Bone marrow-derived mesenchymal stem cells (MSCs) have the potential to differentiate along different mesenchymal lineages including those forming bone, cartilage, tendon, fat, muscle and marrow stroma that supports hematopoiesis. This differentiation potential makes MSCs candidates for cell-based therapeutic strategies for mesenchymal tissue injuries and for hematopoietic disorders by both local and systemic application. In the present study, rat marrow-derived MSCs were ex vivo culture-expanded, labeled with 111In-oxine, and infused into syngeneic rats via intra-artery (i.a.), intravenous (i.v.) and intraperitoneal cavity (i.p.) infusions. In addition, for i.a. and i.v. infusions, a vasodilator, sodium nitroprusside, was administered prior to the cell infusion and examined for its effect on MSC circulation. The dynamic distribution of infused MSCs was monitored by real-time imaging using a gamma camera immediately after infusion and at 48 h postinfusion. After 48 h, radioactivity in excised organs, including liver, lungs, kidneys, spleen and long bones, was measured in a gamma well counter and expressed as a percentage of injected doses. After both i.a. and i.v. infusion, radioactivity associated with MSCs was detected primarily in the lungs and then secondarily in the liver and other organs. When sodium nitroprusside was used, more labeled MSCs cleared the lungs resulting in a larger proportion detected in the liver. Most importantly, the homing of labeled MSCs to the marrow of long bones was significantly increased by the pretreatment with vasodilator. These results indicate multiple homing sites for injected MSCs and that the distribution of MSCs can be influenced by administration of vasodilator.

Keywords:
Mesenchymal stem cells, Indium-111-oxine labeling, Infusion, Imaging, Rat
1.
Abreo, K., A.K. Lieberman, A.V. Moorthy (1985) Distribution studies of 111In-oxine-labeled peritoneal mononuclear cells in tumor-bearing rats. Int J Nucl Med Biol 12: 53–55.
2.
Allay, J.A., J.E. Dennis, S.E. Haynesworth, M.K. Majumdar, D.W. Clapp, L.D. Shultz, A.I. Caplan, S.L. Gerson (1997) LacZ and interleukin-3 expression in vivo after retroviral transplantation of marrow-derived human osteogenic mesenchymal progenitors. Hum Gene Ther 8: 1417–1427.
3.
Bojko, T., D.A. Notterman (1999) Reversal of fortune? Respiratory failure after bone marrow transplantation. Crit Care Med 27: 1061–1062.
4.
Botti, C., D.R.M. Negri, E. Seregni, et al (1997) Comparison of three different methods for radiolabeling human activated T lymphocytes. Eur J Nucl Med 24: 497–504.
5.
Bruder, S.P., N. Jaiswal, S.E. Haynesworth (1997) Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. J Cell Biochem 64: 278–294.
6.
Bruder, S.P., N. Jaiswal, N.S. Ricalton, J.D. Mosca, K.H. Kraus, S. Kadiyala (1998a) Mesenchymal stem cells in osteobiology and applied bone regeneration. Clin Orthop 355S: S247–256.
7.
Bruder, S.P., K.H. Kraus, V.M. Goldberg, S. Kadiyala (1998b) The effect of implants loaded with autologous mesenchymal stem cells on the healing of canine segmental bone defects. J Bone Joint Surg Am 80: 985–996.
8.
Caplan, A.I. (1991) Mesenchymal stem cells. J Orthop Res 9: 641–650.
9.
Chuah, M.K.L., H. Brems, V. Vanslembrouck, D. Collen, T. Vandendriessche (1998) Bone marrow stromal cells as targets for gene therapy of hemophilia A. Hum Gene Ther 9: 353–365.
10.
Crawford, S.W., F.B. Petersen (1992) Long-term survival from respiratory failure after marrow transplantation for malignancy. Am Rev Respir Dis 145: 510–514.
11.
Dennis, J.E., S.E. Haynesworth, R.G. Young, A.I. Caplan (1992) Osteogenesis in marrow-derived mesenchymal cell porous ceramic composites transplanted subcutaneously: Effect of fibronectin and laminin on cell retention and rate of osteogenic expression. Cell Transplant 1: 23–32.
12.
Dexter, T.M., T.D. Allen, L.G. Lajtha (1977) Conditions controlling the proliferation of hemopoietic stem cells in vitro. J Cell Physiol 91: 335–344.
13.
Gordon, M.Y., D. Clarke, J. Atkinson, M.F. Greaves (1990) Hemopoietic progenitor cell binding to the stromal microenvironment in vitro. Exp Hematol 18: 837–842.
14.
Haynesworth, S.E., M.A. Baber, A.I. Caplan (1992) Characterization of cells with osteogenic potential from human marrow. Bone 13: 81–88.
15.
Haynesworth, S.E., M.A. Baber, A.I. Caplan (1996) Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: Effects of dexamethasone and IL-1 alpha. J Cell Physiol 166: 585–592.
16.
Horwitz, E.M., D.J. Prockop, L.A. Fitzpatrick, W.W.K. Koo, P.L. Gordon. M. Neel, M. Sussman, P. Orchard, J.C. Marx, R.E. Pyeritz, M.K. Brenner (1999) Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5: 309–313.
17.
Hou, Z., Q. Nguyen, B. Frenkel, S.K. Nilsson, M. Milne, A.J. van Wijnen, J.L. Stein, P. Quesenberry, J.B. Lian, G.S. Stein (1999) Osteoblast-specific gene expression after transplantation of marrow cells: Implications for skeletal therapy. Proc Natl Acad Sci USA 96: 7294–7299.
18.
Ishida, T., M. Inaba, H. Hisha, et al (1994) Requirement of donor-derived stromal cells in the bone marrow for successful allogeneic bone marrow transplantation. J Immunol 152: 3319–3127.
19.
Jacobsen, K., J. Kravitz, P.W. Kincade, D.G. Osmond (1996) Adhesion receptors on bone marrow stromal cells: In vivo expression of vascular cell adhesion molecule-1 by reticular cells and sinusoidal endothelium in normal and γ-irradiated mice. Blood 87: 73–82.
20.
Jilka, R.L., R.S. Weinstein, K. Takahashi, A.M. Parfitt, S.C. Manolagas (1996) Linkage of decreased bone mass with impaired osteoblastogenesis in a murine model of accelerated senescence. J Clin Invest 97: 1732–1740.
21.
Johnstone, B., T.H. Hering, V.M. Goldberg, J.U. Yoo, A.I. Caplan (1998) In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Exp Cell Res 238: 265–272.
22.
Johnstone, B., J.U. Yoo (1999) Autologous mesenchymal progenitor cells in articular cartilage repair. Clin Orthop 367S: 156–162.
23.
Koc, O.N., S.L. Gerson, B.W. Cooper, S.M. Dyhouse, S.E. Haynesworth, A.I. Caplan, N.T. Tainer, M.L. Lazarus (2000) Rapid hematopoietic recovery after co-infusion of autologous blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high dose chemotherapy. J Clin Oncol 18: 307–316.
24.
Krossnes, B.K., S. Geisler, O. Mella (1998) Intravenous infusion of glucose and the vasodilator sodium nitroprusside in combination with local hyperthermia: Effect on tumor pH and tumor response in the BT4An rat tumor model. Int J Hyperthermia 14: 403–416.
25.
Krossnes, B.K., O. Mella, O. Dahl (1996) Use of the vasodilator sodium nitroprusside during local hyperthermia: Effects on tumor temperature and tumor response in a rat tumor model. Int J Radiat Oncol Biol Phys 36 : 403–415.
26.
Kuppen, P.J., A. Marinelli, J.A. Camps, E.K. Pauwels, C.J. van de Velde, G.J. Fleuren, A.M. Eggermont (1992) Distribution of lymphokine-activated killer (LAK) cells in Wag rats after hepatic-artery or jugular vein infusion. Int J Cancer 9: 266–270.
27.
Kuyama, J., A. McCormack, A.J. George, B.T. Heelan, S. Osman, J.R. Batchelor, A.M. Peters (1997) Indium-111 labeled lymphocytes: Isotope distribution and cell division. Eur J Nucl Med 24: 488–496.
28.
Lazarus, H.K., S.E. Haynesworth, S.L. Gerson, N.S. Rosenthal, A.I. Caplan (1995) Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): Implications for therapeutic use. Bone Marrow Transplant 16: 557–564.
29.
Leneveu, H., F. Bremont, H. Rubie, et al (1999) Respiratory function in children undergoing bone marrow transplantation. Pediatr Pulmonol 28: 31–38.
30.
Lennon, D.P., S.E. Haynesworth, R.G. Young, J.E. Dennis, A.I. Caplan (1995) A chemically defined medium supports in vitro proliferation and maintains the osteochondral potential of rat marrow-derived mesenchymal stem cells. Exp Cell Res 219: 211–222.
31.
Li, K.J., M.S. Dilber, M.R. Abedi, B. Björkstrand, C.I.E. Smith, H. Caroff, G. Gahrton, K.G. Xanthopoulos (1995) Retroviral-mediated gene transfer into human bone marrow stromal cells: Studies of efficiency and in vivo survival in SCID mice. Eur J Haematol 55: 302–306.
32.
Oyama, M., A. Tatlock, S. Fukuta, K. Kavalkovich, B. Johnstone, P.D. Robbins, C.H. Evans, C. Niyibizi (1999) Retrovirally transduced bone marrow stromal cells isolated from a mouse model of human osteogenesis imperfecta (oim) persist in bone and retain the ability to form cartilage and bone after extended passaging. Gene Ther 6: 321–329.
33.
Parfitt, A.M., A.R. Vilanueva, J. Foldes, D.S. Rao (1995) Relations between histologic indices of bone formation: Implications for the pathogenesis of spinal osteoporosis. J Bone Miner Res 10: 466–473.
34.
Pereira, R.F., K.W. Halford, W.D. O’Hara, D.B. Leeper, B.P. Sokolov, M.D. Pollard, O. Bagasra, D.J. Prockop (1995) Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proc Natl Acad Sci USA 92: 4857–4861.
35.
Pereira, R.F., M.D. O’Hara, A.V. Laptev, K.W. Halford, M.D. Pollard, R. Class, D. Simon, K. Livenzey, D.J. Prockop (1998) Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis inperfecta. Proc Natl Acad Sci USA 95: 1142–1147.
36.
Piersma, A.H., R.E. Ploemacher, G.M. Brockbank (1983) Transplantation of bone marrow fibroblastoid stromal cells in mice via the intravenous route. Br J Haematol 54: 285–290.
37.
Pittenger, M.F., A.M. Mackay, S.C. Beck, et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 248: 143–147.
38.
Richardson, D.R. (1976) The microcirculation and regulation of blood flow; in Richardson, D.R. (ed): Basic Circulator Physiology. Boston, Little, Brown, pp 101–136.
39.
Selden, C. (1984) The pulmonary vascular bed as a site for implantation of isolated liver cells in inbred rats. Transplantation 38: 81–83.
40.
Tavassoli, M. (1979) The marrow-blood barrier. Br J Haematol 41: 297–302.
41.
Tavassoli, M., C.L. Hardy (1990) Molecular basis of homing of intravenously transplanted stem cells to the marrow. Blood 76: 1059–1070.
42.
Thakur, M.L. (1983) Radioisotopic labeling of platelets: A historical perspective. Semin Thromb Hemost 9: 79–85.
43.
Tinker, J.H., J.D. Michenfelder (1976) Sodium nitroprusside: Pharmacology, toxicology and therapeutics. Anesthesiology 45: 340–354.
44.
Weimar, I.S., N. Miranda, E.J. Muller, A. Hekman, J.M. Kerst, G.C. de Gast, W.R. Gerritsen (1998) Hepatocyte growth factor/scatter factor (HGF/SF) is produced by human bone marrow stromal cells and promotes proliferation, adhesion and survival of human hematopoietic progenitor cells (CD34+). Exp Hematol 26: 885–894.
45.
Xu, T., L. Chuang, M. Yagami, J. Gasser, M. Thiede (1999) Engraftment potential of transplanted mesenchymal stem cells in non-conditioned rats. Am Soc Bone Miner Res SU168 S437.
46.
Young, R.G., D.L. Butler, W. Weber, A.I. Caplan, S.L. Gordon, D.J. Fink (1998) Use of mesenchymal stem cells in a collagen matrix for Achilles tendon repair. J Orthop Res 16: 406–413.
47.
Zakhireh, B., M.L. Thakur, H.L. Malech, M.S. Cohen, A. Gottschalk, R.K. Root (1979) Indium-111-labeled human polymorphonuclear leukocytes: Viability, random migration, chemotaxis, bactericidal capacity and ultrastructure. J Nucl Med 20: 741–747.
© 2001 S. Karger AG, Basel
2001
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.