Magnetic Resonance Imaging of Bone Marrow Cell-mediated Interleukin-10 Gene Therapy of Atherosclerosis

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Sep 15

PMID 21915349

Citations 3

Authors

Jihong Sun

Xubin Li

Hongqing Feng

Huidong Gu

Tiffany Blair

Jiakai Li

Stephanie Soriano

Yanfeng Meng

Feng Zhang

Qinghua Feng

Xiaoming Yang

Affiliations

Soon will be listed here.

Abstract

Background: A characteristic feature of atherosclerosis is its diffuse involvement of arteries across the entire human body. Bone marrow cells (BMC) can be simultaneously transferred with therapeutic genes and magnetic resonance (MR) contrast agents prior to their transplantation. Via systemic transplantation, these dual-transferred BMCs can circulate through the entire body and thus function as vehicles to carry genes/contrast agents to multiple atherosclerosis. This study was to evaluate the feasibility of using in vivo MR imaging (MRI) to monitor BMC-mediated interleukin-10 (IL-10) gene therapy of atherosclerosis.

Methodology: For in vitro confirmation, donor mouse BMCs were transduced by IL-10/lentivirus, and then labeled with a T2-MR contrast agent (Feridex). For in vivo validation, atherosclerotic apoE(-/-) mice were intravenously transplanted with IL-10/Feridex-BMCs (Group I, n = 5) and Feridex-BMCs (Group II, n = 5), compared to controls without BMC transplantation (Group III, n = 5). The cell migration to aortic atherosclerotic lesions was monitored in vivo using 3.0T MRI with subsequent histology correlation. To evaluate the therapeutic effect of BMC-mediated IL-10 gene therapy, we statistically compared the normalized wall indexes (NWI) of ascending aortas amongst different mouse groups with various treatments.

Principal Findings: Of in vitro experiments, simultaneous IL-10 transduction and Feridex labeling of BMCs were successfully achieved, with high cell viability and cell labeling efficiency, as well as IL-10 expression efficiency (≥90%). Of in vivo experiments, MRI of animal groups I and II showed signal voids within the aortic walls due to Feridex-created artifacts from the migrated BMCs in the atherosclerotic plaques, which were confirmed by histology. Histological quantification showed that the mean NWI of group I was significantly lower than those of group II and group III (P<0.05).

Conclusion: This study has confirmed the possibility of using MRI to track, in vivo, IL-10/Feridex-BMCs recruited to atherosclerotic lesions, where IL-10 genes function to prevent the progression of atherosclerosis.

Citing Articles

Relationship between XspI Site Polymorphisms of LDL-R Gene and Serum IL-2 and IL-10 in Patients with Hypercholesterolemia.

Zhang M, Lu Y, Liu X, Zhang X, Zhang C, Gao W J Clin Lab Anal. 2016; 30(6):1122-1127.

PMID: 27121486 PMC: 6807227. DOI: 10.1002/jcla.21991.

AAV2/8-humanFOXP3 gene therapy shows robust anti-atherosclerosis efficacy in LDLR-KO mice on high cholesterol diet.

Cao M, Theus S, Straub K, Figueroa J, Mirandola L, Chiriva-Internati M J Transl Med. 2015; 13:235.

PMID: 26187646 PMC: 4506442. DOI: 10.1186/s12967-015-0597-7.

Efficacy of single and multiple injections of human umbilical tissue-derived cells following experimental stroke in rats.

Shehadah A, Chen J, Kramer B, Zacharek A, Cui Y, Roberts C PLoS One. 2013; 8(1):e54083.

PMID: 23342081 PMC: 3544758. DOI: 10.1371/journal.pone.0054083.

References

Qiu B, Yang X . Molecular MRI of hematopoietic stem-progenitor cells: in vivo monitoring of gene therapy and atherosclerosis. Nat Clin Pract Cardiovasc Med. 2008; 5(7):396-404. DOI: 10.1038/ncpcardio1217. View

Pinderski L, Fischbein M, Subbanagounder G, Fishbein M, Kubo N, Cheroutre H . Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient Mice by altering lymphocyte and macrophage phenotypes. Circ Res. 2002; 90(10):1064-71. DOI: 10.1161/01.res.0000018941.10726.fa. View

Bulte J, Douglas T, Witwer B, Zhang S, Strable E, Lewis B . Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol. 2001; 19(12):1141-7. DOI: 10.1038/nbt1201-1141. View

Krause D, Theise N, Collector M, Henegariu O, Hwang S, Gardner R . Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001; 105(3):369-77. DOI: 10.1016/s0092-8674(01)00328-2. View

Lacraz S, Nicod L, Chicheportiche R, Welgus H, Dayer J . IL-10 inhibits metalloproteinase and stimulates TIMP-1 production in human mononuclear phagocytes. J Clin Invest. 1995; 96(5):2304-10. PMC: 185881. DOI: 10.1172/JCI118286. View

Pinderski Oslund L, Hedrick C, Olvera T, Hagenbaugh A, Territo M, Berliner J . Interleukin-10 blocks atherosclerotic events in vitro and in vivo. Arterioscler Thromb Vasc Biol. 1999; 19(12):2847-53. DOI: 10.1161/01.atv.19.12.2847. View

Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T . Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med. 2002; 8(4):403-9. DOI: 10.1038/nm0402-403. View

Namiki M, Kawashima S, Yamashita T, Ozaki M, Sakoda T, Inoue N . Intramuscular gene transfer of interleukin-10 cDNA reduces atherosclerosis in apolipoprotein E-knockout mice. Atherosclerosis. 2004; 172(1):21-9. DOI: 10.1016/j.atherosclerosis.2003.08.032. View

Mallat Z, Heymes C, Ohan J, Faggin E, Leseche G, Tedgui A . Expression of interleukin-10 in advanced human atherosclerotic plaques: relation to inducible nitric oxide synthase expression and cell death. Arterioscler Thromb Vasc Biol. 1999; 19(3):611-6. DOI: 10.1161/01.atv.19.3.611. View

10.

Chae E, Song E, Sohn J, Kim S, Woo C, Gong G . Allogeneic renal graft rejection in a rat model: in vivo MR imaging of the homing trait of macrophages. Radiology. 2010; 256(3):847-54. DOI: 10.1148/radiol.10091732. View

11.

Han X, Kitamoto S, Wang H, Boisvert W . Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice. FASEB J. 2010; 24(8):2869-80. PMC: 2909283. DOI: 10.1096/fj.09-148155. View

12.

Qiu B, Gao F, Walczak P, Zhang J, Kar S, Bulte J . In vivo MR imaging of bone marrow cells trafficking to atherosclerotic plaques. J Magn Reson Imaging. 2007; 26(2):339-43. DOI: 10.1002/jmri.21016. View

13.

Qiu B, Treuting P, Zhan X, Xie D, Frevert C, Yang X . Dual transfer of GFP gene and MGd into stem-progenitor cells: toward in vivo MRI of stem cell-mediated gene therapy of atherosclerosis. Acad Radiol. 2010; 17(5):547-52. DOI: 10.1016/j.acra.2010.02.004. View

14.

Yang X . Imaging of vascular gene therapy. Radiology. 2003; 228(1):36-49. DOI: 10.1148/radiol.2281020307. View

15.

Rubic T, Lorenz R . Downregulated CD36 and oxLDL uptake and stimulated ABCA1/G1 and cholesterol efflux as anti-atherosclerotic mechanisms of interleukin-10. Cardiovasc Res. 2005; 69(2):527-35. DOI: 10.1016/j.cardiores.2005.10.018. View

16.

Orlic D, Kajstura J, Chimenti S, Bodine D, Leri A, Anversa P . Bone marrow stem cells regenerate infarcted myocardium. Pediatr Transplant. 2003; 7 Suppl 3:86-8. DOI: 10.1034/j.1399-3046.7.s3.13.x. View

17.

Blanco E, Monux G, Mas A, Serrano F, de la Concha E, Urcelay E . Role of IL-10 promoter polymorphisms in the development of severe aorto-iliac occlusive disease. Hum Immunol. 2008; 69(10):651-4. DOI: 10.1016/j.humimm.2008.07.005. View

18.

Moore K, de Waal Malefyt R, Coffman R, OGarra A . Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001; 19:683-765. DOI: 10.1146/annurev.immunol.19.1.683. View

19.

Russell J . Of mice and men, rats and atherosclerosis. Cardiovasc Res. 2003; 59(4):810-1. DOI: 10.1016/s0008-6363(03)00530-3. View

20.

Kleemann R, Zadelaar S, Kooistra T . Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res. 2008; 79(3):360-76. PMC: 2492729. DOI: 10.1093/cvr/cvn120. View