Marrow mesenchymal stem cells (MSCs) are multipotent progenitor cells and reported to be immunoprivileged as well as immunosuppressive. Hence, MSCs might be ideal candidates for allogeneic transplantation to induce regeneration of damaged tissues/organs. To confirm the differentiation capability of allogeneic MSCs in vivo is important for the acceleration of regenerative medicine. Consequently, we have established an in vivo rat model using subcutaneous implantation of a hydroxyapatite (HA) ceramic/MSCs composite. Osteogenic differentiation was used as an indicator of differentiation. When syngeneic MSCs were implanted, MSCs showed osteogenic differentiation as evidenced by new bone formation as well as high alkaline phosphatase (ALP) activity. When allogeneic MSCs were implanted, none of the allografts survived or showed osteogenic differentiation. However, when the recipient rats were treated with FK506 immunosuppressant, allogeneic MSCs showed osteogenic differentiation. Although this finding might not be adequate for the acceleration of regenerative medicine, these results did confirm that MSCs are not intrinsically immunoprivileged but that under appropriate immunosuppressant treatment, allogeneic MSCs can survive and show differentiation capability in vivo.
AkahaneM.; OhgushiH.; KuriyamaS.; AkahaneT.; TakakuraY.Hydroxyapatite ceramics as a carrier of gene-transduced bone marrow cells.J. Orthop. Sci.7: 677–682; 2002.
3.
AkahaneM.; OhgushiH.; YoshikawaT.; SempukuT.; TamaiS.; TabataS.; DohiY.Osteogenic phenotype expression of allogeneic rat marrow cells in porous hydroxyapatite ceramics.J. Bone Miner. Res.14: 561–568; 1999.
4.
ArinzehT. L.; PeterS. J.; ArchambaultM. P.; van den BosC.; GordonS.; KrausK.; SmithA.; KadiyalaS.Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect.J. Bone Joint Surg. Am.85–A: 1927–1935; 2003.
5.
BartholomewA.; SturgeonC.; SiatskasM.; FerrerK.; McIntoshK.; PatilS.; HardyW.; DevineS.; UckerD.; DeansR.; MoseleyA.; HoffmanR.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp. Hematol.30: 42–48; 2002.
6.
EliopoulosN.; StaggJ.; LejeuneL.; PommeyS.; GalipeauJ.Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice.Blood106: 4057–4065; 2005.
7.
FriedensteinA. J.; ChailakhyanR. K.; LatsinikN. V.; PanasyukA. F.; Keiliss-BorokI. V.Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues.Cloning in vitro and retransplantation in vivo. Transplantation17: 331–340; 1974.
8.
GillT. J.3rd; KunzH. W.; MisraD. N.; HassettA. L.The major histocompatibility complex of the rat.Transplantation43: 773–785; 1987.
KatoK.; AokiH.; TabataT.; OgisoM.Biocompatibility of apatite ceramics in mandibles.Biomater. Med. Devices Artif. Organs7: 291–297; 1979.
11.
KotobukiN.; HiroseM.; MachidaH.; KatouY.; MurakiK.; TakakuraY.; OhgushiH.Viability and osteogenic potential of cryopreserved human bone marrow-derived mesenchymal cells.Tissue Eng.11: 663–673; 2005.
12.
KotobukiN.; HiroseM.; TakakuraY.; OhgushiH.Cultured autologous human cells for hard tissue regeneration: Preparation and characterization of mesenchymal stem cells from bone marrow.Artif. Organs28: 33–39; 2004.
13.
KotobukiN.; KawagoeD.; NomuraD.; KatouY.; MurakiK.; FujimoriH.; GotoS.; IokuK.; OhgushiH.Observation and quantitative analysis of rat bone marrow stromal cells cultured in vitro on newly formed transparent beta-tricalcium phosphate.J. Mater. Sci. Mater. Med.17: 33–41; 2006.
14.
MajumdarM. K.; ThiedeM. A.; MoscaJ. D.; MoormanM.; GersonS. L.Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells.J. Cell Physiol.176: 57–66; 1998.
15.
ManiatopoulosC.; SodekJ.; MelcherA. H.Bone formation in vitro by stromal cells obtained from bone marrow of young adult rats.Cell Tissue Res.254: 317–330; 1988.
16.
MorishitaT.; HonokiK.; OhgushiH.; KotobukiN.; MatsushimaA.; TakakuraY.Tissue engineering approach to the treatment of bone tumors: Three cases of cultured bone grafts derived from patients' mesenchymal stem cells.Artif. Organs30: 115–118; 2006.
17.
NautaA. J.; WesterhuisG.; KruisselbrinkA. B.; LurvinkE. G.; WillemzeR.; FibbeW. E.Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a non-myeloablative setting.Blood108: 2114–2120; 2006.
18.
OhgushiH.; KitamuraS.; KotobukiN.; HiroseM.; MachidaH.; MurakiK.; TakakuraY.Clinical application of marrow mesenchymal stem cells for hard tissue repair.Yonsei Med. J.45(Suppl.): 61–67; 2004.
19.
OhgushiH.; KotobukiN.; FunaokaH.; MachidaH.; HiroseM.; TanakaY.; TakakuraY.Tissue engineered ceramic artificial joint—ex vivo osteogenic differentiation of patient mesenchymal cells on total ankle joints for treatment of osteoarthritis.Biomaterials26: 4654–4661; 2005.
20.
PittengerM. F.; MackayA. M.; BeckS. C.; JaiswalR. K.; DouglasR.; MoscaJ. D.; MoormanM. A.; SimonettiD. W.; CraigS.; MarshakD. R.Multilineage potential of adult human mesenchymal stem cells.Science284: 143–147; 1999.
21.
RasmussonI.; RingdenO.; SundbergB.; Le BlancK.Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms.Exp. Cell Res.305: 33–41; 2005.
22.
SempukuT.; OhgushiH.; OkumuraM.; TamaiS.Osteogenic potential of allogeneic rat marrow cells in porous hydroxyapatite ceramics: A histological study.J. Orthop. Res.14: 907–913; 1996.
23.
SudresM.; NorolF.; TrenadoA.; GregoireS.; CharlotteF.; LevacherB.; LatailladeJ. J.; BourinP.; HolyX.; VernantJ. P.; KlatzmannD.; CohenJ. L.Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice.J. Immunol.176: 7761–7767; 2006.
