Marrow stromal cells (MSCs, also termed mesenchymal stem cells) have been proposed as a promising cellular therapy for tissue injury including radiation-induced marrow failure, but evidence for a direct effect is lacking. To assess the effects of MSCs on survival after lethal irradiation, we infused syngeneic MSCs (either as immortalized MSCs clones or primary MSCs) intravenously into wild-type C57/Bl6 mice within 24 hours of lethal total body irradiation (TBI). Mice receiving either of the MSC preparations had significantly improved survival when compared to controls. In vivo imaging, immune histochemistry, and RT-PCR employed to detect MSCs indicated that the infused MSCs were predominantly localized to the lungs and rapidly cleared following infusion. Our results suggest that a single infusion of MSCs can improve survival after otherwise lethal TBI but the effect is not due to a direct interaction with, or contribution to, the damaged marrow by MSCs. 1. Introduction High-dose ionizing radiation causes damage to many organs, especially those with highly proliferative cells such as the bone marrow and the gastrointestinal tract [1, 2]. Bone marrow failure is often the cause of death following moderate-to-severe exposures to radiation [3]. Several pharmacologic agents especially cytokines such as granulocyte colony stimulating factor (GCSF), granulocyte monocyte colony stimulating factor (GMCSF), interleukin 3 (IL3), and thrombopoietin (TPO) have been shown in various experimental models to mitigate hematopoietic effects of radiation and are approved for clinical use in scenarios of radiation-induced aplasia [4–6]. The efficacy of these agents is, however, limited to intermediate dose ranges which do not result in complete marrow ablation. Exposure to higher doses that result in complete marrow ablation requires the transplantation of a new lympho-hematopoietic system from a suitable donor [7]. As such transplantations are impractical to be performed expeditiously following exposure to high-dose radiation (accidental or nuclear attacks), there is significant interest in improving the efficacy of pharmacological agents as mentioned above and explore novel agents with efficacy at doses higher than what cytokines are typically effective. “Off-the shelf” cellular therapies that can be expanded from a few initial cells, frozen, and thawed for quick infusion and do not require extensive tissue-matching have been explored as alternatives to full allogeneic stem cell transplantation following such radiation exposures. Marrow stromal cells (MSCs, also referred
References
[1]
L. V. Karkanitsa, “Radiation damage to hematopoiesis: what do we know better?” Stem Cells, vol. 15, pp. 71–73, 1997.
[2]
F. Hérodin, N. Grenier, and M. Drouet, “Revisiting therapeutic strategies in radiation casualties,” Experimental Hematology, vol. 35, no. 4, supplement 1, pp. 28–33, 2007.
[3]
J. E. Moulder, “Post-irradiation approaches to treatment of radiation injuries in the context of radiological terrorism and radiation accidents: a review,” International Journal of Radiation Biology, vol. 80, no. 1, pp. 3–10, 2004.
[4]
F. Hérodin and M. Drouet, “Cytokine-based treatment of accidentally irradiated victims and new approaches,” Experimental Hematology, vol. 33, no. 10, pp. 1071–1080, 2005.
[5]
R. P. Gale and A. Butturini, “The role of hematopoietic growth factors in nuclear and radiation accidents,” Experimental Hematology, vol. 18, no. 8, pp. 958–964, 1990.
[6]
R. P. Gale and A. Butturini, “Use of hematopoietic growth factors in radiation accidents,” International Journal of Radiation Oncology Biology Physics, vol. 19, no. 5, pp. 1291–1295, 1990.
[7]
T. M. Fliedner, N. J. Chao, J. L. Bader et al., “Stem cells, multiorgan failure in radiation emergency medical preparedness: a U.S./European Consultation Workshop,” Stem Cells, vol. 27, no. 5, pp. 1205–1211, 2009.
[8]
K. Le Blanc, I. Rasmusson, B. Sundberg et al., “Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells,” The Lancet, vol. 363, no. 9419, pp. 1439–1441, 2004.
[9]
B. Parekkadan and J. M. Milwid, “Mesenchymal stem cells as therapeutics,” 2010, http://www.annualreviews.org/doi/full/10.1146/annurev-bioeng-070909-105309?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed&.
[10]
L. Vija, D. Farge, J. F. Gautier et al., “Mesenchymal stem cells: stem cell therapy perspectives for type 1 diabetes,” Diabetes and Metabolism, vol. 35, no. 2, pp. 85–93, 2009.
[11]
L. C. Amado, A. P. Saliaris, K. H. Schuleri et al., “Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 32, pp. 11474–11479, 2005.
[12]
C. Lange, B. Brunswig-Spickenheier, H. Cappallo-Obermann et al., “Radiation rescue: mesenchymal stromal cells protect from lethal irradiation,” PLoS ONE, vol. 6, no. 1, Article ID e14486, 2011.
[13]
K. X. Hu, Q. Y. Sun, M. Guo, and H. S. Ai, “The radiation protection and therapy effects of mesenchymal stem cells in mice with acute radiation injury,” British Journal of Radiology, vol. 83, no. 985, pp. 52–58, 2010.
[14]
B. A. Roecklein and B. Torok-Storb, “Functionally distinct human marrow stromal cell lines immortalized by transduction with the human papilloma virus E6/E7 genes,” Blood, vol. 85, no. 4, pp. 997–1005, 1995.
[15]
A. Sorrentino, M. Ferracin, G. Castelli et al., “Isolation and characterization of CD146+ multipotent mesenchymal stromal cells,” Experimental Hematology, vol. 36, no. 8, pp. 1035–1046, 2008.
[16]
Y. Lin, J. Molter, Z. Lee, and S. L. Gerson, “Bioluminescence imaging of hematopoietic stem cell repopulation in murine models,” Methods in Molecular Biology, vol. 430, pp. 295–306, 2008.
[17]
G. Yang, A. Abate, A. G. George, Y. H. Weng, and P. A. Dennery, “Maturational differences in lung NF-κB activation and their role in tolerance to hyperoxia,” Journal of Clinical Investigation, vol. 114, no. 5, pp. 669–678, 2004.
[18]
A. C. M. Assis, J. L. Carvalho, B. A. Jacoby et al., “Time-dependent migration of systemically delivered bone marrow mesenchymal stem cells to the infarcted heart,” Cell Transplantation, vol. 19, no. 2, pp. 219–230, 2010.
[19]
I. M. Barbash, P. Chouraqui, J. Baron et al., “Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution,” Circulation, vol. 108, no. 7, pp. 863–868, 2003.
[20]
J. Gao, J. E. Dennis, R. F. Muzic, M. Lundberg, and A. I. Caplan, “The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion,” Cells Tissues Organs, vol. 169, no. 1, pp. 12–20, 2001.
[21]
D. L. Kraitchman, A. W. Heldman, E. Atalar et al., “In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction,” Circulation, vol. 107, no. 18, pp. 2290–2293, 2003.
[22]
C. Lange, F. T？gel, H. Ittrich et al., “Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats,” Kidney International, vol. 68, no. 4, pp. 1613–1617, 2005.
[23]
J. J. Min, Y. Ahn, S. Moon et al., “In vivo bioluminescence imaging of cord blood derived mesenchymal stem cell transplantation into rat myocardium,” Annals of Nuclear Medicine, vol. 20, no. 3, pp. 165–170, 2006.
[24]
F. T？gel, Y. Yang, P. Zhang, Z. Hu, and C. Westenfelder, “Bioluminescence imaging to monitor the in vivo distribution of administered mesenchymal stem cells in acute kidney injury,” American Journal of Physiology, vol. 295, no. 1, pp. F315–F321, 2008.
[25]
C. Weir, M. C. Morel-Kopp, A. Gill et al., “Mesenchymal stem cells: isolation, characterisation and in vivo fluorescent dye tracking,” Heart Lung and Circulation, vol. 17, no. 5, pp. 395–403, 2008.
