Therapies based on stem cells have shown very attractive potential in many clinical studies. However, the data about the safety of stem cells application remains insufficient. The present study was designed to evaluate the overall toxicology of human umbilical cord mesenchymal stem cells (hUC-MSCs) in cynomolgus monkeys with repeated administrations. hUC-MSCs were administered by intravenous injection once every 2 weeks for 6 weeks. The dose levels employed in this study were 2×106, 1×107 cells/kg body weight. Toxicity was evaluated by clinical observations (body weight, body temperature, and ophthalmology exams), pathology (blood cell counts, clinical biochemistry, urinalysis, and bone marrow smears), immunologic consequences (lymphoproliferation assay, the secretion of interferon-γ and interleukin-4, the percentage of CD3, CD4, CD8 T cells, and the ratio of CD4 and CD8 T cells) and anatomic pathology. Pharmacodynamics in blood and distribution of hUC-MSCs in the tissues of cynomolgus monkeys were measured by real-time polymerase chain reaction. All animals survived until scheduled euthanasia. No stem cells transplantation-related toxicity was found in this study. hUC-MSCs could be found in the blood of cynomolgus monkeys beyond 8 h. The findings of this 6-week toxicity study showed that the transplantation of hUC-MSCs did not affect the general health of cynomolgus monkeys.
LuLL, LiuYJ, YangSG, ZhaoQJ, WangX, GongW, HanZB, XuZS, LuYX, LiuD, ChenZZ, HanZC. 2006. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica, 91:1017–1026.
LeeOK, KuoTK, ChenWM, LeeKD, HsiehSL, ChenTH. 2004. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood, 103:1669–1675.
6.
SteigmanSA, FauzaDO. 2007. Isolation of mesenchymal stem cells from amniotic fluid and placenta. Curr Protoc Stem Cell Biol, Chapter 1,Unit 1E:2.
7.
JaquetK, KrauseKT, DenschelJ, FaesslerP, NauerzM, GeidelS, BoczorS, LangeC, StuteN, ZanderA, KuckKH. 2005. Reduction of myocardial scar size after implantation of mesenchymal stem cells in rats: what is the mechanism?Stem Cells Dev, 14:299–309.
8.
ShakeJG, GruberPJ, BaumgartnerWA, SenechalG, MeyersJ, RedmondJM, PittengerMF, MartinBJ. 2002. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg, 73:1919–1925discussion 1926.
9.
BartunekJ, CroissantJD, WijnsW, GofflotS, de LavareilleA, VanderheydenM, KaluzhnyY, MazouzN, WillemsenPet al.2007. Pretreatment of adult bone marrow mesenchymal stem cells with cardiomyogenic growth factors and repair of the chronically infarcted myocardium. Am J Physiol Heart Circ Physiol, 292:H1095–H1104.
10.
ChenSL, FangWW, YeF, LiuYH, QianJ, ShanSJ, ZhangJJ, ChunhuaRZ, LiaoLM, LinS, SunJP. 2004. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol, 94:92–95.
11.
FlorenzanoF, MinguellJJ. 2005. Autologous mesenchymal stem cell transplantation after acute myocardial infarction. Am J Cardiol, 95:435.
12.
WollertKC, MeyerGP, LotzJ, Ringes-LichtenbergS, LippoltP, BreidenbachC, FichtnerS, KorteT, HornigBet al.2004. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet, 364:141–148.
13.
UndaleAH, WestendorfJJ, YaszemskiMJ, KhoslaS. 2009. Mesenchymal stem cells for bone repair and metabolic bone diseases. Mayo Clin Proc, 84:893–902.
14.
Le BlancK, FrassoniF, BallL, LocatelliF, RoelofsH, LewisI, LaninoE, SundbergB, BernardoMEet al.2008. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet, 371:1579–1586.
15.
NakaoN, NakayamaT, YahataT, MugurumaY, SaitoS, MiyataY, YamamotoK, NaoeT. 2010. Adipose tissue-derived mesenchymal stem cells facilitate hematopoiesis in vitro and in vivo: advantages over bone marrow-derived mesenchymal stem cells. Am J Pathol, 177:547–554.
BeggsKJ, LyubimovA, BornemanJN, BartholomewA, MoseleyA, DoddsR, ArchambaultMP, SmithAK, McIntoshKR. 2006. Immunologic consequences of multiple, high-dose administration of allogeneic mesenchymal stem cells to baboons. Cell Transplant, 15:711–721.
22.
HurttME, PlackeME, KillingerJM, SingerAW, KennedyGLJr.1992. 13-week inhalation toxicity study of dimethylformamide (DMF) in cynomolgus monkeys. Fundam Appl Toxicol, 18:596–601.
23.
SmithBB, CosenzaME, ManciniA, DunstanC, GregsonR, MartinSW, SmithSY, DavisH. 2003. A toxicity profile of osteoprotegerin in the cynomolgus monkey. Int J Toxicol, 22:403–412.
24.
BraenAP, PerronJ, TellierP, CatalaAR, KolaitisG, GengW. 2010. A 4-week intrathecal toxicity and pharmacokinetic study with trastuzumab in cynomolgus monkeys. Int J Toxicol, 29:259–267.
25.
BlairM, ChappelCI. 1998. 4-week range-finding and 1-year oral toxicity studies of sucrose acetate isobutyrate (SAIB) in the cynomolgus monkey. Food Chem Toxicol, 36:121–126.
26.
BugelskiPJ, ThiemPA, TrunehA, MorganDG. 1991. Recombinant human soluble CD4 does not inhibit immune function in cynomolgus monkeys. Toxicol Pathol, 19:580–588.
27.
DasKP, GreyBE, ZehrRD, WoodCR, ButenhoffJL, ChangSC, EhresmanDJ, TanYM, LauC. 2008. Effects of perfluorobutyrate exposure during pregnancy in the mouse. Toxicol Sci, 105:173–181.
28.
ChamanzaR, MarxfeldHA, BlancoAI, NaylorSW, BradleyAE. 2010. Incidences and range of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) used in toxicity studies. Toxicol Pathol, 38:642–657.
29.
JoCH, KimOS, ParkEY, KimBJ, LeeJH, KangSB, HanHS, RheeSH, YoonKS. 2008. Fetal mesenchymal stem cells derived from human umbilical cord sustain primitive characteristics during extensive expansion. Cell Tissue Res, 334:423–433.
30.
Le BlancK, RasmussonI, SundbergB, GotherstromC, HassanM, UzunelM, RingdenO. 2004. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet, 363:1439–1441.
31.
LimJH, LeeMH, YiHG, KimCS, KimJH, SongSU. 2010. Mesenchymal stromal cells for steroid-refractory acute graft-versus-host disease: a report of two cases. Int J Hematol, 92:204–207.
32.
BernardoME, BallLM, CometaAM, RoelofsH, ZeccaM, AvanziniMA, BertainaA, VintiL, LankesterAet al.2011. Co-infusion of ex vivo-expanded, parental MSCs prevents life-threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation. Bone Marrow Transplant, 46:200–207.
33.
PrasadVK, LucasKG, KleinerGI, TalanoJA, JacobsohnD, BroadwaterG, MonroyR, KurtzbergJ. 2011. Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol Blood Marrow Transplant, 17:534–541.
34.
TriggME, InversoDM. 2008. Nausea and vomiting with high-dose chemotherapy and stem cell rescue therapy: a review of antiemetic regimens. Bone Marrow Transplant, 42:501–506.
35.
KimDH, JamalN, SaragosaR, LoachD, WrightJ, GuptaV, KuruvillaJ, LiptonJH, MindenM, MessnerHA. 2007. Similar outcomes of cryopreserved allogeneic peripheral stem cell transplants (PBSCT) compared to fresh allografts. Biol Blood Marrow Transplant, 13:1233–1243.
36.
Del MastroL, VenturiniM, ViscoliC, BergaglioM, SignoriniA, BighinC, BertelliG, SeminoC, PietraGet al.2001. Intensified chemotherapy supported by DMSO-free peripheral blood progenitor cells in breast cancer patients. Ann Oncol, 12:505–508.
37.
IsakovaIA, DufourJ, LanclosC, BruhnJ, PhinneyDG. 2010. Cell-dose-dependent increases in circulating levels of immune effector cells in rhesus macaques following intracranial injection of allogeneic MSCs. Exp Hematol, 38:957–967.e1.
38.
MauryaDK, DoiC, PyleM, RachakatlaRS, DavisD, TamuraM, TroyerD. 2011. Non-random tissue distribution of human naive umbilical cord matrix stem cells. World J Stem Cells, 3:34–42.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
