Abstract
Mesenchymal stem cells (MSC) obtained from human bone marrow have been described as adult stem cells with the ability of extensive self-renewal and clonal expansion, as well as the capacity to differentiate into various tissue types and to modulate the immune system. Some data indicate that leukapheresis products may also contain non-hematopoietic stem cells, as they occur in whole bone marrow transplantation (BMT). However, there is still controversy whether MSC expand in the host after transplantation like blood progenitor cells do. Therefore, we were interested in finding out if graft MSC can be detected in leukapheresis products and in bone marrow after BMT and peripheral blood stem cell transplantation (PBSCT). Every sample from total bone marrow transplants exhibited growth of MSC after in vitro culture, but not one of nine leukapheresis products did. In addition, bone marrow aspirates of 9 patients receiving BMT and of 18 patients after PBSCT were examined for origin of MSC. Almost all MSC samples exhibited a complete host profile, whereas peripheral blood cells were of donor origin. We conclude that even if trace amounts of MSC are co-transplanted during PBSCT or BMT, they do not expand significantly in the host bone marrow.
Similar content being viewed by others
References
Caplan AI (1991) Mesenchymal stem cells. J Orthop Res 9:641–650
Caplan AI (1994) The mesengenic process. Clin Plast Surg 21:429–435
Reyes M, Lund T, Lenvik T, Aguiar D, Koodie L, Verfaillie CM (2001) Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood 98:2615–2625
Cassiede P, Dennis JE, Ma F, Caplan AI (1996) Osteochondrogenic potential of marrow mesenchymal progenitor cells exposed to TGF-beta 1 or PDGF-BB as assayed in vivo and in vitro. J Bone Miner Res 11:1264–1273
Kadiyala S, Young RG, Thiede MA, Bruder SP (1997) Culture expanded canine mesenchymal stem cells possess osteochondrogenic potential in vivo and in vitro. Cell Transplant 6:125–134
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147
Jaiswal RK, Jaiswal N, Bruder SP, Mbalaviele G, Marshak DR, Pittenger MF (2000) Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. J Biol Chem 275:9645–9652
Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD (2002) Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105:93–98
Wakitani S, Saito T, Caplan AI (1995) Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve 18:1417–1426
Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G et al (1998) Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279:1528–1530
Kopen GC, Prockop DJ, Phinney DG (1999) Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A 96:10711–10716
Liechty KW, MacKenzie TC, Shaaban AF, Radu A, Moseley AM, Deans R et al (2000) Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 6:1282–1286
Haynesworth SE, Baber MA, Caplan AI (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
Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL (1998) Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol 176:57–66
Cheng L, Qasba P, Vanguri P, Thiede MA (2000) Human mesenchymal stem cells support megakaryocyte and pro-platelet formation from CD34(+) hematopoietic progenitor cells. J Cell Physiol 184:58–69
Koc ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI et al (2000) Rapid hematopoietic recovery after coinfusion 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
Almeida-Porada G, El Shabrawy D, Porada C, Zanjani ED (2002) Differentiative potential of human metanephric mesenchymal cells. Exp Hematol 30:1454–1462
Li Y, Hisha H, Inaba M, Lian Z, Yu C, Kawamura M et al (2000) Evidence for migration of donor bone marrow stromal cells into recipient thymus after bone marrow transplantation plus bone grafts: a role of stromal cells in positive selection. Exp Hematol 28:950–960
Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S et al (2002) Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30:42–48
Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P et al (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99:3838–3843
Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M et al (2004) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363:1439–1441
Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O (2003) Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 57:11–20
Rasmusson I, Ringden O, Sundberg B, Le Blanc K (2003) Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 76:1208–1213
Gotherstrom C, Ringden O, Westgren M, Tammik C, Le Blanc K (2004) Immunomodulatory effects of human foetal liver-derived mesenchymal stem cells. Bone Marrow Transplant 33:1167
Friedenstein AJ, Gorskaja JF, Kulagina NN (1976) Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 4:267–274
Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J et al (2001) Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7:430–436
Conrad C, Gottgens B, Kinston S, Ellwart J, Huss R (2002) GATA transcription in a small rhodamine 123(low)CD34(+) subpopulation of a peripheral blood-derived CD34(−)CD105(+) mesenchymal cell line. Exp Hematol 30:887–895
Lazarus HM, Haynesworth SE, Gerson SL, Caplan AI (1997) Human bone marrow-derived mesenchymal (stromal) progenitor cells (MPCs) cannot be recovered from peripheral blood progenitor cell collections. J Hematother 6:447–455
Cilloni D, Carlo-Stella C, Falzetti F, Sammarelli G, Regazzi E, Colla S et al (2000) Limited engraftment capacity of bone marrow-derived mesenchymal cells following T-cell-depleted hematopoietic stem cell transplantation. Blood 96:3637–3643
Keating A, Singer JW, Killen PD, Striker GE, Salo AC, Sanders J et al (1982) Donor origin of the in vitro haematopoietic microenvironment after marrow transplantation in man. Nature 298:280–283
Simmons PJ, Przepiorka D, Thomas ED, Torok-Storb B (1987) Host origin of marrow stromal cells following allogeneic bone marrow transplantation. Nature 328:429–432
Hongeng S, Petvises S, Rerkamnuaychoke B, Worapongpaiboon S, Tardtong P, Apibal S et al (2001) Host origin of marrow mesenchymal stem cells following allogeneic cord-blood stem-cell transplantation. Int J Hematol 74:235–236
Koc ON, Peters C, Aubourg P, Raghavan S, Dyhouse S, DeGasperi R et al (1999) Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases. Exp Hematol 27:1675–1681
Laver J, Jhanwar SC, O’Reilly RJ, Castro-Malaspina H (1987) Host origin of the human hematopoietic microenvironment following allogeneic bone marrow transplantation. Blood 70:1966–1968
Devine SM, Bartholomew AM, Mahmud N, Nelson M, Patil S, Hardy W et al (2001) Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol 29:244–255
Mosca JD, Hendricks JK, Buyaner D, Davis-Sproul J, Chuang LC, Majumdar MK et al (2000) Mesenchymal stem cells as vehicles for gene delivery. Clin Orthop Relat Res:S71–S90
Bruder SP, Jaiswal N, Haynesworth SE (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
Brendel C, Kuklick L, Hartmann O, Kim TD, Boudriot U, Schwell D et al (2005) Distinct gene expression profile of human mesenchymal stem cells in comparison to skin fibroblasts employing cDNA microarray analysis of 9600 genes. Gene Expr (in press)
Thiede C, Florek M, Bornhäuser M, Ritter M, Mohr B, Brendel C et al (1999) Rapid quantification of mixed chimerism using multiplex amplification of short tandem repeat markers and fluorescence detection. Bone Marrow Transplant 23:1055–1060
Reyes M, Koodie L, Jahagirdar B, Verfaillie CM (2001) Ex vivo and in vivo primitive hematopoiesis from a non-hematopoietic stem cell. Blood 98:713a
Galotto M, Berisso G, Delfino L, Podesta M, Ottaggio L, Dallorso S et al (1999) Stromal damage as consequence of high-dose chemo/radiotherapy in bone marrow transplant recipients. Exp Hematol 27:1460–1466
Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI (2001) The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 169:12–20
Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY et al (2002) Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc Natl Acad Sci U S A 99:8932–8937
Agematsu K, Nakahori Y (1991) Recipient origin of bone marrow-derived fibroblastic stromal cells during all periods following bone marrow transplantation in humans. Br J Haematol 79:359–365
Ikpeazu C, Davidson MK, Halteman D, Browning PJ, Brandt SJ (2000) Donor origin of circulating endothelial progenitors after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 6:301–308
O’Donoghue K, Chan J, de la Fuente J, Kennea N, Sandison A, Anderson JR et al (2004) Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. Lancet 364:179–182
Cutler C, Giri S, Jeyapalan S, Paniagua D, Viswanathan A, Antin JH (2001) Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis. J Clin Oncol 19:3685–3691
Flowers ME, Parker PM, Johnston LJ, Matos AV, Storer B, Bensinger WI et al (2002) Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood 100:415–419
Acknowledgements
This work was supported by a grant from the Bundesministerium für Bildung und Forschung, grant 01GN0125. The authors would like to thank Kathleen Stabla, Dagmar Schwell, Jenny Eckhardt and Sarah Fehl for technical assistance. We also would like to thank Ramona Vietzke, who organised all transplantation data conscientiously and skillfully.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dickhut, A., Schwerdtfeger, R., Kuklick, L. et al. Mesenchymal stem cells obtained after bone marrow transplantation or peripheral blood stem cell transplantation originate from host tissue. Ann Hematol 84, 722–727 (2005). https://doi.org/10.1007/s00277-005-1067-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-005-1067-8