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Tracking mesenchymal stem cells in the liver by magnetic resonance imaging

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Tracking mesenchymal stem cells in the liver by magnetic resonance imaging

PASTOR, Catherine

PASTOR, Catherine. Tracking mesenchymal stem cells in the liver by magnetic resonance imaging. Journal of Hepatology , 2005, vol. 43, no. 5, p. 915-6

DOI : 10.1016/j.jhep.2005.07.021 PMID : 16171892

Available at:

http://archive-ouverte.unige.ch/unige:40292

Disclaimer: layout of this document may differ from the published version.

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Tracking mesenchymal stem cells in the liver by magnetic resonance imaging

Catherine M. Pastor*

Laboratoire de physiopathologie he´patique et imagerie mole´culaire, Hoˆpitaux Universitaires de Gene`ve, Rue Micheli-du-Crest, 24, 1211 Geneva 14, Switzerland

In vivo MR imaging of intravascularly injected magnetically labeled mesenchymal stem cells in rat kidney and liver. Bos C, Delmas Y, Desmouliere A, Solanilla A, Hauger O, Grosset C, Dubus I, Ivanovic Z, Rosenbaum J, Charbord P, Combe C, Bulte JW, Moonen CT, Ripoche J, Grenier N.

Purpose:To evaluate in vivo magnetic resonance (MR) imaging with a conventional 1.5-T system for depiction and tracking of intravascularly injected superparamagnetic iron oxide (SPIO)-labeled mesenchymal stem cells (MSCs).

Materials and Methods: This study was conducted in accordance with French law governing animal research and met guidelines for animal care and use. Rat MSCs were labeled with SPIO and transfection agent. Relaxation rates at 1.5 T, cell viability, proliferation, differentiation capacity, and labeling stability were assessed in vitro as a function of SPIO concentration. MSCs were injected into renal arteries of healthy rats (labeled cells in four, unlabeled cells in two) and portal veins of rats treated with carbon tetrachloride to induce centrolobular liver necrosis (labeled cells and unlabeled cells in two each).

Follow-up serial T2*-weighted gradient-echo MR imaging and R2* mapping were performed. MR imaging findings were compared histologically.

Results:SPIO labeling caused a strong R2* effect that increased linearly with iron dose; R2* increase for cells labeled for 48 h with 50mg of iron per milliliter was 50 sec (K1) per million cells per milliliter. R2* was proportional to iron load of cells. SPIO labeling did not affect cell viability (PO27). Labeled cells were able to differentiate into adipocytes and osteocytes. Proliferation was substan- tially limited for MSCs labeled with 100mg Fe/mL or greater. Label half-life was longer than 11 days. In normal kidneys, labeled MSCs caused signal intensity loss in renal cortex. After labeled MSC injection, diseased liver had diffuse granular appearance. Cells were detected for up to 7 days in kidney and 12 days in liver. Signal intensity loss and fading over time were confirmed with serial R2*

mapping. At histologic analysis, signal intensity loss

correlated with iron-loaded cells, primarily in renal glomeruli and hepatic sinusoids; immunohistochemical analysis results confirmed these cells were MSCs.

Conclusions: MR imaging can aid in monitoring of intravascularly administered SPIO-labeled MSCs in vivo in kidney and liver.

[Abstract reproduced by permission of Radiology 2004;233:781–9]

Recent progress in the isolation of stem cells along with improved understanding of their functions has extended the use of stem cells in cardiovascular and neurologic diseases [1]. The development of stem cell-based therapies requires a quantitative and qualitative assessment of initial stem cell distribution to target organs (homing) as well as engraftment and in situ differentiation. Several imaging techniques are proposed to track stem cells in vivo within individual organs over long periods of time [1]. However, tracking a small number of cells in the body is a difficult task and the ideal technique has not yet been delineated[1]. The need for high concentrations of contrast agents and high ionizing radiation preclude the use of computed tomography for such tracking.

Bioluminescence utilizes light generated by the enzyme luciferase that has high absorption and scatters in living tissues. Moreover, this technique requires the stable expression of nonhuman genes. Fluorescence (another optical imaging) uses exogenous fluorophores that have high photon absorption and scatter that limit imaging to near-surface organs. Single photon emission computed tomography and positron emission tomography have also been used with different methods: direct loading of a radiometal, enzymatic conversion and retention of a radioactive substrate that permit to follow stem cells indefinitely after stable integration of a transgene, or receptor-mediated targeting that requires stable expression of specific receptors and injection of the corresponding radioactive ligands. Genetic modifications of stem cells, ionizing radiation, and difficulties in quantification are the main disadvantages of these techniques.

Given its high spatial resolution, magnetic resonance imaging (MRI) is another interesting technique that is used to track stem cells in the heart and brain [2]. A recent publication emphasizes the interest of MRI to localize stem

0168-8278/$30.00q2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

* Tel.:C41 22 372 93 53; fax:C41 22 372 93 66.

E-mail address:catherine.pastor@hcuge.ch (C.M. Pastor).

Journal Club / Journal of Hepatology 43 (2005) 913–916 915

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cells in the liver[3]. In this study, rat mesenchymal stem cells (MSCs) were isolated from bone marrow and labeled with a superparamagnetic iron oxide (SPIO) using a dendrimer transfection agent. In vitro, the capacity of MSCs to differentiate into adipocytic and osteogenic lineages was not altered by SPIO-labeling. MR imaging was performed with a 1.5-T clinical system and the R2*

effect generated by SPIO in cultured cells was stable over 12 days. For in vivo experiments, labeled cells were injected into the portal vein of rats that had previously a single oral dose of CCl4 to induce hepatic inflammation and permit cell engraftment. In vivo MR imaging was performed before and after portal injection as well as 4, 8, and 12 days later. The R2* effect was significantly increased following SPIO-labeled MSCs injection in comparison to injection with unlabeled cells and the effect persisted during 12 days. Labeled cells distributed within the entire liver. The granular pattern of distribution within the liver on MR imaging corresponded to MSCs engraftment along all sinusoids on histological examin- ation. The presence of CD90 antigens at histological examination (which are not detected in normal livers) confirmed the engraftment of MSCs.

MSCs were loaded ex vivo with a clinically approved SPIO. This contrast agent is easily internalized by endocytosis in macrophages. In contrast to macrophages, stem cells do not take appreciable amounts of SPIO and Boss et al.[3]enhanced the cell uptake by adding a transfection agent (dendrimer) that facilitates endocytosis [4]. In stem cells, the magnetic probes concentrate into endosomes and following biodegradation and metabolization incorporate into the normal iron pool[4]. These magnetic probes are sensitive enough to be detected in vivo, following incorporation into MSCs, within the liver by MRI.

In most previous studies using MR imaging of stem cell engraftment, cells were locally implanted into animal brain, spine, and heart. After implantation, cells migrate slowly (a few millimeters a week) and the entire organ engraftment requires multiple injections. In the study by Boss et al.[3], the intraportal injection of MSCs is attractive because cells distribute throughout the organ following a single injection.

Alternatively, hepatic MR imaging following intravenously injection of iron oxide-labeled human hematopoietic progenitor cells has recently be reported in mice [5].

Moreover, following intravenous injection in rats, an external magnet placed near the liver can attract iron- oxide-labeled MSCs into the liver[6].

Cellular-based therapies using stem cells might be a possible treatment for acute or chronic liver diseases, especially when the liver matrix remains intact[7]. Several cell populations have been considered in this context, and among them MSCs might help in replacing diseased hepatocytes. MSCs are fibroblastlike, non-hemopoietic,

plastic adherent cells that have the potential to differentiate to lineages of mesenchymal tissues such as bone, cartilage, fat, tendon, muscle, and marrow stroma [8]. The pre- dominant source of MSCs is adult bone marrow but isolation of MSCs from umbilical cord blood has been described. Importantly, MSCs are able to differentiate into functional hepatic-like cells in vitro [9]. After 4 weeks of induction, MSCs acquire a cuboid morphology and marker genes specific of liver cells. Functions of these differentiated cells include albumin production, glycogen storage, urea secretion, uptake of low-density lipoprotein, and phenobar- bital-inducible cytochrome P450 activity [9]. However, whether MSCs differentiate in vivo has never been demonstrated.

For the first time, MSCs labeled with a clinically approved contrast agent were successfully tracked within the liver by a conventional MR system following intraportal injection. Advantages of MRI are the low toxicity of SPIO, the ability to follow labeled cells for several weeks, and the high spatial resolution that permits precise localization of injected cells. However, once MSCs are localized within the liver, they should proliferate and differentiate into hepatic- like cells before being able to replace diseased hepatocytes and treat acute or chronic liver diseases.

References

[1] Frangioni JV, Hajjar RJ. In vivo tracking of stem cells for clinical trials in cardiovascular disease. Circulation 2004;110:3378–3383.

[2] Mahmood U. Can MR imaging be used to track delivery of intravascularly administered stem cells? Radiology 2004;233:625–626.

[3] Bos C, Delmas Y, Desmoulie`re A, Solanilla A, Hauger O, Grosset C, et al. In vivo MR imaging of intravascularly injected magnetically labeled mesenchymal stem cells in rat kidney and liver. Radiology 2004;233:781–789.

[4] Bulte JW, Douglas T, Witwer B, Zhang SC, Strable E, Lewis BK, et al.

Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol 2001;19:1141–1147.

[5] Daldrup-Link HE, Rudelius M, Piontek G, Metz S, Brauer R, Debus G, et al. Migration of iron oxide-labeled human hematopoietic progenitor cells in a mouse model: in vivo monitoring with 1.5-T MR imaging equipment. Radiology 2005;234:197–205.

[6] Arbab AS, Jordan EK, Wilson LB, Yocum GT, Lewis BK, Frank JA. In vivo trafficking and targeted delivery of magnetically labeled stem cells. Hum Gene Ther 2004;15:351–360.

[7] Dahlke MH, Popp FC, Larsen S, Schlitt HJ, Rasko JE. Stem cell therapy of the liver-fusion or fiction? Liver Transpl 2004;10:

471–479.

[8] Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–147.

[9] Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, Chou SH, et al.

In vitro hepatic differentiation of human mesenchymal stem cells.

Hepatology 2004;40:1275–1284.

doi:10.1016/j.jhep.2005.07.021 Journal Club / Journal of Hepatology 43 (2005) 913–916 916

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