Perivascular multipotent mesenchymal progenitors exist in a variety of tissues, including the placenta. Here, we suggest that the abundant vasculature present in the human placenta can serve as a source of myogenic cells to regenerate skeletal muscle. Chorionic villi dissected from the mid-gestation human placenta were first transplanted intact into the gastrocnemius muscles of SCID/mdx mice, where they participated in muscle regeneration by producing myofibers expressing human dystrophin and spectrin. In vitro-cultured placental villi released rapidly adhering and migratory CD146+CD34−CD45−CD56− cells of putative perivascular origin that expressed mesenchymal stem cell markers. CD146+CD34−CD45−CD56− perivascular cells isolated and purified from the placental villi by flow cytometry were indeed highly myogenic in culture, and generated dystrophin-positive myofibers, and they promoted angiogenesis after transplantation into SCID/mdx mouse muscles. These observations confirm the existence of mesenchymal progenitor cells within the walls of human blood vessels, and suggest that the richly vascularized human placenta is an abundant source of perivascular myogenic cells able to migrate within dystrophic muscle and regenerate myofibers.
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References
1.
Turner. 1872. Observations on the structure of the human placenta. J Anat Physiol, 7:120–380.
2.
StraussF. 1964. [Structure and function of the human placenta.]Bibl Gynaecol, 28:3–29.
3.
In't AnkerPS, ScherjonSA, Kleijburg-van der KeurC, de Groot-SwingsGM, ClaasFH, FibbeWE, KanhaiHH. 2004. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells, 22:1338–1345.
HuppertzB, PeetersLL. 2005. Vascular biology in implantation and placentation. Angiogenesis, 8:157–167.
6.
DemirR, KayisliUA, CayliS, HuppertzB. 2006. Sequential steps during vasculogenesis and angiogenesis in the very early human placenta. Placenta, 27:535–539.
7.
PattilloRA, GeyGO, DelfsE, MattinglyRF. 1968. In vitro identification of the trophoblastic stem cell of the human villous placenta. Am J Obstet Gynecol, 100:582–588.
8.
KaufmannP, StarkJ, StegnerHE. 1977. The villous stroma of the human placenta. I. The ultrastructure of fixed connective tissue cells. Cell Tissue Res, 177:105–121.
9.
PrusaAR, HengstschlagerM. 2002. Amniotic fluid cells and human stem cell research: a new connection. Med Sci Monit, 8:RA253–RA257.
10.
PrusaAR, MartonE, RosnerM, BernaschekG, HengstschlagerM. 2003. Oct-4-expressing cells in human amniotic fluid: a new source for stem cell research?Hum Reprod, 18:1489–1493.
11.
TamagawaT, IshiwataI, SaitoS. 2004. Establishment and characterization of a pluripotent stem cell line derived from human amniotic membranes and initiation of germ layers in vitro. Hum Cell, 17:125–130.
De CoppiP, BartschGJr., SiddiquiMM, XuT, SantosCC, PerinL, MostoslavskyG, SerreAC, SnyderEY, YooJJ, FurthME, SokerS, AtalaA. 2007. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol, 25:100–106.
14.
MikiT, MitamuraK, RossMA, StolzDB, StromSC. 2007. Identification of stem cell marker-positive cells by immunofluorescence in term human amnion. J Reprod Immunol, 75:91–96.
15.
Portmann-LanzCB, SchoeberleinA, HuberA, SagerR, MalekA, HolzgreveW, SurbekDV. 2006. Placental mesenchymal stem cells as potential autologous graft for pre- and perinatal neuroregeneration. Am J Obstet Gynecol, 194:664–673.
16.
AlvianoF, FossatiV, MarchionniC, ArpinatiM, BonsiL, FranchinaM, LanzoniG, CantoniS, CavalliniC, BianchiF, TazzariPL, PasquinelliG, ForoniL, VenturaC, GrossiA, BagnaraGP. 2007. Term amniotic membrane is a high throughput source for multipotent mesenchymal stem cells with the ability to differentiate into endothelial cells in vitro. BMC Dev Biol, 7:11.
17.
IguraK, ZhangX, TakahashiK, MitsuruA, YamaguchiS, TakashiTA. 2004. Isolation and characterization of mesenchymal progenitor cells from chorionic villi of human placenta. Cytotherapy, 6:543–553.
18.
ZhangX, MitsuruA, IguraK, TakahashiK, IchinoseS, YamaguchiS, TakahashiTA. 2006. Mesenchymal progenitor cells derived from chorionic villi of human placenta for cartilage tissue engineering. Biochem Biophys Res Commun, 340:944–952.
19.
PoloniA, RosiniV, MondiniE, MauriziG, ManciniS, DiscepoliG, BiasioS, BattagliniG, BerardinelliE, SerraniF, LeoniP. 2008. Characterization and expansion of mesenchymal progenitor cells from first-trimester chorionic villi of human placenta. Cytotherapy, 10:690–697.
20.
StrakovaZ, LivakM, KrezalekM, IhnatovychI. 2008. Multipotent properties of myofibroblast cells derived from human placenta. Cell Tissue Res, 332:479–488.
21.
BattulaVL, TremlS, AbeleH, BuhringHJ. 2008. Prospective isolation and characterization of mesenchymal stem cells from human placenta using a frizzled-9-specific monoclonal antibody. Differ Res Biol Divers, 76:326–336.
22.
BrookeG, TongH, LevesqueJP, AtkinsonK. 2008. Molecular Trafficking Mechanisms of Multipotent Mesenchymal Stem Cells Derived from Human Bone Marrow and Placenta. Stem cells and development.
23.
CrisanM. 2008. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell, 3:301–313.
24.
ZimmerlinL, DonnenbergVS, PfeiferME, MeyerEM, PeaultB, RubinJP, DonnenbergAD. 2009. Stromal vascular progenitors in adult human adipose tissue. Cytometry A, 77:22–30.
25.
ChenCW, MontelaticiE, CrisanM, CorselliM, HuardJ, LazzariL, PeaultB. 2009. Perivascular multi-lineage progenitor cells in human organs: regenerative units, cytokine sources or both?Cytokine Growth Factor Rev, 20:429–434.
26.
DellavalleA, SampaolesiM, TonlorenziR, TagliaficoE, SacchettiB, PeraniL, InnocenziA, GalvezBG, MessinaG, MorosettiR, LiS, BelicchiM, PerettiG, ChamberlainJS, WrightWE, TorrenteY, FerrariS, BiancoP, CossuG. 2007. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat Cell Biol, 9:255–267.
27.
PeaultB, RudnickiM, TorrenteY, CossuG, TremblayJP, PartridgeT, GussoniE, KunkelLM, HuardJ. 2007. Stem and progenitor cells in skeletal muscle development, maintenance, and therapy. Mol Ther, 15:867–877.
28.
ZhengB, CaoB, CrisanM, SunB, LiG, LogarA, YapS, PollettJB, DrowleyL, CassinoT, GharaibehB, DeasyBM, HuardJ, PeaultB. 2007. Prospective identification of myogenic endothelial cells in human skeletal muscle. Nat Biotechnol, 25:1025–1034.
KangY, WangF, FengJ, YangD, YangX, YanX. 2006. Knockdown of CD146 reduces the migration and proliferation of human endothelial cells. Cell Res, 16:313–318.
31.
ChanJ, O'DonoghueK, GavinaM, TorrenteY, KenneaN, MehmetH, StewartH, WattDJ, MorganJE, FiskNM. 2006. Galectin-1 induces skeletal muscle differentiation in human fetal mesenchymal stem cells and increases muscle regeneration. Stem Cells, 24:1879–1891.
32.
HughesS, Chan-LingT. 2004. Characterization of smooth muscle cell and pericyte differentiation in the rat retina in vivo. Investig Ophthalmol Vis Sci, 45:2795–2806.
33.
CovasDT, PanepucciRA, FontesAM, SilvaWAJr., OrellanaMD, FreitasMC, NederL, SantosAR, PeresLC, JamurMC, ZagoMA. 2008. Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146+ perivascular cells and fibroblasts. Exp Hematol, 36:642–654.
34.
Angers-LoustauA, CoteJF, TremblayML. 1999. Roles of protein tyrosine phosphatases in cell migration and adhesion. Biochem Cell Biol, 77:493–505.
35.
ShihIM. 1999. The role of CD146 (Mel-CAM) in biology and pathology. J Pathol, 189:4–11.
36.
CaceresM, HidalgoR, SanzA, MartinezJ, RieraP, SmithPC. 2008. Effect of platelet-rich plasma on cell adhesion, cell migration, and myofibroblastic differentiation in human gingival fibroblasts. J Periodontol, 79:714–720.
KnudsenKA, McElweeSA, MyersL. 1990. A role for the neural cell adhesion molecule, NCAM, in myoblast interaction during myogenesis. Dev Biol, 138:159–168.
39.
Belles-IslesM, RoyR, DansereauG, GouletM, RoyB, BouchardJP, TremblayJP. 1993. Rapid selection of donor myoblast clones for muscular dystrophy therapy using cell surface expression of NCAM. Eur J Histochem, 37:375–380.
40.
StewartJD, MasiTL, CummingAE, MolnarGM, WentworthBM, SampathK, McPhersonJM, YaegerPC. 2003. Characterization of proliferating human skeletal muscle-derived cells in vitro: differential modulation of myoblast markers by TGF-beta2. J Cell Physiol, 196:70–78.
41.
DeasyBM, FeduskaJM, PayneTR, LiY, AmbrosioF, HuardJ. 2009. Effect of VEGF on the regenerative capacity of muscle stem cells in dystrophic skeletal muscle. Mol Ther, 17:1788–1798.
42.
DeasyBM, JankowskiRJ, HuardJ. 2001. Muscle-derived stem cells: characterization and potential for cell-mediated therapy. Blood Cells Mol Dis, 27:924–933.
43.
CaoB, DeasyBM, PollettJ, HuardJ. 2005. Cell therapy for muscle regeneration and repair. Phys Med Rehabil Clin N Am, 16:889–907, viii.
44.
CollettGD, CanfieldAE. 2005. Angiogenesis and pericytes in the initiation of ectopic calcification. Circ Res, 96:930–938.
45.
InverniciG, EmanueliC, MadedduP, CristiniS, GadauS, BenettiA, CiusaniE, StassiG, SiragusaM, NicosiaR, PeschleC, FascioU, ColomboA, RizzutiT, ParatiE, AlessandriG. 2007. Human fetal aorta contains vascular progenitor cells capable of inducing vasculogenesis, angiogenesis, and myogenesis in vitro and in a murine model of peripheral ischemia. Am J Pathol, 170:1879–1892.
46.
YangYI, KimHI, ChoiMY, SonSH, SeoMJ, SeoJY, JangWH, YounYC, ChoiKJ, CheongSH, ShelbyJ. 2010. Ex vivo organ culture of adipose tissue for in situ mobilization of adipose-derived stem cells and defining the stem cell niche. J Cell Phys, 224:807–816.
47.
MaierCL, ShepherdBR, YiT, PoberJS. 2010. Explant outgrowth, propagation and characterization of human pericytes. Microcirculation, 17:367–380.
48.
AlbihnA, WaelchliRO, SamperJ, OriolJG, CroyBA, BetteridgeKJ. 2003. Production of capsular material by equine trophoblast transplanted into immunodeficient mice. Reproduction, 125:855–863.
49.
RajashekharG, TraktuevDO, RoellWC, JohnstoneBH, Merfeld-ClaussS, Van NattaB, RosenED, MarchKL, ClaussM. 2008. IFATS collection: Adipose stromal cell differentiation is reduced by endothelial cell contact and paracrine communication: role of canonical Wnt signaling. Stem Cells, 26:2674–2681.
50.
GenbacevO, SchubachSA, MillerRK. 1992. Villous culture of first trimester human placenta—model to study extravillous trophoblast (EVT) differentiation. Placenta, 13:439–461.
51.
NewbyD, MarksL, CousinsF, DuffieE, LyallF. 2005. Villous explant culture: characterization and evaluation of a model to study trophoblast invasion. Hypertens Pregnancy, 24:75–91.
52.
DominiciM, Le BlancK, MuellerI, Slaper-CortenbachI, MariniF, KrauseD, DeansR, KeatingA, ProckopD, HorwitzE. 2006. Minimal criteria for defining multipotent mesenchymal stromal cells. International Society for Cellular Therapy position statement. Cytotherapy, 8:315–317.
53.
LeeMY, HuangJP, ChenYY, AplinJD, WuYH, ChenCY, ChenPC, ChenCP. 2009. Angiogenesis in differentiated placental multipotent mesenchymal stromal cells is dependent on integrin alpha5beta1. PLoS ONE, 4:e6913.
54.
da Silva MeirellesL, CaplanAI, NardiNB. 2008. In Search of the in vivo Identity of Mesenchymal Stem Cells. Stem Cells, 26:2287–2299.
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