. 2017

PLoS ONE

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The therapeutic potential of tonsil-derived mesenchymal stem cells (TMSC) prepared from human tonsillar tissue has been studied in animal models for several diseases such as hepatic injury, hypoparathyroidism, diabetes and muscle dystrophy. In this study, we examined the therapeutic effects of TMSC in a dextran sulfate sodium (DSS)-induced colitis model. TMSC were injected in DSS-induced colitis mice via intraperitoneal injection twice (TMSC[x2]) or four times (TMSC[x4]). Control mice were injected with either phosphate-buffered saline or human embryonic kidney 293 cells. Body weight, stool condition and disease activity index (DAI) were examined daily. Colon length, histologic grading, and mRNA expression of pro-inflammatory cytokines, interleukin 1β (IL-1β), IL-6, IL-17 and tumor necrosis factor α, and anti-inflammatory cytokines, IL-10, IL-11 and IL-13, were also measured. Our results showed a significant improvement in survival rates and body weight gain in colitis mice injected with TMSC[x2] or TMSC[x4]. Injection with TMSC also significantly decreased DAI scores throughout the experimental period; at the end of experiment, almost complete reversal of DAI scores to normal was found in colitis mice treated with TMSC[x4]. Colon length was also significantly recovered in colitis mice treated with TMSC[x4]. However, histopathological alterations induced by DSS treatment were not apparently improved by injection with TMSC. Finally, treatment with TMSC[x4] significantly reversed the mRNA levels of IL-1β and IL-6, although expression of all pro-inflammatory cytokines tested was induced in colitis mice. Under our experimental conditions, however, no apparent alterations in the mRNA levels of all the anti-inflammatory cytokines tested were found. In conclusion, our findings demonstrate that multiple injections with TMSC produced a therapeutic effect in a mouse model of DSS-induced colitis.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Therapeutic potential of tonsil-derived mesenchymal stem cells in dextran sulfate sodium-induced experimental murine colitis

Song

Lee

et al. 2017

PLoS ONE

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“…Functional characterization was done by testing the ability of MSCs to differentiate in osteoblasts and adipocytes. Experiments were performed as earlier described by our group 45 . In short, MSCs were cultured with osteogenic or adipogenic differentiation medium.…”

Section: Methodsmentioning

confidence: 99%

Mesenchymal stromal cells prevent progression of liver fibrosis in a novel zebrafish embryo model

Helm

Groenewoud

Jonge‐Muller

et al. 2018

Sci Rep

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Chronic liver damage leads to the onset of fibrogenesis. Rodent models for liver fibrosis have been widely used, but are less suitable for screening purposes. Therefore the aim of our study was to design a novel model for liver fibrosis in zebrafish embryos, suitable for high throughput screening. Furthermore, we evaluated the efficacy of mesenchymal stromal cells (MSCs) to inhibit the fibrotic process and thereby the applicability of this model to evaluate therapeutic responses. Zebrafish embryos were exposed to TAA or CCL4 and mRNA levels of fibrosis-related genes (Collagen-1α1, Hand-2, and Acta-2) and tissue damage-related genes (TGF-β and SDF-1a, SDF-1b) were determined, while Sirius-red staining was used to estimate collagen deposition. Three days after start of TAA exposure, MSCs were injected after which the fibrotic response was determined. In contrast to CCL4, TAA resulted in an upregulation of the fibrosis-related genes, increased extracellular matrix deposition and decreased liver sizes suggesting the onset of fibrosis. The applicability of this model to evaluate therapeutic responses was shown by local treatment with MSCs which resulted in decreased expression of the fibrosis-related RNA markers. In conclusion, TAA induces liver fibrosis in zebrafish embryos, thereby providing a promising model for future mechanistic and therapeutic studies.

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“…Three-dimensional cultures provide a more physiological environment for cells, and trigger enhanced expression of other desirable phenotypes, such as improved MSC stemness and increased survival post-transplantation [ 18 ]. Spheroid formation can be considered as an optimisation of MSC culture to enhance their therapeutic potential [ 17 , 18 , 21 ], and MSC spheroid treatments have already been tested with moderate success in bone regeneration [ 22 , 23 ] and in inflammatory and ischaemic models, such as colitis and stroke [ 19 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Changes in the secretome of tri-dimensional spheroid-cultured human mesenchymal stem cells in vitro by interleukin-1 priming

et al. 2018

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BackgroundMesenchymal stem cells (MSCs) are one of the most promising candidates for the treatment of major neurological disorders. Desirable therapeutic properties of MSCs include reparative and regenerative potential but, despite their proven safety, the efficacy of MSCs remains controversial. Therefore, it is essential to optimise culture protocols to enhance the therapeutic potential of the MSC secretome. Here we aimed to: assess the increase in secretion of cytokines that may induce repair, regeneration, or immunomodulation when cultured in three dimensions; study the effect of interleukin (IL)-1 priming on two- (2D) and three-dimensional (3D) cultures of MSC; and evaluate the potential use of the modified secretome using microglial-MSC co-cultures.MethodsWe established a 3D spheroid culture of human MSCs, and compared the secretome in 2D and 3D cultures under primed (IL-1) and unprimed conditions. BV2 microglial cells were stimulated with lipopolysaccharide (LPS) and treated with spheroid conditioned media (CM) or were co-cultured with whole spheroids. Concentrations of secreted cytokines were determined by enzyme-linked immunosorbent assay (ELISA). Protein arrays were used to further evaluate the effect of IL-1 priming in 2D and 3D cultures.Results3D culture of MSCs significantly increased secretion of the IL-1 receptor antagonist (IL-1Ra), vascular endothelial growth factor (VEGF), and granulocyte-colony stimulating factor (G-CSF) compared with 2D culture, despite priming treatments with IL-1 being more effective in 2D than in 3D. The addition of CM of 3D-MSCs reduced LPS-induced tumour necrosis factor (TNF)-α secretion from BV2 cells, while the 3D spheroid co-cultured with the BV2 cells induced an increase in IL-6, but had no effect on TNF-α release. Protein arrays indicated that priming treatments trigger a more potent immune profile which is necessary to orchestrate an effective tissue repair. This effect was lost in 3D, partly because of the overexpression of IL-6.ConclusionsIncreased secretion of anti-inflammatory markers occurs when MSCs are cultured in 3D, but this specific secretome did not translate into anti-inflammatory effects on LPS-treated BV2 cells in co-culture. These data highlight the importance of optimising priming treatments and culture conditions to maximise the therapeutic potential of MSC spheroids.

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Intraluminal Injection of Mesenchymal Stromal Cells in Spheroids Attenuates Experimental Colitis

Abstract: Intraluminally injected MSC spheroids at least partially attenuate experimental colitis, with fewer phagocytes and proinflammmatory cytokines, when a high dose of MSCs in spheroids was administered.

Cited by 23 publications

References 54 publications

Therapeutic potential of tonsil-derived mesenchymal stem cells in dextran sulfate sodium-induced experimental murine colitis

Therapeutic potential of tonsil-derived mesenchymal stem cells in dextran sulfate sodium-induced experimental murine colitis

Mesenchymal stromal cells prevent progression of liver fibrosis in a novel zebrafish embryo model

Changes in the secretome of tri-dimensional spheroid-cultured human mesenchymal stem cells in vitro by interleukin-1 priming

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