Research Article

Intravenous administration of bone marrow mesenchymal stromal cells is safe for the lung in a chronic myocardial infarction model

Department of Surgery & Research Center for Cardiac Regenerative Medicine, Cardiovascular Institute & Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China

Department of Thoracic & Cardiovascular Surgery, Second Hospital of Lanzhou University, Lanzhou, 730030, China

^*Authors contributed equally

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Qin Jiang^*

^*Authors contributed equally

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Hao Zhang

† Author for correspondence

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Email the corresponding author at drzhanghao@yahoo.com

Peifeng Jin

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Xin Yuan

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Yingjie Wei

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Shengshou Hu

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Published Online:11 Mar 2011https://doi.org/10.2217/rme.10.104

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Abstract

Aims: Intravenous administration of bone marrow mesenchymal stromal cells (MSCs) is an attractive option for the treatment of myocardial infarction (MI). Previous studies revealed that MSC infusion could limit the deterioration of cardiac function following acute MI; however, little is known regarding the safety and efficacy of MSC infusion for chronic MI. In this study, we address cell retention after intravenous injection in a chronic MI model, and the fate and impact of distributed MSCs in the lung and heart. Methods: MI model was created by coronary ligation in female rats. A total of 3 weeks later, 5 × 10⁶ bromodeoxyuridine-labeled male MSCs in 300 µl phosphate-buffered solution (PBS) were infused intravenously (cell transplantation group, n = 37). The same volume of PBS was infused and served as the control group (n = 37). A total of 20 healthy rats received intravenous PBS injections and served as the sham group. 1 day and 4 weeks after cell or PBS infusion, echocardiography was performed and cell retention was evaluated by quantitative real-time PCR. The fate of the migrated cells was detected through immunohistochemistry and the expression of inflammatory and anti-inflammatory protein was evaluated in lung and heart. The lung and heart function was also assessed. Results: 1 day after cell implantation, the percentage of retained cells relative to the initial number of injected cells in heart and lung was 0.54 ± 0.19% and 51.69 ± 12.96%, respectively. After 4 weeks, it decreased to 0.24 ± 0.09% and 0.22 ± 0.17%. The entrapped MSCs did not differentiate into alveolar epithelial-like cells. Likewise, the left ventricular function was not improved. No adverse effects on lung function were observed after cell infusion. The expression of pro-inflammatory factors, including TNF-α, IL-1β, malondialdehyde and myeloperoxidase, and anti-inflammatory factors, including TNF-α-induced protein 6, in the lung and heart was not significantly regulated after cell transplantation. Conclusion: Although the majority of intravenous infused cells were harbored in the lung, they did not cause deterioration of lung function. However, they did not activate the release of inflammatory/anti-inflammatory proteins, or stimulate angiogenesis or myogenesis in the old infarcted myocardium. Thus, intravenous administration of MSCs for chronic MI needs further experimental study.

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Bibliography

1 Yamahara K, Nagaya N: Mesenchymal stem cells for the treatment of heart disease. Regen. Med.2(2),107–109 (2007).
Google Scholar
2 Huang NF, Li S: Mesenchymal stem cells for vascular regeneration. Regen. Med.3(6),877–892 (2008).
Google Scholar
3 van Ramshorst J, Bax JJ, Beeres SL et al.: Intramyocardial bone marrow cel injection for chronic myocardial ischemia: a randomized controlled trial. JAMA301(19),1997–2004 (2009).
Medline CASGoogle Scholar
4 Losordo DW, Schatz RA, White CJ et al.: Intramyocardial transplantation of autologous CD34⁺ stem cells for intractable angina: a Phase I/IIa double-blind, randomized controlled trial. Circulation115(25),3165–3172 (2007).
MedlineGoogle Scholar
5 Hare JM, Traverse JH, Henry TD et al.: A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (Prochymal) after acute myocardial infarction. J. Am. Coll. Cardiol.54(24),2277–2286 (2009).
Medline CASGoogle Scholar
6 Boomsma RA, Swaminathan PD, Geenen DL: Intravenously injected mesenchymal stem cells home to viable myocardium after coronary occlusion and preserve systolic function without altering infarct size. Int. J. Cardiol.122(1),17–28 (2007).
MedlineGoogle Scholar
7 Lee RH, Pulin AA, Seo MJ et al.: Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell5(1),54–63(2009).
Medline CASGoogle Scholar
8 Wang F, Guan J: Cellular cardiomyoplasty and cardiac tissue engineering for myocardial therapy. Adv. Drug Deliv. Rev.62(7–8),784–797 (2010).
Medline CASGoogle Scholar
9 Hou M, Yang KM, Zhang H et al.: Transplantation of mesenchymal stem cells from human bone marrow improves damaged heart function in rats. Int. J. Cardiol.115(2),220–228 (2007).
MedlineGoogle Scholar
10 Zhang H, Fazel S, Tian H et al.: Increasing donor age adversely impacts beneficial effects of bone marrow but not smooth muscle myocardial cell therapy. Am. J. Physiol. Heart Circ. Physiol.289(5),H2089–H2096 (2005).
Medline CASGoogle Scholar
11 Su W, Zhang H, Jia Z, Zhou C, Wei Y, Hu S: Cartilage-derived stromal cells: is it a novel cell resource for cell therapy to regenerate infarcted myocardium? Stem Cells24(2),349–356 (2006).
MedlineGoogle Scholar
12 Xin Y, Wang YM, Zhang H et al.: Aging adversely impacts biological properties of human bone marrow-derived mesenchymal stem cells: implications for tissue engineering heart valve construction. Artif. Organs34(3),215–222 (2010).
MedlineGoogle Scholar
13 Zhang H, Zhu SJ, Wang W, Wei YJ, Hu SS: Transplantation of microencapsulated genetically modified xenogeneic cells augments angiogenesis and improves heart function. Gene Ther.15(1),40–48 (2008).
Medline CASGoogle Scholar
14 Chu SJ, Lee TY, Yan HC, Lin SH, Li MH: L-Arginine prevents air embolism-induced acute lung injury in rats. Crit. Care Med.33(9),2056–2060 (2005).
Medline CASGoogle Scholar
15 Li MH, Huang KL, Wu SY et al.: Baicalin attenuates air embolism-induced acute lung injury in rat isolated lungs. Br. J. Pharmacol.157(2),244–251 (2009).
Medline CASGoogle Scholar
16 Kinoshita M, Ono S, Mochizuki H: Neutrophils mediate acute lung injury in rabbits: role of neutrophil elastase. Eur. Surg. Res.32(6),337–346 (2000).
Medline CASGoogle Scholar
17 Song P, Zhang H, Lu MJ et al.: Role of cardiopulmonary bypass and arrested heart status in the early cell distribution after intracoronary infusion of bone marrow stromal cells. J. Surg. Res.153(1),66–70(2009).
MedlineGoogle Scholar
18 Dai W, Hale SL, Martin BJ et al.: Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short- and long-term effects. Circulation112(2),214–223 (2005).
MedlineGoogle Scholar
19 Dimmeler S, Burchfield J, Zeiher AM: Cell-based therapy of myocardial infarction. Arterioscler. Thromb. Vasc. Biol.28(2),208–216 (2008).
Medline CASGoogle Scholar
20 Sherman W, Martens TP, Viles-Gonzalez JF, Siminiak T: Catheter-based delivery of cells to the heart. Nat. Clin. Pract. Cardiovasc. Med.3(Suppl. 1),S57–S64 (2006).
MedlineGoogle Scholar
21 Barbash IM, Chouraqui P, Baron J et al.: Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation108(7),863–868 (2003).
MedlineGoogle Scholar
22 Fischer UM, Harting MT, Jimenez F et al.: Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev.18(5),683–692 (2009).
Medline CASGoogle Scholar
23 Li SH, Lai TY, Sun Z et al.: Tracking cardiac engraftment and distribution of implanted bone marrow cells: comparing intra-aortic, intravenous, and intramyocardial delivery. J. Thorac. Cardiovasc. Surg.137(5),1225–1233 e1221(2009).
MedlineGoogle Scholar
24 Al Kindi A, Ge Y, Shum-Tim D, Chiu RC: Cellular cardiomyoplasty: routes of cell delivery and retention. Front Biosci.13,2421–2434 (2008).
Medline CASGoogle Scholar
25 Toma C, Wagner WR, Bowry S et al.: Fate of culture-expanded mesenchymal stem cells in the microvasculature: in vivo observations of cell kinetics. Circ. Res.104(3),398–402 (2009).
Medline CASGoogle Scholar
26 Card JW, Zeldin DC, Bonner JC, Nestmann ER: Pulmonary applications and toxicity of engineered nanoparticles. Am. J. Physiol. Lung Cell Mol. Physiol.295(3),L400–L411(2008).
Medline CASGoogle Scholar
27 Loebinger MR, Janes SM: Stem cells for lung disease. Chest132(1),279–285 (2007).
MedlineGoogle Scholar
28 Wong AP, Keating A, Lu WY et al.: Identification of a bone marrow-derived epithelial-like population capable of repopulating injured mouse airway epithelium. J. Clin. Invest.119(2),336–348 (2009).
Medline CASGoogle Scholar
29 Milner CM, Higman VA, Day AJ: TSG-6: a pluripotent inflammatory mediator? Biochem. Soc. Trans.34(Pt 3),446–450 (2006).
Medline CASGoogle Scholar
30 Oh JY, Roddy GW, Choi H et al.: Anti-inflammatory protein TSG-6 reduces inflammatory damage to the cornea following chemical and mechanical injury. Proc. Natl Acad. Sci. USA107(39),16875–16880 (2010).
Medline CASGoogle Scholar
31 Fang L, Gao XM, Moore XL et al.: Differences in inflammation, MMP activation and collagen damage account for gender difference in murine cardiac rupture following myocardial infarction. J. Mol. Cell Cardiol.43(5),535–544 (2007).
Medline CASGoogle Scholar
32 Paolocci N, Tavazzi B, Biondi R et al.: Metalloproteinase inhibitor counters high-energy phosphate depletion and AMP deaminase activity enhancing ventricular diastolic compliance in subacute heart failure. J. Pharmacol. Exp. Ther.317(2),506–513 (2006).
Medline CASGoogle Scholar
33 Salem HK, Thiemermann C: Mesenchymal stromal cells: current understanding and clinical status. Stem Cells28(3),585–596 (2010).
Medline CASGoogle Scholar
34 Harting MT, Jimenez F, Xue H et al.: Intravenous mesenchymal stem cell therapy for traumatic brain injury. J. Neurosurg.110(6),1189–1197 (2009).
Medline CASGoogle Scholar

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Published online 11 March 2011

Published in print March 2011

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Acknowledgements

The authors thank J Bauer (Vanderbilt University, Nashville, TN, USA) for his excellent language editing.

Financial & competing interests disclosure

This study was supported by the Natural Science Foundation of China (81070099) and the Fok Ying-Tong Education Foundation (121041). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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