Non-invasive imaging reveals conditions that impact distribution and persistence of cells after <i>in vivo</i> administration

Scarfe, Lauren; Taylor, Arthur; Sharkey, Jack; Harwood, Rachel; Barrow, Michael; Comenge, Joan; Beeken, Lydia; Astley, Cai; Santeramo, Ilaria; Hutchinson, Claire; Ressel, Lorenzo; Smythe, Jon; Austin, E. B.; Lévy, Raphaël; Rosseinsky, Matthew J.; Adams, Dave J.; Poptani, Harish; Park, Brian K.; Murray, Patricia; Wilm, Bettina

doi:10.1101/202101

Cited by 19 publications

(47 citation statements)

References 56 publications

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“…11 On culling the mice, no tumor was detected in the major body organs (liver, spleen, brain, heart, and lungs). A key objective of this study was to investigate what happened to the free and encapsulated SPIONs after day 1 when BLI showed that the majority of the cells had died.…”

Section: Animal Injection and In Vivo Monitoring Of The Bio-distributmentioning

confidence: 99%

“…11 Here, MRI allowed the monitoring of in vivo clearing and accumulation pattern of particles ( was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

Section: Mri Complementary To Blimentioning

confidence: 99%

“…34 We and others have shown that most cells die after injection. 11,15,35 Therefore, understanding the in vivo fate of cell-labelling nanoparticles, especially following the death of the labelled cells is important for the interpretation of imaging studies and to assess the risk of toxicity. In the current study, we focus on the effect of formulation on the fate of SPIONs after the in vivo injection of labelled cells.…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7] For this purpose, in addition to, and/or in combination with genetic reporters, nanoparticles are successfully used as contrast agents for cell labelling and tracking with various imaging modalities. [8][9][10][11][12] Cellular biodistribution, viability and proliferation can be monitored by bioluminescence imaging (BLI) the cells transduced with the genetic reporter firefly luciferase (Luc). [12][13][14] Cell death results in a decrease in bioluminescence signal, whilst cell division and tumor formation leads to an amplification of the signal.…”

Section: Introductionmentioning

confidence: 99%

“…16 Appropriate MRI contrast agents 17,18 for cell tracking include superparamagnetic iron oxide nanoparticles (SPIONs) which generate a negative contrast. 11,[19][20][21][22][23][24] The uptake efficiency of SPIONs is strongly influenced by their functionalization. 21,25 Recently, positively-charged DEAE (diethylaminoethyl)-dextran coated SPIONs have been synthesized for enhanced cellular uptake and MRI contrast.…”

Section: Introductionmentioning

confidence: 99%

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In vivo fate of free and encapsulated iron oxide nanoparticles after injection of labelled stem cells

Ashraf

Taylor

Sharkey

et al. 2018

Preprint

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Nanoparticle contrast agents are useful tools to label stem cells and monitor the in vivo biodistribution of labeled cells in pre-clinical models of disease. In this context, understanding the in vivo fate of the particles after injection of labelled cells is important for their eventual clinical use as well as for the interpretation of imaging results. We examined how the formulation of superparamagnetic iron oxide nanoparticles (SPIONs) impacts the labelling efficiency, magnetic characteristics and fate of the particles by comparing individual SPIONs with polyelectrolyte multilayer capsules containing SPIONs. At low labelling concentration, encapsulated SPIONs served as an efficient labelling agent for stem cells. The bio-distribution after intra-cardiac injection of labelled cells was monitored longitudinally by MRI and as an endpoint by inductively coupled plasma-optical emission spectrometry. The results suggest that, after being released from labelled cells after cell death, both formulations of particles are initially stored in liver and spleen and are not completely cleared from these organs 2 weeks post-injection.

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Section: Animal Injection and In Vivo Monitoring Of The Bio-distributmentioning

confidence: 99%

Section: Mri Complementary To Blimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vivo fate of free and encapsulated iron oxide nanoparticles after injection of labelled stem cells

Ashraf

Taylor

Sharkey

et al. 2018

Preprint

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Characterizing Fibrosis and Inflammation in a Partial Bile Duct Ligation Mouse Model by Multiparametric Magnetic Resonance Imaging

Liu

Cai

Ding

et al. 2021

Magnetic Resonance Imaging

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Background Partial bile duct ligation (PBDL) model is a reliable cholestatic fibrosis experimental model that showed complex histopathological changes. Magnetic resonance imaging (MRI) features of PBDL have not been well characterized. Purpose To investigate the potential of MRI parameters in assessing fibrosis in PBDL and explore the relationships between MRI and pathological features. Animal Model Established PBDL models. Population Fifty‐four mice were randomly divided into four timepoints PBDL groups and one sham group. Field Strength/Sequence 3.0 T; MRI sequences included T1‐weighted fast spin‐echo (FSE), T2‐weighted single shot FSE, variable flip angle T1 mapping, multi‐echo SE T2 mapping, multi‐echo gradient‐echo T2* mapping, and multi‐b‐value diffusion‐weighted imaging. Assessment MRI examination was performed at the corresponding timepoints after surgery. Native T1, ΔT1 (T1native‐T1post), T2, T2*, apparent diffusion coefficient (ADC) values, histogram parameters (skewness and kurtosis), intravoxel incoherent motion parameters (f, D, and D*) within the entire ligated (PBDL), non‐ligated liver (PBDL), and whole liver (sham) were obtained. Fibrosis and inflammation were assessed in Masson and H&E staining slices using the Metavir and activity scoring system. Statistical Tests One‐way ANOVA, Spearman's rank correlation, and receiver operating characteristic curves were performed. P < 0.05 was considered statistically significant. Results Fibrosis and inflammation were finally staged as F3 and A3 in ligated livers but were not observed in non‐ligated or sham livers. Ligated livers displayed significantly elevated native T1, ΔT1, T2, and reduced ADC and T2* than other livers. Spearman's correlation showed better correlation with inflammation (r = 0.809) than fibrosis (r = 0.635) in T2 and both ΔT1 and ADC showed stronger correlation with fibrosis (r = 0.704 and r = −0.718) than inflammation (r = 0.564 and r = −0.550). Area under the curve (AUC) for ΔT1 performed the highest (0.896). When combined with all relative parameters, AUC increased to 0.956. Data Conclusion Multiparametric MRI can evaluate and differentiate pathological changes in PBDL. ΔT1 and ADC better correlated with fibrosis while T2 stronger with inflammation. Level of Evidence 1 Technical Efficacy Stage 2

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Firefly luciferase offers superior performance to AkaLuc for tracking the fate of administered cell therapies

Amadeo

Plagge

Chacko

et al. 2021

Eur J Nucl Med Mol Imaging

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Introduction A novel, red-shifted bioluminescence imaging (BLI) system called AkaBLI has been recently developed for cell tracking in preclinical models and to date, limited data is available on how it performs in relation to existing systems. Purpose To systematically compare the performance of AkaBLI and the standard Firefly luciferase (FLuc) systems to monitor the biodistribution and fate of cell therapies in rodents. Methods Umbilical cord mesenchymal stromal cells (MSCs) were transduced to produce two genetically engineered populations, expressing either AkaLuc or the engineered FLuc luc2. The bioluminescence of AkaLuc+ and FLuc+ cells was assessed both in vitro (emission spectra, saturation kinetics and light emission per cell) and in vivo (substrate kinetics following intraperitoneal and subcutaneous administration and biodistribution of the cells up to day 7). Results Introduction of the reporter genes has no effect on MSC phenotype. For BLI, the FLuc system is superior to AkaBLI in terms of (i) light output, producing a stronger signal after subcutaneous substrate delivery and more consistent signal kinetics when delivered intraperitoneally; (ii) absence of hepatic background; and (iii) safety, where the AkaLuc substrate was associated with a reaction in the skin of the mice in vivo. Conclusion We conclude that there is no advantage in using the AkaBLI system to track the biodistribution of systemically administered cell-based regenerative medicine therapies in vivo.

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Non-invasive imaging reveals conditions that impact distribution and persistence of cells after in vivo administration

Cited by 19 publications

References 56 publications

In vivo fate of free and encapsulated iron oxide nanoparticles after injection of labelled stem cells

In vivo fate of free and encapsulated iron oxide nanoparticles after injection of labelled stem cells

Characterizing Fibrosis and Inflammation in a Partial Bile Duct Ligation Mouse Model by Multiparametric Magnetic Resonance Imaging

Firefly luciferase offers superior performance to AkaLuc for tracking the fate of administered cell therapies

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