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[(In)-339.2(vitro)-335.3(dif)-7.4(ferentia)-7.9(tion)]TJ
/F9 1 Tf
8.9663 0 0 8.9663 323.0361 561.5999 Tm
[(Adipogenic)-577.3(induction.)]TJ
/F4 1 Tf
10.2305 0 TD
[(hAdMSCs)-575.6(were)-571.2(plated)-576.8(at)-569(1)]TJ
/F5 1 Tf
13.2339 0 TD
()Tj
/F4 1 Tf
.7145 0 TD
(10)Tj
6.7246 0 0 5.9768 548.844 565.5684 Tm
(5)Tj
8.9663 0 0 8.9663 313.0582 550.6581 Tm
[(cells/mL)-934.3(in)-930.1(Keratinocyte-SFM-based)-938.4(media)-926.7(containing)]TJ
0 -1.2266 TD
[(0.2)-166.3(mM)-337.8(ascorbic)-333.3(acid,)-330.7(0.09)-165.9(mM)-337.8(calcium,)-329.5(5)-170.2(ng/mL)-333.8(rEGF,)-332.3(and)]TJ
0 -1.2203 TD
[(5%)-260.4(FBS.)-255.4(The)-259.2(medium)-262.2(was)-255.4(replaced)-260.1(with)-261.9(adipocyte)-260.8(induction)]TJ
T*
[(medium)-293.8(\(NH)-297.6(Adipodiff)-297.7(medium;)-290.4(Miltenyi)-295.8(Biotec\))-300.3(or)-288(control)]TJ
0 -1.2266 TD
[(medium)-578.3(when)-577.4(cells)-576.6(reached)-581.1(50%)-576(conuency.)-576.1(Cells)-577.5(were)]TJ
0 -1.2203 TD
[(maintained)-443.8(in)-436.9(culture)-442.9(for)-440.2(21)-441.6(days,)-434.8(with)-439(90%)-436.9(of)-439.5(the)-440(media)]TJ
T*
[(being)-312.8(replaced)-304.4(every)-309.2(3)-309.3(days.)-302(Adipogenic)-313.4(differentiation)-309.6(was)]TJ
0 -1.2266 TD
[(monitored)-342.9(by)-331.3(Oil)-332.6(red)-332.4(O)-331.8(staining.)]TJ
/F9 1 Tf
1.1128 -1.2203 TD
[(Osteogenic)-602.1(induction.)]TJ
/F4 1 Tf
10.1293 0 TD
[(hAdMSCs)-600.9(were)-596.5(plated)-602.1(at)-594.3(1)]TJ
/F5 1 Tf
13.335 0 TD
()Tj
/F4 1 Tf
.7145 0 TD
(10)Tj
6.7246 0 0 5.9768 548.844 466.9227 Tm
(5)Tj
8.9663 0 0 8.9663 313.0582 452.0125 Tm
[(cells/mL)-934.3(in)-930.1(Keratinocyte-SFM-based)-938.4(media)-926.7(containing)]TJ
0 -1.2203 TD
[(0.2)-166.3(mM)-337.8(ascorbic)-333.3(acid,)-330.7(0.09)-165.9(mM)-337.8(calcium,)-329.5(5)-170.2(ng/mL)-333.8(rEGF,)-332.3(and)]TJ
0 -1.2266 TD
[(5%)-254.1(FBS.)-249.1(The)-252.9(medium)-249.5(was)-249(replaced)-253.8(with)-249.3(osteoblast)-256.7(induction)]TJ
0 -1.2203 TD
[(medium)-331.7(\(NH)-335.6(Osteodiff)-331.1(medium;)-334.6(Miltenyi)-333.7(Biotec\))-331.9(or)-325.9(control)]TJ
T*
[(medium.)-397.9(The)-398.3(cells)-393.3(were)-394.1(maintained)-399.5(in)-392.6(culture)-398.6(for)-396(14)-397.4(days,)]TJ
0 -1.2266 TD
[(with)-363.1(90%)-361.1(of)-357.3(the)-364.2(media)-357.6(being)-363.4(replaced)-361.3(every)-359.7(3)-359.9(days.)-358.9(Osteo-)]TJ
0 -1.2203 TD
[(genic)-288.7(differentiation)-290.6(was)-280.7(detected)-284.1(by)-280.7(Alizarin)-287(red)-281.8(S)-283(staining.)]TJ
/F9 1 Tf
1.1128 -1.2203 TD
[(Chondrogenic)-1143.9(induction.)]TJ
/F4 1 Tf
11.8491 0 TD
[(hAdMSCs)-1144.7(were)-1146.6(plated)-1145.9(at)]TJ
-12.962 -1.2266 TD
(2.5)Tj
/F5 1 Tf
1.4163 0 TD
()Tj
/F4 1 Tf
.7208 0 TD
(10)Tj
6.7246 0 0 5.9768 341.1779 368.3338 Tm
(5)Tj
8.9663 0 0 8.9663 349.8519 364.3086 Tm
[(cells/mL)-599.2(in)-588.6(Keratinocyte-SFM-based)-603.3(media)-591.5(con-)]TJ
-4.1036 -1.2203 TD
[(taining)-587.3(0.2)-166.3(mM)-578.1(ascorbic)-579.9(acid,)-577.3(0.09)-165.8(mM)-584.4(calcium,)-576(5)-170.2(ng/mL)]TJ
T*
[(rEGF,)-288(and)-290.4(5%)-285.7(FBS.)-280.7(Cells)-286.7(were)-293(centrifuged)-288.3(at)-284.5(500)]TJ
/F9 1 Tf
21.7066 0 TD
(g)Tj
/F4 1 Tf
.784 0 TD
[(for)-288.5(5)-163.9(min,)]TJ
-22.4906 -1.2266 TD
[(resuspended)-887.7(in)-873.2(chondrogenic)-879.4(induction)-880.6(medium)-881.8(\(NH)]TJ
0 -1.2203 TD
[(chondrogenic)-639.1(medium;)-625.5(Miltenyi)-630.9(Biotec\),)-632(and)-631.9(centrifuged)]TJ
T*
[(again)-465.6(at)-461.5(500)]TJ
/F9 1 Tf
6.1206 0 TD
(g)Tj
/F4 1 Tf
.9611 0 TD
[(for)-465.5(5)-163.9(min)-466.1(to)-464.8(form)-463.1(pellets.)-461.8(The)-467.9(pellets)-465.3(were)]TJ
-7.0817 -1.2203 TD
[(maintained)-254.1(in)-247.2(culture)-253.2(using)-248(polypropylene)-257(tubes)-247.7(for)-250.5(14)-251.9(days,)]TJ
0 -1.2266 TD
[(with)-609.7(50%)-607.6(of)-603.9(the)-604.4(media)-604.2(being)-610(replaced)-607.9(every)-606.3(34)-605.5(days.)]TJ
0 -1.2203 TD
[(Chondrogenic)-349.2(differentiation)-341.2(was)-337.6(assayed)-344.1(by)-337.6(toluidine)-337.6(blue)]TJ
T*
[(O)-338.2(staining.)]TJ
/F9 1 Tf
1.1128 -1.2266 TD
[(Myogenic)-685.7(induction.)]TJ
/F4 1 Tf
9.7879 0 TD
[(hAdMSCs)-683.1(were)-685(plated)-684.3(at)-682.9(1)]TJ
/F5 1 Tf
13.6765 0 TD
()Tj
/F4 1 Tf
.7145 0 TD
(10)Tj
6.7246 0 0 5.9768 548.844 258.7464 Tm
(5)Tj
8.9663 0 0 8.9663 313.0582 243.7795 Tm
[(cells/mL)-934.3(in)-930.1(Keratinocyte-SFM-based)-938.4(media)-926.7(containing)]TJ
0 -1.2203 TD
[(0.2)-166.3(mM)-337.8(ascorbic)-333.3(acid,)-330.7(0.09)-165.9(mM)-337.8(calcium,)-329.5(5)-170.2(ng/mL)-333.8(rEGF,)-332.3(and)]TJ
0 -1.2266 TD
[(5%)-424.8(FBS.)-419.8(When)-423(cell)-423.6(growth)-424.4(reached)-423(50%,)-420.9(the)-421.1(medium)-420.2(was)]TJ
0 -1.2203 TD
[(replaced)-272.7(with)-261.9(induction)-273.6(medium)-262.2(\(SkGM)-266.5(medium)-268.5(containing)]TJ
T*
[(0.1%)-338.7(hEGF,)-341.3(dexamethason,)-338.3(GA)-335.3(1000,)-336.1(1%)-336.3(insulin,)-345.4(bovine)-337.2(se-)]TJ
T*
[(rum)-448.5(albumin)-449.6(and)-448.5(Fetuin;)-445.9(LONZA\))-448.4(and)-448.5(maintained)-450.1(for)-446.5(14)]TJ
0 -1.2267 TD
[(days.)-415.8(The)-410.9(cells)-418.5(were)-413.1(xed)-412.7(with)-413.7(4%)-412.1(paraformaldehyde)-417.6(and)]TJ
0 -1.2203 TD
[(incubated)-470.1(with)-464.3(a)-467.4(human)-460.5(myosin)-468.2(antibody)-464.1(\(1:500)-463(dilution;)]TJ
T*
[(Chemicon\).)-278.9(After)-274.8(3)-271.4(washes)-278.9(in)-272.5(PBS,)-271.3(cells)-279.4(were)-274(incubated)-274.1(with)]TJ
0 -1.2266 TD
[(a)-505.3(combination)-501.2(of)-502.8(AlexaFluor)-506.1(488-conjugated)-504.9(donkey)-504.8(anti-)]TJ
0 -1.2203 TD
[(mouse)-344.3(secondary)-336.8(antibodies)-338(and)-341(stained)-339.9(with)-337.8(DAPI)-341.4(for)-332.7(nu-)]TJ
T*
[(cleic)-340.6(acid)-327.8(detection.)]TJ
/F9 1 Tf
1.1128 -1.2266 TD
[(Neurogenic)-555.5(induction.)]TJ
/F4 1 Tf
10.3127 0 TD
[(hAdMSCs)-556.6(were)-552.2(plated)-551.5(at)-550.1(1)]TJ
/F5 1 Tf
13.1517 0 TD
()Tj
/F4 1 Tf
.7145 0 TD
(10)Tj
6.7246 0 0 5.9768 548.844 116.2771 Tm
(5)Tj
8.9663 0 0 8.9663 313.0582 101.3102 Tm
[(cells/mL)-472.7(in)-468.5(DMEM)-469.9(containing)-472.6(10%)-468.5(FBS,)-470.4(20)-163.4(ng/mL)-466.6(rEGF,)]TJ
0 -1.2203 TD
[(and)-429.5(20)-169.7(ng/mL)-428.7(FGF)-424.9(for)-427.6(3)-429.5(days.)-428.5(The)-429.9(medium)-426.6(was)-432.4(replaced)]TJ
0 -1.2266 TD
[(with)-470.6(neuronal)-469.8(induction)-469.7(medium)-470.8(\(DMEM)-464(containing)-472.6(10%)]TJ
0 -1.2203 TD
[(FBS,)-242.8(2%)-235.1(DMSO,)-238.6(200)]TJ
/F8 1 Tf
8.9027 0 TD
(m)Tj
/F4 1 Tf
.5501 0 TD
[(M)-239.1(BHA,)-234.9(1)]TJ
/F8 1 Tf
4.5272 0 TD
(m)Tj
/F4 1 Tf
.5501 0 TD
[(M)-239.1(hydrocortisone,)-246.3(5)]TJ
/F8 1 Tf
8.9532 0 TD
(m)Tj
/F4 1 Tf
.5501 0 TD
(g/mL)Tj
-24.0334 -1.2203 TD
[(insulin,)-434(0.5)-166.3(mM)-432.6(IBMX)-431.8(and)-429.5(1)-170.2(m)0(M)-426.3(cAMP\))-437.6(or)-427.1(control)-436.5(media.)]TJ
/F1 1 Tf
-27.9978 77.1964 TD
(1298)Tj
49.6665 0 TD
[(RA)-334.4(ET)-338.7(AL.)]TJ
ET
endstream
endobj
77 0 obj
<>stream
/GS1 gs
BT
/F4 1 Tf
8.9663 0 0 8.9663 59.7543 725.7825 Tm
0 0 0 1 k
0 Tc
0 Tw
[(The)-246.6(cells)-247.8(were)-248.7(maintained)-247.7(for)-250.5(8)-239.8(t)0(o)-249.8(1)0(0)-245.6(days)-242.2(at)-246.6(37)]TJ
/F5 1 Tf
20.6253 0 TD
()Tj
/F4 1 Tf
.3983 0 TD
[(C,)-243.4(xed)-248.3(with)]TJ
-21.0237 -1.2203 TD
[(4%)-633.4(paraformaldehyde,)-641.8(and)-631.9(incubated)-634.5(with)-635(human)-637.5(anti-)]TJ
0 -1.2266 TD
[(bodies)-571.4(against)-568.6(MAP2)-563.8(\(1:200)-564.2(dilution;)-568.3(Chemicon\),)-569.8(neuron)]TJ
0 -1.2203 TD
[(specic)-665.3(enolase)-667.9(\(1:10)-659.5(dilution;)-663.1(Abcam\),)-663.2(beta)-661.9(III)-663.9(tubulin)]TJ
T*
[(\(TUJ1\))-454.3(\(1:1,000)-452.8(dilution;)-454.5(Abcam\),)-454.5(or)-452.4(GFAP)-454.8(\(1:250)-450.4(dilution;)]TJ
0 -1.2266 TD
[(Chemicon\).)-278.9(After)-274.8(3)-271.4(washes)-278.9(in)-272.5(PBS,)-271.3(cells)-279.4(were)-274(incubated)-274.1(with)]TJ
0 -1.2203 TD
[(a)-322(combination)-330.5(of)-319.4(AlexaFluor)-329.1(488-)-321.5(or)-325.9(555-conjugated)-321.6(donkey)]TJ
T*
[(anti-mouse)-516.1(or)-515.6(anti-rabbit)-513.6(secondary)-513.8(antibodies.)-517.9(After)-515.1(sec-)]TJ
0 -1.2266 TD
[(ondary)-367.9(antibody)-363(staining,)-363.9(cells)-368(were)-362.5(stained)-365.2(with)-369.4(DAPI)-360.4(for)]TJ
0 -1.2203 TD
[(nucleic)-339.1(acid)-334.1(detection.)]TJ
/F7 1 Tf
9.9626 0 0 9.9626 59.7543 605.2534 Tm
[(Kar)-8.2(yotype)-335(anal)-9.5(ysis)]TJ
/F4 1 Tf
8.9663 0 0 8.9663 69.7323 587.3951 Tm
[(Karyotyping)-293.4(was)-287(performed)-290.9(by)-287(the)-294.6(Cytogenomic)-290.6(Services)]TJ
-1.1128 -1.2203 TD
[(Facility)-423.4(of)-420.6(Samkwang)-419.9(Medical)-418.5(Laboratories)-423.3(\(Seoul,)-426.7(Korea\).)]TJ
0 -1.2266 TD
[(To)-271.3(analyze)-269(the)-269.3(karyotype)-270.9(of)-268.8(hAdMSCs,)-275(cells)-266.8(from)-273.4(3)-265.1(different)]TJ
0 -1.2203 TD
[(donors)-241.6(were)-236.1(cultured)-237.2(and)-239.8(harvested)-236.5(at)-240.3(passage)-235(4,)-236.4(7,)-236.4(10,)-229.6(or)-237.4(12.)]TJ
T*
[(Cell)-354.9(division)-350.6(was)-343.9(blocked)-352.4(in)-348.4(metaphase)-350.7(by)-350.3(adding)-352(0.05)]TJ
/F8 1 Tf
24.9629 0 TD
(m)Tj
/F4 1 Tf
.5501 0 TD
(g/)Tj
-25.5129 -1.2266 TD
[(mL)-525.4(colcemid)-527.3(\(Invitrogen\))-534.5(for)-528.7(1)-524.3(t)0(o)-528(2)-163.9(h.)-524.8(The)-531.1(chromosomes)]TJ
0 -1.2203 TD
[(were)-337.2(then)-335.9(observed)-335.2(by)-331.3(GTG-banding.)]TJ
/F7 1 Tf
9.9626 0 0 9.9626 59.7543 499.7479 Tm
[(Sing)-9.4(le)-334(nucleot)-8.1(ide)-333.9(polym)-8.2(orphis)-7.4(m)-333.6(analysi)-9.3(s)]TJ
/F4 1 Tf
8.9663 0 0 8.9663 69.7323 481.8896 Tm
[(Single-nucleotide)-378.6(polymorphisms)-369.4(\(SNPs\))-375.1(of)-370(hAdMSCs)-373.3(at)]TJ
-1.1128 -1.2203 TD
[(different)-195.2(passages)-185.7(\(0,)-186.3(3,)-185.8(6,)-185.8(or)-186.8(9\))-189.7(were)-185.5(analyzed.)-186.4(Approximately)]TJ
0 -1.2266 TD
[(750)-169.3(ng)-368.2(of)-376.3(genomic)-371.3(DNA)-375.8(was)-369.2(used)-372.3(for)-370.7(genotyping)-375.8(using)-374.4(an)]TJ
0 -1.2203 TD
[(Illumina)-374.9(HumanHap300)-367.9(BeadChip)-367.9(\(Illumina\))-375.9(instrument)-372.5(at)]TJ
T*
[(SNP)-347.6(Genetics)-341.7(Inc.)-342.8(Samples)-343.1(were)-343.6(processed)-344.7(according)-344.7(to)-338.4(the)]TJ
0 -1.2266 TD
[(Illumina)-311.7(Innium-II)-316.2(assay)-309.6(manual.)-311.3(Briey,)-308.3(each)-311.9(sample)-306.7(was)]TJ
0 -1.2203 TD
[(whole-genome)-411.6(amplied,)-406.3(fragmented,)-410.6(precipitated,)-407.9(and)-410.6(re-)]TJ
T*
[(suspended)-520.4(in)-512.8(the)-509.6(appropriate)-517(hybridization)-512.7(buffer.)-516.1(Dena-)]TJ
T*
[(tured)-201.4(samples)-200.5(were)-204.5(hybridized)-202.4(on)-195.8(a)-201.8(prepared)-202.4(HumanHap300)]TJ
0 -1.2266 TD
[(BeadChip)-222.5(for)-225.2(a)-220.8(minimum)-219.5(of)-224.5(16)-163.4(h)-224.7(a)0(t)-221.3(4)0(8)]TJ
/F5 1 Tf
16.408 0 TD
()Tj
/F4 1 Tf
.3983 0 TD
[(C.)-218.1(After)-224.2(hybridization,)]TJ
-16.8063 -1.2203 TD
[(the)-395.8(Beadchips)-393.7(were)-394.1(processed)-395.2(for)-389.6(the)-395.8(single-base)-394.7(extension)]TJ
T*
[(reaction,)-486.7(stained,)-488.3(and)-480.1(imaged)-482.1(on)-486.7(an)-483.4(Illumina)-482.4(Bead)-486(Array)]TJ
0 -1.2266 TD
[(Reader.)-414.8(The)-411(normalized)-405.4(bead)-411.5(intensity)-412.4(data)-407.2(obtained)-415.3(from)]TJ
0 -1.2203 TD
[(each)-419.4(sample)-420.5(were)-419.4(loaded)-416.4(into)-421.2(the)-421.1(Beadstudio)-422.5(3.0)-412.9(software)]TJ
T*
[(\(Illumina\),)-359.8(which)-352.7(converted)-357.9(uorescent)-359.8(intensities)-362.2(into)-357.9(SNP)]TJ
0 -1.2266 TD
[(genotypes.)-425.5(The)-417.3(SNP)-417.1(clusters)-425.2(for)-414.9(genotype)-421.3(calling)-421.9(were)-419.4(ex-)]TJ
0 -1.2203 TD
[(amined)-266.1(for)-269.5(all)-265.8(SNPs)-266.7(using)-266.9(Beadstudio)-270.8(3.0)-261.2(software.)-268.9(Genomic)]TJ
T*
[(proles)-259.2(were)-255(created)-249.4(using)-254.3(the)-256.7(Illumina)-254.8(Genome)-255.2(Viewer)-255.1(and)]TJ
T*
[(Chromosome)-438.9(Browser)-440(of)-439.5(the)-433.7(Illumina)-438.2(Beadstudio)-441.5(3.0)-431.9(soft-)]TJ
0 -1.2266 TD
[(ware,)-213.3(which)-219.9(plots)-211.8(SNP)-214.8(genotyping)-217.8(data)-211.2(to)-218.2(view,)-211.1(identify,)-217.6(and)]TJ
0 -1.2203 TD
[(annotate)-275(chromosomal)-276.7(aberrations.)]TJ
/F7 1 Tf
9.9626 0 0 9.9626 59.7543 240.7747 Tm
[(Stab)-9(ility)-334.7(ev)-6.4(aluation)]TJ
/F4 1 Tf
8.9663 0 0 8.9663 69.7323 222.9732 Tm
[(hAdMSCs)-588.3(from)-583.2(3)-581.2(different)-587.2(donors)-589.3(at)-581.7(passage)-589(3)-581.2(were)]TJ
-1.1128 -1.2266 TD
[(placed)-398.6(in)-392.6(1-mL)-392.6(syringes)-392(at)-398.3(1.5)]TJ
/F5 1 Tf
13.8914 0 TD
()Tj
/F4 1 Tf
.7145 0 TD
(10)Tj
6.7246 0 0 5.9768 199.6724 216 Tm
(7)Tj
8.9663 0 0 8.9663 206.5889 211.9747 Tm
(cells/500)Tj
/F8 1 Tf
4.1542 0 TD
(m)Tj
/F4 1 Tf
.5501 0 TD
[(L)-395(saline)-396.9(and)]TJ
-21.0806 -1.2203 TD
[(stored)-254.7(under)-248.6(a)-246.1(cold)-248.9(condition)-256.1(for)-244.2(up)-249.3(to)-249.8(72)-169.7(h.)-246.6(The)-246.6(number)-253.9(and)]TJ
T*
[(survival)-548.9(rate)-538(of)-547(hAdMSCs)-544(and)-537(the)-547.5(expression)-541.1(of)-547(surface)]TJ
T*
[(markers)-332.9(were)-330.9(measured)-332(3)-328.3(times)-331.6(each)-330.9(at)-335.1(0,)-324.9(12,)-330.7(24,)-330.7(48,)-330.7(56,)-324.4(64,)]TJ
0 -1.2266 TD
[(or)-338.6(72)-163.4(h.)]TJ
/F7 1 Tf
9.9626 0 0 9.9626 59.7543 140.8818 Tm
[(Pre)-8.2(clinical)-341.6(toxicity)-341.5(test)]TJ
/F4 1 Tf
8.9663 0 0 8.9663 69.7323 123.0236 Tm
[(The)-271.8(toxicity)-269.6(study)-276.1(was)-268(conducted)-271.7(under)-273.9(Good)-266.5(Laboratory)]TJ
-1.1128 -1.2203 TD
[(Practice)-573.1(\(GLP\))-566.8(conditions)-567.2(and)-568.6(appropriate)-567.6(veterinary)-569.7(su-)]TJ
T*
[(pervision)-598.9(at)-594.3(Seoul)-594.1(National)-594.4(University)-601.1(Hospital)-594.2(\(SNUH\))]TJ
0 -1.2266 TD
[(Clinical)-433.8(Research)-438.2(Institute)-436.6(\(Seoul,)-439.4(Korea\))-436.1(with)-432.7(approval)-433.1(of)]TJ
0 -1.2203 TD
[(Institutional)-474.8(Animal)-464.2(Care)-461.9(and)-461.1(Use)-464.2(Committee)-470.2(\(SNUH-IA-)]TJ
T*
[(CUC)-242(No.)-239.6(0801801\).)-240.2(Six-week-old)-241.6(SCID)-242.4(mice)-240.5(\(91)-239.8(males)-242.1(and)-239.8(91)]TJ
0 -1.2267 TD
[(females\))-401(were)-400.5(purchased)-401.8(from)-399.8(Harlan)-398.6(and)-397.9(were)-400.5(kept)-398.2(for)-402.3(1)]TJ
28.0042 74.5598 TD
[(week.)-236.4(For)-235.5(the)-237.7(toxicity)-237.9(test,)-239(80)-233(healthy)-242.2(males)-235.8(\(19.924.3)-167.3(g)-238.4(body)]TJ
0 -1.2203 TD
[(weight,)-256.5(B.W.\))-261.2(and)-258.8(80)-251.9(healthy)-261.2(females)-261.4(\(15.719.1)-167.3(g)-257.3(B.W.\))-254.9(were)]TJ
0 -1.2266 TD
[(selected)-253.9(and)-258.8(divided)-250.7(into)-256.8(saline)-257.8(control)-253.2(and)-252.5(low-dose)-262(\(5)]TJ
/F5 1 Tf
24.5708 0 TD
()Tj
/F4 1 Tf
.7208 0 TD
(10)Tj
6.7246 0 0 5.9768 546.5762 707.8676 Tm
(6)Tj
8.9663 0 0 8.9663 310.8472 692.9006 Tm
[(hAdMSCs/kg)-410.4(B.W.\),)-409.6(medium-dose)-408.7(\(3.5)]TJ
/F5 1 Tf
17.9255 0 TD
()Tj
/F4 1 Tf
.7208 0 TD
(10)Tj
6.7246 0 0 5.9768 486.992 696.8691 Tm
(7)Tj
8.9663 0 0 8.9663 494.0219 692.9006 Tm
(hAdMSCs/kg)Tj
-20.4293 -1.2203 TD
[(B.W.\),)-441.2(and)-448.5(high-dose)-445.8(MSC)-446.4(groups)-441.9(\(2.5)]TJ
/F5 1 Tf
17.8875 0 TD
()Tj
/F4 1 Tf
.7208 0 TD
(10)Tj
6.7246 0 0 5.9768 486.6519 685.9274 Tm
(8)Tj
8.9663 0 0 8.9663 494.0219 681.9589 Tm
(hAdMSCs/kg)Tj
-20.4293 -1.2266 TD
[(B.W.\),)-447.5(each)-457.3(with)-451.6(20)-454.3(males)-450.7(and)-454.8(20)-448(females.)-454(The)-455.2(cells)-450.2(were)]TJ
0 -1.2203 TD
[(injected)-286.3(once)-283.6(into)-288.4(the)-288.3(tail)-285.3(vein.)-282.4(All)-286.7(groups)-283.8(were)-286.7(observed)-291(for)]TJ
T*
[(13)-410(weeks.)-408.4(High-dose)-417.1(MSCs)-416.1(were)-406.8(administered)-420.5(particularly)]TJ
0 -1.2266 TD
[(slowly)-251.1(and)-246.2(carefully)-253(at)-252.9(a)-246.1(rate)-253.5(of)-249.8(10)]TJ
/F8 1 Tf
15.1813 0 TD
(m)Tj
/F4 1 Tf
.5501 0 TD
[(L/5)-169.9(s)-247.9(t)0(o)-249.8(avoid)-249.8(embolism.)]TJ
-15.7314 -1.2203 TD
[(The)-335.1(cells)-330(were)-337.2(suspended)-337(in)-335.7(10)-163.4(mL)-335.7(saline/kg)-332.8(B.W.)]TJ
1.1128 -1.2203 TD
[(The)-689.2(animals)-684.9(were)-691.3(observed)-695.6(twice)-687.7(a)-688.7(day)-689.8(for)-686.8(clinical)]TJ
-1.1128 -1.2203 TD
[(symptoms)-436.7(\(vital)-431.9(signs,)-434.2(appearance,)-437.3(presence)-435.7(and)-435.9(extent)-436.2(of)]TJ
0 -1.2266 TD
[(any)-266.6(abnormal)-264.3(response,)-266.5(etc.\).)-271.5(The)-265.5(body)-261.2(weight)-266.3(and)-265.1(food)-268.2(and)]TJ
0 -1.2203 TD
[(drink)-337.5(intake)-340(of)-338.4(the)-338.9(animals)-337.2(were)-343.6(measured)-338.4(before)-336.9(the)-345.2(injec-)]TJ
T*
[(tion)-408.5(and)-410.6(every)-410.3(week)-410.5(until)-410.6(study)-415.2(termination.)-410.2(Five)-413.3(male)-411.5(or)]TJ
0 -1.2266 TD
[(female)-468.8(mice)-468.2(from)-469.4(each)-463.6(group)-472.2(were)-470(randomly)-463.8(selected)-475.2(for)]TJ
0 -1.2203 TD
[(urine)-331.3(and)-334.7(ophthalmic)-337.3(tests)-338.6(at)-335.1(13)-334.1(weeks)-329.6(postinjection.)]TJ
1.1128 -1.2203 TD
[(At)-355.9(the)-364.2(study)-358.3(completion,)-365.2(animals)-362.4(that)-357.9(survived)-365.4(were)-362.5(an-)]TJ
-1.1128 -1.2266 TD
[(esthetized)-422.4(using)-425(isourane,)-423.1(their)-425.3(blood)-421.2(was)-419.8(collected)-422.7(from)]TJ
0 -1.2203 TD
[(the)-370.5(inferior)-369.1(vena)-370.3(cava,)-368.7(and)-366.3(an)-369.6(autopsy)-371.6(was)-362.9(performed.)-376(Or-)]TJ
T*
[(gan)-380.4(weight)-380.1(and)-385.3(tissue)-380.9(pathological)-384.5(examinations)-383.8(were)-381.5(per-)]TJ
T*
[(formed)-453.3(on)-455.1(10)-454.3(mice)-455.5(from)-450.4(each)-457.3(group.)-456.1(The)-455.2(remaining)-452.2(mice)]TJ
0 -1.2266 TD
[(were)-330.9(observed)-341.5(by)-331.3(the)-332.6(naked)-339(eye)-333(at)-335.1(the)-332.5(time)-336.6(of)-332(autopsy.)]TJ
1.1128 -1.2203 TD
[(Statistical)-237.7(analyses)-240.5(were)-242.4(performed)-240.3(by)-236.5(analysis)-244.1(of)-237.2(variance)]TJ
-1.1128 -1.2203 TD
[(followed)-352.7(by)-356.6(the)-357.8(Dunnett)]TJ
/F9 1 Tf
11.3812 0 TD
(t)Tj
/F4 1 Tf
.3225 0 TD
[(-test)-356.7(or)-351.2(Duncan/Tukey)-359.5(test)-356.2(using)]TJ
-11.7037 -1.2266 TD
[(SPSS)-414.1(software)-424.1(\(version)-417.5(12.0K)-415.3(for)-421.3(Windows\).)-416.4(Statistical)-421.1(dif-)]TJ
0 -1.2203 TD
[(ferences)-333.6(were)-337.2(considered)-339.3(signicant)-338(for)]TJ
/F9 1 Tf
17.9318 0 TD
(P)Tj
/F5 1 Tf
.7714 0 TD
(<)Tj
/F4 1 Tf
.7145 0 TD
(0.05.)Tj
/F7 1 Tf
9.9626 0 0 9.9626 310.8472 413.9715 Tm
[(Tumorig)-10.7(enicity)-337.2(test)]TJ
/F4 1 Tf
8.9663 0 0 8.9663 320.8251 396.1133 Tm
[(The)-328.8(tumorigenicity)-335.2(study)-326.7(was)-331.2(also)-329.6(conducted)-334.9(under)-330.8(GLP)]TJ
-1.1128 -1.2203 TD
[(conditions)-586.2(with)-578.1(approval)-584.9(of)-584.9(IACUC)-580.6(\(SNUH-IACUC)-587.7(No.)]TJ
0 -1.2266 TD
[(0603303\))-370.1(at)-373(SNUH)-379.2(Clinical)-370.6(Research)-375(Institute.)-382.7(Six-week-old)]TJ
0 -1.2203 TD
[(BALB/c-nu)-428.9(nude)-431.3(mice)-423.9(\(58)-429.5(male)-424.1(and)-429.5(58)-422.7(female\))-431.3(were)-425.8(pur-)]TJ
T*
[(chased)-272(from)-273.4(Harlan)-272.2(and)-271.5(kept)-271.7(for)-269.5(1)-271.4(week.)-274.3(Fifty)-266.2(healthy)-273.8(males)]TJ
0 -1.2266 TD
[(and)-334.7(50)-334.1(healthy)-337.1(females)-337.3(were)-337.2(selected)-342.4(for)-339.1(the)-332.5(tumorigenicity)]TJ
0 -1.2203 TD
[(test.)-314.9(Test)-314.5(groups)-321.7(were)-311.9(divided)-320.2(into)-313.7(low-)-318.2(\(2)]TJ
/F5 1 Tf
19.1205 0 TD
()Tj
/F4 1 Tf
.7208 0 TD
(10)Tj
6.7246 0 0 5.9768 497.707 334.318 Tm
(6)Tj
8.9663 0 0 8.9663 503.8865 330.3495 Tm
(hAdMSCs/)Tj
-21.5295 -1.2203 TD
[(kg)-413.5(B.W.\),)-409.6(medium-)-414.4(\(2)]TJ
/F5 1 Tf
10.0281 0 TD
()Tj
/F4 1 Tf
.7145 0 TD
(10)Tj
6.7246 0 0 5.9768 416.1826 323.3763 Tm
(7)Tj
8.9663 0 0 8.9663 423.2125 319.4078 Tm
[(hAdMSCs/kg)-416.7(B.W.\),)-415.9(and)-410.6(high-)]TJ
-12.532 -1.2203 TD
[(dose)-348.4(MSC)-351.5(groups)-353.4(\(2)]TJ
/F5 1 Tf
9.3136 0 TD
()Tj
/F4 1 Tf
.7208 0 TD
(10)Tj
6.7246 0 0 5.9768 409.7763 312.4346 Tm
(8)Tj
8.9663 0 0 8.9663 416.2393 308.4661 Tm
[(hAdMSCs/kg)-353.5(B.W.\).)-352.7(To)-347.2(compare)]TJ
-11.7543 -1.2266 TD
[(tumor)-420.2(formation,)-425.1(negative)-422.9(\()-82.7(MRC-5)-426.8(cells;)-421.5(human)-422.5(fetal)-421.2(lung)]TJ
0 -1.2203 TD
[(cell)-423.6(line\))-421.8(and)-423.2(positive)-430.9(\(A375)-424(cells;)-421.5(human)-422.5(malignant)-426.3(mela-)]TJ
T*
[(noma)-547(cell)-543.7(line\))-548.3(control)-550.4(groups)-543(were)-545.9(also)-550.9(prepared.)-546.8(Each)]TJ
0 -1.2266 TD
[(group)-333.1(had)-334.7(10)-334.1(males)-330.6(and)-334.7(10)-334.1(females.)]TJ
1.1128 -1.2203 TD
[(Cells)-362.5(were)-362.5(injected)-362.2(subcutaneously)-365.8(once)-365.7(and)-360(the)-364.2(animals)]TJ
-1.1128 -1.2203 TD
[(were)-223.4(observed)-227.7(for)-225.2(26)-226.6(weeks.)-225.1(All)-223.4(animals)-223.3(were)-229.7(observed)-227.7(twice)]TJ
0 -1.2266 TD
[(a)-208.2(day)-209.3(for)-212.6(their)-216.6(clinical)-211.6(symptoms.)-218.4(The)-208.6(presence)-214.4(of)-211.9(tumors)-219.2(was)]TJ
0 -1.2203 TD
[(assessed)-349(twice)-352.6(a)-347.3(week)-353.6(between)-351(the)-351.5(rst)-353.2(injection)-350(and)-353.7(study)]TJ
T*
[(completion.)-390.5(The)-392(tumor)-388.6(dimensions)-399.1(were)-387.8(measured)-395.3(using)-387.1(a)]TJ
0 -1.2266 TD
[(caliper,)-251(and)-252.5(the)-250.4(tumor)-255.8(size)-250.8(was)-249.1(calculated)-256(using)-254.3(the)-250.4(equation)]TJ
0 -1.2203 TD
(\()Tj
/F8 1 Tf
.3225 0 TD
(p)Tj
/F4 1 Tf
.5501 0 TD
(/6)Tj
/F5 1 Tf
1.2709 0 TD
()Tj
/F4 1 Tf
.7208 0 TD
(length)Tj
/F5 1 Tf
2.9338 0 TD
()Tj
/F4 1 Tf
.7208 0 TD
(width)Tj
/F5 1 Tf
2.7821 0 TD
()Tj
/F4 1 Tf
.7145 0 TD
[(height\).)-391.5(According)-390.8(to)-388.9(the)-389.5(recommen-)]TJ
-10.0155 -1.2203 TD
[(dation)-271.9(of)-275.1(the)-269.3(SNUH-IACUC,)-280.4(animals)-273.9(were)-274(euthanized)-273.2(when)]TJ
T*
[(the)-269.3(diameter)-276.5(of)-268.8(the)-275.6(tumor)-268.4(exceeded)-272.6(250)-169.3(mm.)]TJ
/F7 1 Tf
9.9626 0 0 9.9626 310.8472 141.0519 Tm
[(Human)-338.2(clin)-8.6(ical)-333(trial)-338.5(for)-336.3(SCI)]TJ
/F4 1 Tf
8.9663 0 0 8.9663 320.8251 123.2504 Tm
[(The)-259.2(phase)-264.7(I)-255(study)-263.5(of)-262.5(autologous)-266.9(adipose)-264.3(stem)-258.5(cells)-260.5(for)-263.2(SCI)]TJ
-1.1128 -1.2266 TD
[(was)-331.2(approved)-331.8(by)-331.3(the)-332.6(Korea)-328.2(Food)-335.4(and)-328.4(Drug)-330.3(Administration)]TJ
0 -1.2203 TD
[(with)-280.9(Investigational)-281.5(New)-279.7(Drug)-279.8(Application)-279.4(number)-279.2(of)-281.5(BPD-)]TJ
T*
[(455)-302(\(April)-301.8(29,)-305.4(2009\))-302(and)-303.1(the)-307.3(Institutional)-310.4(Review)-300.8(Board)-306.2(\(No.)]TJ
0 -1.2266 TD
[(2009002-RNL-ASTROSTEM\))-948.1(at)-942.1(SAM)-940.8(Anyang)-946(Hospital)]TJ
0 -1.2203 TD
[(\(Anyang,)-418.3(Korea\).)-420.1(The)-417.3(clinical)-420.3(trial)-418.7(\(clinicaltrials.gov)-428(Identi-)]TJ
T*
[(er:)-303.7(NCT01274975\))-309.6(started)-308.9(in)-310.4(July)-306.9(1,)-305.9(2009,)-304.5(and)-303.1(completed)-311.3(in)]TJ
/F1 1 Tf
-28.0042 77.2028 TD
[(SAFETY)-336.6(OF)-337.5(I.V.)-331(INFUSION)-338.3(OF)]TJ
6.2762 0 0 6.2762 191.5086 749.7069 Tm
(H)Tj
8.9663 0 0 8.9663 196.044 749.7069 Tm
(A)Tj
6.2762 0 0 6.2762 202.507 749.7069 Tm
(D)Tj
8.9663 0 0 8.9663 206.9857 749.7069 Tm
[(MSCS)-335.4(IN)-335.1(ANIMALS)-333.3(AND)-337.2(HUMANS)-19744.6(1299)]TJ
ET
endstream
endobj
81 0 obj
<>stream
/GS1 gs
BT
/F4 1 Tf
8.9663 0 0 8.9663 62.022 725.7825 Tm
0 0 0 1 k
0 Tc
0 Tw
[(February)-388.5(15,)-381.3(2010.)-380.3(The)-385.7(candidates)-386(were)-387.8(given)-385(the)-383.1(informa-)]TJ
0 -1.2203 TD
[(tion)-427.5(regarding)-430.6(the)-427.4(expected)-429.6(efcacy)-423.2(and)-429.5(safety)-429.7(of)-426.9(the)-427.4(trial)]TJ
0 -1.2266 TD
[(resulted)-376.9(from)-374.6(preclinical)-378(tests,)-379.4(in)-373.6(which)-371.6(the)-376.8(SCI)-373.8(model)-373.5(ani-)]TJ
0 -1.2203 TD
[(mals)-431.9(had)-429.5(signicantly)-434.5(improved)-426.9(motor)-434.2(functions)-433.3(with)-432.7(hu-)]TJ
T*
[(man)-639.1(adipose)-643.7(stem)-644.2(cells)-639.8(and)-638.2(showed)-644.3(no)-644.8(adverse)-637.4(effect.)]TJ
0 -1.2266 TD
[(Procedures)-263.2(were)-261.4(performed)-265.6(after)-260.3(obtaining)-265.7(written)-263(informed)]TJ
0 -1.2203 TD
[(consent)-339.3(from)-336.6(each)-330.9(participant.)]TJ
1.1128 -1.2203 TD
[(Eight)-666.1(male)-664.4(patients)-667.5(were)-666(enrolled)-674.3(who)-665.4(had)-663.5(suffered)]TJ
-1.1128 -1.2266 TD
[(traumatic)-362.8(SCI)-361.2(at)-360.4(least)-358.8(12)-359.4(months)-363(before)-362.2(this)-356.5(study.)-361.2(The)-360.4(fol-)]TJ
0 -1.2203 TD
[(lowing)-430.3(ASIA)-433.3(impairment)-431.2(scale)-427.2([13])-436.2(is)-428.5(used)-429.2(in)-430.6(grading)-430(the)]TJ
T*
[(degree)-425.1(of)-426.9(impairment:)-427.8(A)]TJ
/F5 1 Tf
11.4318 0 TD
(=)Tj
/F4 1 Tf
.7145 0 TD
[(Complete.)-432.2(No)-426.4(sensory)-424.8(or)-427.1(motor)]TJ
-12.1463 -1.2203 TD
[(function)-653.3(is)-656.1(preserved)-652.4(in)-651.9(the)-655(sacral)-648.8(segments)-653.2(S4-S5.)-650.6(B)]TJ
/F5 1 Tf
26.1136 0 TD
(=)Tj
/F4 1 Tf
-26.1136 -1.2266 TD
[(Incomplete.)-550.6(Sensory)-542.1(but)-543.7(not)-544.1(motor)-548.1(function)-545.8(is)-542.3(preserved)]TJ
0 -1.2203 TD
[(below)-518.1(the)-522.2(neurological)-524.2(level)-519.8(and)-524.4(includes)-521.1(the)-522.2(sacral)-516(seg-)]TJ
T*
[(ments)-540.1(S4-S5.)-543.1(C)]TJ
/F5 1 Tf
7.2208 0 TD
(=)Tj
/F4 1 Tf
.7208 0 TD
[(Incomplete.)-544.3(Motor)-543(function)-539.5(is)-542.3(preserved)]TJ
-7.9416 -1.2266 TD
[(below)-543.4(the)-541.2(neurological)-543.2(level,)-535.3(and)-543.3(more)-538.4(than)-544.2(half)-538(of)-540.7(key)]TJ
0 -1.2203 TD
[(muscles)-415.3(below)-410.6(the)-414.7(neurological)-416.7(level)-412.3(have)-408.2(a)-410.5(muscle)-413.9(grade)]TJ
/F5 1 Tf
T*
(<)Tj
/F4 1 Tf
.7208 0 TD
[(3.)-419.7(D)]TJ
/F5 1 Tf
2.1055 0 TD
(=)Tj
/F4 1 Tf
.7145 0 TD
[(Incomplete.)-424.2(Motor)-422.8(function)-425.6(is)-422.2(preserved)-418.5(below)-423.2(the)]TJ
-3.5408 -1.2266 TD
[(neurological)-283.9(level,)-282.4(and)-277.8(at)-278.2(least)-282.9(half)-278.8(of)-281.4(key)-280.6(muscles)-276.1(below)-284.1(the)]TJ
0 -1.2203 TD
[(neurological)-296.6(level)-292.1(have)-288.1(a)-290.4(muscle)-293.8(grade)-292.1(greater)-290.1(than)-291.3(or)-294.3(equal)]TJ
T*
[(to)-332(3.)-337.5(E)]TJ
/F5 1 Tf
3.054 0 TD
(=)Tj
/F4 1 Tf
.7145 0 TD
[(Normal.)-335.8(Sensory)-339.8(and)-328.4(motor)-339.4(function)-337.1(is)-333.6(normal.)]TJ
-2.6556 -1.2203 TD
[(The)-505.8(inclusion)-502.6(criteria)-507.1(were)-508(grade)-500.7(A)-500.9(o)0(r)-509.3(B)-502.5(on)-499.3(the)-509.6(ASIA)]TJ
-1.1128 -1.2266 TD
[(Impairment)-379.2(Scale)-380.1(and)-372.6(an)-375.9(age)-376.9(of)-376.3(1960)-376.9(years.)-375.5(Exclusion)-380.7(cri-)]TJ
0 -1.2203 TD
[(teria)-465.7(included)-465.9(ventilator-assisted)-474.8(breathing,)-471.6(history)-465.5(of)-464.8(ma-)]TJ
T*
[(lignancies)-508.7(within)-509.1(the)-503.3(past)-502.2(5)-505.3(years,)-508.3(concomitant)-505.6(infectious)]TJ
0 -1.2266 TD
[(diseases)-351.2(such)-346.8(as)-342.3(HIV)-346.3(or)-344.9(HBV)-347.2(infection,)-348.4(anemia,)-347.8(myocardial)]TJ
0 -1.2203 TD
[(infarction,)-412(chronic)-404.4(renal)-405.4(failure,)-410.3(fever)-406.4(\(above)-406.2(38)]TJ
/F5 1 Tf
21.5675 0 TD
()Tj
/F4 1 Tf
.392 0 TD
[(C\),)-408.2(mental)]TJ
-21.9595 -1.2203 TD
[(confusion)-302.8(or)-294.3(dysphasia,)-292.2(use)-299.7(of)-294.1(immunosuppressant)-302.7(therapy,)]TJ
0 -1.2266 TD
[(or)-332.3(a)-334.6(serious)-339.7(pre-existing)-337.3(medical)-335.1(disease.)]TJ
1.1128 -1.2203 TD
[(Before)-474.6(liposuction)-484.9(operation,)-478.9(patients)-477.8(were)-476.3(assessed)-481.8(for)]TJ
-1.1128 -1.2203 TD
[(hematology,)-685.6(blood)-680.4(chemistry,)-683.7(and)-682.5(urinalysis,)-689.4(and)-682.4(were)]TJ
0 -1.2266 TD
[(screened)-487.9(for)-484.5(HIV,)-488.4(HBV/HCV,)-482.6(and)-486.4(VDRL.)-488.6(A)-481.9(chest)-484.9(X-ray,)]TJ
0 -1.2203 TD
[(pulmonary)-324.4(function)-324.5(test,)-321.2(spinal)-316.1(cord)-321.9(independence)-323.4(measure)]TJ
T*
[(\(SCIM\),)-408.1(visual)-408.3(analog)-405.2(scale,)-411.1(spinal)-404.7(magnetic)-406.4(resonance)-414.8(im-)]TJ
T*
[(aging,)-555.6(electrophysiological)-558.4(examination)-553.2(of)-553.3(motor)-554.4(and)-549.7(so-)]TJ
0 -1.2266 TD
[(matosensory)-267(evoked)-263.6(potentials)-269.2(\()-89(MEP)-262.4(and)-265.1(SEP,)-265(respectively\),)]TJ
0 -1.2203 TD
[(and)-404.2(a)-404.2(neurological)-404.1(examination)-407.7(using)-406(ASIA)-401.7(were)-406.8(obtained)]TJ
T*
[(for)-332.7(each)-337.2(patient.)]TJ
1.1128 -1.2266 TD
[(The)-202.3(hAdMSCs)-208.9(were)-204.5(harvested)-211.3(under)-204.4(sterile)-205.4(conditions)-206.8(and)]TJ
-1.1128 -1.2203 TD
[(delivered)-279.8(directly)-274.1(at)-278.2(cold)-274.1(temperature)-286.4(without)-279.2(cryopreserva-)]TJ
T*
[(tion)-174.6(procedure.)-176.3(The)-170.7(quality)-175.3(control)-171(test)-179.2(including)-170.9(cell)-177(viability,)]TJ
0 -1.2266 TD
[(fungal,)-281.2(bacterial,)-279.3(endotoxin,)-277.2(and)-277.8(mycoplasma)-278.7(contamination)]TJ
0 -1.2203 TD
[(carried)-316.4(out)-320.7(before)-318(the)-319.9(time)-317.6(of)-319.4(delivery.)-315.8(Four)-319.1(100-mL)-322(normal)]TJ
T*
[(saline)-264.1(containing)-270.3(100)-257.8(million)-264.5(cells/each)-265.6(were)-267.7(prepared)-265.7(and)-265.1(a)]TJ
T*
[(total)-373.5(of)-376.3(4)]TJ
/F5 1 Tf
4.2427 0 TD
()Tj
/F4 1 Tf
.7208 0 TD
(10)Tj
6.7246 0 0 5.9768 115.4834 247.5779 Tm
(8)Tj
8.9663 0 0 8.9663 122.1732 243.6094 Tm
[(autologous)-374.4(hAdMSCs)-379.6(per)-368.7(patient)-375.4(was)-375.5(intro-)]TJ
-6.7086 -1.2266 TD
[(duced)-348(into)-345.3(the)-351.5(cephalic)-344.9(vein)-349(over)-345.5(3)-347.3(t)0(o)-344.7(4)-163.9(h.)-347.7(Patients)-351.4(were)-343.6(in-)]TJ
0 -1.2203 TD
[(terviewed)-262.7(and)-252.5(monitored)-260.7(extensively)-259.5(on)-259.1(days)-254.8(1,)-255.3(4,)-255.3(and)-258.8(7)-252.4(and)]TJ
T*
[(weeks)-291.7(4)-290.4(and)-284.1(12)-289.9(after)-291.9(transplantation.)-298.1(Patients)-288.1(were)-293(followed)]TJ
0 -1.2267 TD
[(up)-274.6(for)-269.5(a)-271.4(total)-272.3(of)-268.8(12)-270.9(weeks)-272.7(post-transplantation.)]TJ
/F1 1 Tf
9.9626 0 0 9.9626 62.022 169.5684 Tm
[(Resul)-8.7(ts)]TJ
/F7 1 Tf
0 -1.6787 TD
[(Morphol)-10.1(ogy)-336.5(and)-335.7(phenot)-9.1(ype)-336.5(of)-333.6(culture-)]TJ
0 -1.195 TD
[(exp)-6.4(anded)-335.6(hAdM)-8.9(SC)]TJ
/F4 1 Tf
8.9663 0 0 8.9663 72 123.0803 Tm
[(AdMSCs)-344.6(were)-343.6(spindle-shaped)-347.4(with)-344.1(a)-340.9(broblast-like)-348.1(mor-)]TJ
-1.1128 -1.2203 TD
[(phology)-370.4(and)-366.3(were)-362.5(attached)-372.3(to)-363.6(the)-370.5(plate)-365.2(during)-364.2(cell)-366.7(culture.)]TJ
0 -1.2266 TD
[(These)-469.1(characteristics)-473.8(were)-470(well)-463.8(preserved)-469.1(during)-471.6(repeated)]TJ
0 -1.2203 TD
[(subculture.)-939.8(For)-937.4(immunophenotypic)-942.9(characterization)-944.9(of)]TJ
T*
[(hAdMSCs,)-515.3(culture-expanded)-518.8(cells)-513.4(at)-512.1(passage)-513.2(3)-511.7(were)-514.3(pre-)]TJ
T*
[(pared)-478.7(from)-475.7(5)-473.7(donors,)-484.8(and)-473.8(surface)-476.7(protein)-480(expression)-484.2(was)]TJ
0 -1.2266 TD
[(examined)-394.7(by)-388.2(ow)-393.1(cytometry.)-398.6(The)-392(results)-394.3(of)-388.9(FACS)-396.5(analysis)]TJ
27.9978 54.0293 TD
[(with)-489.6(5)-480.1(different)-486(donor)-486.9(samples)-485(are)-487(listed)-486(in)-481.1(Table)-484.6(1.)-483(The)]TJ
0 -1.2203 TD
[(hAdMSCs)-626.2(were)-621.8(positive)-626.9(for)-623.6(CD29,)-623.2(CD44,)-623.2(CD73,)-616.8(CD90,)]TJ
T*
[(CD105,)-357.1(and)-360(HLA-ABC,)-360.1(but)-354(were)-362.5(negative)-359.6(for)-358(CD31,)-351.3(CD34,)]TJ
0 -1.2266 TD
[(CD45,)-338.6(and)-334.7(HLA-DR.)]TJ
1.1128 -1.2203 TD
[(To)-340.9(investigate)-346(immunophenotypic)-348.5(changes)-346.3(during)-345.2(subse-)]TJ
-1.1128 -1.2203 TD
[(quent)-338.3(subculture,)-339.1(hAdMSCs)-335.3(harvested)-337.7(at)-328.8(different)-340.6(passages)]TJ
0 -1.2266 TD
[(\(1,)-413.9(2,)-413.4(4,)-413.4(7,)-413.4(or)-408.1(10\))-416.8(from)-412.5(3)-410.5(donors)-418.6(were)-413.1(analyzed)-411.1(for)-414.9(the)-414.7(ex-)]TJ
0 -1.2203 TD
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T*
[(sage)-270.7(of)-275.1(hAdMSCs)-272.1(showed)-271.2(a)-265.1(homogenous)-278.9(population)-273(of)-268.8(cells)]TJ
0 -1.2266 TD
[(with)-280.9(high)-274(expression)-281.9(levels)-274.5(of)-275.1(CD73)-278.8(and)-271.5(CD90)-278.8(and)-271.5(very)-277.6(low)]TJ
0 -1.2203 TD
[(expression)-319.8(levels)-306.1(of)-313.1(CD31,)-307(CD34,)-307(and)-309.4(CD45)-310.4(\(Table)-314.3(2\).)-306.4(CD73)]TJ
T*
[(was)-362.9(expressed)-357.3(at)-360.4(a)-359.9(high)-356.2(level)-361.7(\()]TJ
/F5 1 Tf
14.0811 0 TD
()Tj
/F4 1 Tf
.7208 0 TD
[(98%\))-355.2(up)-363.1(to)-357.3(passage)-361.4(7,)-356.5(and)]TJ
-14.8019 -1.2266 TD
[(decreased)-499.7(to)-490.1(80%)-493.8(in)-487.5(passage)-494.2(10.)-495.1(The)-493.2(expression)-496.9(of)-490.1(CD90)]TJ
0 -1.2203 TD
[(continued)-383.8(to)-370(be)]TJ
/F5 1 Tf
7.5685 0 TD
()Tj
/F4 1 Tf
.7208 0 TD
[(97%)-373.7(up)-369.4(to)-376.3(passage)-374.1(10.)-375(Negative)-375.2(markers)]TJ
-8.2893 -1.2203 TD
[(such)-795.7(as)-797.5(CD31,)-787.6(CD34,)-793.9(and)-796.3(CD45)-791(remained)-797.9(very)-789.8(low)]TJ
T*
[(throughout)-413.1(all)-398.6(passages.)-403.6(Cell)-399.2(viability)-403.1(evaluated)-406.3(by)-400.9(trypan)]TJ
0 -1.2266 TD
[(blue)-439.2(exclusion)-440.9(was)]TJ
/F5 1 Tf
9.2251 0 TD
(>)Tj
/F4 1 Tf
.7208 0 TD
[(95%)-436.9(before)-438.1(cell)-442.5(transplantation)-440.6(\(data)]TJ
-9.9459 -1.2203 TD
[(not)-392.3(shown\).)-388.9(To)-385.1(minimize)-387.9(the)-389.5(risk)-389.3(of)-382.6(contamination,)-395.6(all)-385.9(cell)]TJ
T*
[(culture)-348(steps)-345.8(took)-339.2(place)-345(in)-342(a)-341(GMP-grade)-342(clean)-340.7(room)-345.2(facility)]TJ
0 -1.2267 TD
[(and)-391.6(the)-383.1(clinical)-388.6(and/or)-385.4(preclinical)-390.6(lot)-386.2(was)-381.8(produced)-390.8(under)]TJ
0 -1.2203 TD
[(GMP)-346.7(conditions.)-348.8(No)-350.5(evidence)-344.8(of)-344.7(bacterial,)-348.9(fungal,)-344.4(or)-344.9(myco-)]TJ
ET
313.058 710.135 239.131 .22681 re
f
313.058 582.69 239.131 .28351 re
f
313.058 691.143 239.131 .28351 re
f
BT
/F6 1 Tf
8.9663 0 0 8.9663 326.2676 725.7825 Tm
(Table)Tj
/F4 1 Tf
3.0603 0 TD
(1.)Tj
/F6 1 Tf
1.2519 0 TD
[(Immunophenotype)-338.4(of)-330(Culture-Expanded)]TJ
-3.7179 -1.1128 TD
[(Human)-336.3(Mesenchymal)-332.8(Stem)-335.7(Cells)-335.7(at)-333.9(Passage)]TJ
/F4 1 Tf
22.0353 0 TD
(3)Tj
/F9 1 Tf
-24.1029 -2.0423 TD
[(Surface)-338.9(markers)-5889.4(The)-338.3(positive)-332.7(percentage)-339.8(\(%\))-336.3(\(n)]TJ
/F5 1 Tf
25.1273 0 TD
(=)Tj
/F9 1 Tf
.7208 0 TD
(5\))Tj
/F4 1 Tf
-25.8481 -2.0929 TD
[(CD29)-14612.8(99.81)]TJ
/F5 1 Tf
19.5125 0 TD
()Tj
/F4 1 Tf
.7145 0 TD
(0.18)Tj
-20.227 -1.1128 TD
[(CD31)-15118.7(0.50)]TJ
/F5 1 Tf
19.5125 0 TD
()Tj
/F4 1 Tf
.7145 0 TD
(0.34)Tj
-20.227 -1.1128 TD
[(CD34)-15118.7(1.95)]TJ
/F5 1 Tf
19.5125 0 TD
()Tj
/F4 1 Tf
.7145 0 TD
(0.87)Tj
-20.227 -1.1128 TD
[(CD44)-14612.8(99.77)]TJ
/F5 1 Tf
19.5125 0 TD
()Tj
/F4 1 Tf
.7145 0 TD
(0.18)Tj
-20.227 -1.1065 TD
[(CD45)-15118.7(0.60)]TJ
/F5 1 Tf
19.5125 0 TD
()Tj
/F4 1 Tf
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(0.39)Tj
-20.227 -1.1128 TD
[(CD73)-14612.8(98.12)]TJ
/F5 1 Tf
19.5125 0 TD
()Tj
/F4 1 Tf
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(1.64)Tj
-20.227 -1.1128 TD
[(CD90)-14612.8(99.99)]TJ
/F5 1 Tf
19.5125 0 TD
()Tj
/F4 1 Tf
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(0.01)Tj
-20.227 -1.1128 TD
[(CD105)-14112.8(99.95)]TJ
/F5 1 Tf
19.5125 0 TD
()Tj
/F4 1 Tf
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(0.03)Tj
-20.227 -1.1065 TD
[(HLA-DR)-13642.7(0.68)]TJ
/F5 1 Tf
19.5125 0 TD
()Tj
/F4 1 Tf
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(0.52)Tj
-20.227 -1.1128 TD
[(HLA-ABC)-12490.9(98.91)]TJ
/F5 1 Tf
19.5125 0 TD
()Tj
/F4 1 Tf
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(0.93)Tj
7.9702 0 0 7.9702 321.0519 570.8975 Tm
[(Data)-326.5(are)-332.8(expressed)-324(as)-335.9(mean)]TJ
/F5 1 Tf
12.5831 0 TD
()Tj
/F4 1 Tf
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[(standard)-322.2(deviation.)]TJ
ET
312.435 262.545 239.754 .28342 re
f
312.435 57.373 239.754 .22681 re
f
419.584 233.291 132.605 .28348 re
f
312.435 215.66 239.754 .22681 re
f
BT
/F6 1 Tf
8.9663 0 0 8.9663 325.9842 288.17 Tm
(Table)Tj
/F4 1 Tf
3.0603 0 TD
(2.)Tj
/F6 1 Tf
1.2456 0 TD
[(Immunophenotype)-338.4(of)-336.4(Culture-Expanded)]TJ
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[(Human)-336.3(Mesenchymal)-332.8(Stem)-335.7(Cells)]TJ
1.2203 -1.1128 TD
[(at)-334(Different)-337(Passages)]TJ
/F4 1 Tf
11.0588 0 TD
(\(110\))Tj
/F9 1 Tf
-3.3511 -2.0423 TD
[(Surface)-332.5(markers)-337.9([positive)]TJ
1.8969 -1.1128 TD
[(percentage)-333.5(\(%\)])]TJ
-16.1234 -2.0044 TD
[(Donor)-333.9(\(sex\))-2948.3(Passages)-655.1(CD73)-649.6(CD90)-655.9(CD31)-649.6(CD34)-655.9(CD45)]TJ
/F4 1 Tf
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[(#60018)-332.2(\()-89(Male\))-1526(P1)-3175(99.89)-835.6(99.98)-1088.5(1.88)-1335.6(0.51)-1341.9(0.53)]TJ
7.7772 -1.1128 TD
[(P2)-3175(98.25)-835.6(99.80)-1088.5(3.48)-1335.6(3.76)-1341.9(3.36)]TJ
T*
[(P4)-3175(99.62)-835.6(99.98)-1088.5(1.20)-1335.6(1.39)-1341.9(1.19)]TJ
0 -1.1065 TD
[(P7)-3175(99.89)-835.6(99.93)-1088.5(1.64)-1335.6(0.71)-1341.9(1.40)]TJ
0 -1.1128 TD
[(P10)-2675(99.89)-835.6(99.71)-1088.5(2.02)-1335.6(1.55)-1341.9(1.73)]TJ
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[(#60023)-332.2(\()-89(Male\))-1526(P1)-3175(90.24)-835.6(99.96)-1088.5(0.52)-1335.6(1.89)-1341.9(0.40)]TJ
7.7772 -1.1128 TD
[(P2)-3175(86.54)-835.6(99.88)-1088.5(1.00)-1335.6(0.78)-1341.9(0.50)]TJ
0 -1.1065 TD
[(P4)-3175(99.75)-835.6(99.99)-1088.5(1.24)-1335.6(1.16)-1341.9(1.03)]TJ
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[(P7)-3175(99.40)-835.6(99.81)-1088.5(3.26)-1335.6(0.81)-1341.9(2.00)]TJ
T*
[(P10)-2675(81.52)-835.6(98.73)-1088.5(0.77)-1335.6(0.27)-1341.9(0.22)]TJ
-7.7772 -1.1065 TD
[(#60028)-332.2(\(Female\))-657(P1)-3175(96.47)-835.6(99.96)-1088.5(0.50)-1335.6(1.42)-1341.9(0.31)]TJ
7.7772 -1.1128 TD
[(P2)-3175(98.26)-835.6(99.88)-1088.5(4.54)-1335.6(3.29)-1341.9(3.04)]TJ
T*
[(P4)-3175(99.26)-835.6(99.99)-1088.5(1.29)-1335.6(1.14)-1341.9(0.80)]TJ
T*
[(P7)-3175(98.87)-835.6(99.91)-1088.5(4.04)-1335.6(1.09)-1341.9(3.28)]TJ
0 -1.1065 TD
[(P10)-2675(83.62)-835.6(97.39)-1088.5(0.82)-1335.6(0.20)-1341.9(0.25)]TJ
/F1 1 Tf
-35.7055 76.5009 TD
(1300)Tj
49.6665 0 TD
[(RA)-334.4(ET)-338.7(AL.)]TJ
ET
endstream
endobj
86 0 obj
<>stream
/GS1 gs
BT
/F4 1 Tf
8.9663 0 0 8.9663 59.7543 725.7825 Tm
0 0 0 1 k
0 Tc
0 Tw
[(plasmal)-442.6(contamination)-443.2(was)-438.7(observed)-442.7(in)-436.9(cells)-443.8(tested)-441.3(before)]TJ
0 -1.2203 TD
[(shipping)-408(and)-397.9(cell)-404.6(viability)-403.1(evaluated)-399.9(by)-400.9(trypan)-401.9(blue)-401.2(exclu-)]TJ
0 -1.2266 TD
[(sion)-289.2(was)]TJ
/F5 1 Tf
4.3059 0 TD
(>)Tj
/F4 1 Tf
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[(95%)-285.2(before)-286.4(cell)-290.8(transplantation)-295.2(\(data)-287.5(not)-291.2(shown\).)]TJ
/F7 1 Tf
9.9626 0 0 9.9626 59.7543 677.9337 Tm
[(Diffe)-10(rentiat)-8(ion)-333.9(capa)-6.4(bility)-340.4(of)-333.6(culture-)]TJ
0 -1.195 TD
[(ex)-6.4(panded)-335.6(hAdM)-8.9(SCs)]TJ
/F4 1 Tf
8.9663 0 0 8.9663 69.7323 648.1699 Tm
[(The)-385.7(ability)-392.5(of)-388.9(hAdMSCs)-385.9(to)-388.9(differentiate)-394.6(into)-389.5(various)-389.3(cell)]TJ
-1.1128 -1.2203 TD
[(types)-336.2(was)-331.2(investigated.)-332.9(Culture-expanded)-336.3(cells)-330(at)-335.1(passage)-329.8(3)]TJ
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[(were)-476.3(capable)-469.1(of)-471.1(in)-474.8(vitro)-469.8(differentiation)-480.3(into)-471.7(adipocytes)-477.1(as)]TJ
0 -1.2203 TD
[(assessed)-412.2(by)-400.9(Oil)-402.1(red)-408.3(O)-401.4(staining)-405.3(\(Fig.)-407.8(1A\),)-402.6(osteoblasts)-409.8(as)-405.5(as-)]TJ
T*
[(sessed)-341.9(by)-337.6(Alizarin)-337.6(red)-338.7(S)-333.6(staining)-342(\(Fig.)-338.2(1B\),)-334.7(chondroblasts)-342(as)]TJ
0 -1.2266 TD
[(assessed)-298.4(by)-287(toluidine)-299.7(blue)-293.7(O)-287.6(staining)-297.8(\(Fig.)-287.6(1C\),)-293.9(myoblasts)-293.5(as)]TJ
0 -1.2203 TD
[(assessed)-292.1(by)-280.7(myosin)-284.9(immunostaining)-291.3(\(Fig.)-281.3(1D\),)-288.8(and)-284.1(neuronal)]TJ
T*
[(cells)-462.8(as)-462.4(assessed)-462.8(by)-464.1(MAP2,)-459.2(neuron)-466.8(specic)-462.9(enolase,)-462.2(TUJ1,)]TJ
T*
[(and)-334.7(GFAP)-334.7(immunostaining)-341.9(\(Fig.)-331.9(1EH\).)]TJ
/F7 1 Tf
9.9626 0 0 9.9626 59.7543 538.5825 Tm
[(Stab)-9(ility)-334.7(of)-339.2(culture-)-7.9(expan)-6.4(ded)-335.7(hAdMS)-8.7(Cs)]TJ
/F4 1 Tf
8.9663 0 0 8.9663 69.7323 520.7243 Tm
[(The)-442.6(hAdMSCs)-442.8(from)-444.1(3)-435.8(different)-448.1(donors)-443.9(were)-438.4(culture-ex-)]TJ
-1.1128 -1.2203 TD
[(panded)-402.2(to)-401.6(prove)-403.8(their)-400(genetic)-402.9(stability)-406.9(during)-395.8(proliferation)]TJ
T*
[(by)-388.2(karyotyping,)-392.7(which)-390.6(is)-390.5(often)-392.7(used)-391.3(to)-388.9(analyze)-389.1(the)-389.5(genetic)]TJ
0 -1.2266 TD
[(stability)-495.4(of)-490.1(stem)-486.1(cells)-494.4([1416].)-488.3(Chromosomal)-492.6(analysis)-490.7(was)]TJ
0 -1.2203 TD
[(performed)-474.3(on)-461.4(hAdMSCs)-468.1(at)-467.9(passages)-470.2(4,)-464(7,)-464(10,)-463.5(and)-467.5(12.)-463.5(No)]TJ
T*
[(chromosomal)-245.1(abnormality)-241.1(was)-242.7(observed)-246.7(in)-240.9(any)-241.3(sample)-237.1(up)-243(to)]TJ
T*
[(passage)-424.6(12.)-419.3(A)-418.7(representative)-422.8(karyotype)-422.6(image)-422.2(is)-415.8(shown)-423.5(in)]TJ
0 -1.2266 TD
[(Fig.)-337.8(2.)]TJ
1.1128 -1.2203 TD
[(Karyotyping)-299.7(would)-296.8(be)-295.2(sufcient)-297.2(to)-294.1(identify)-296.9(the)-300.9(numerical)]TJ
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[(and)-296.8(structural)-299.5(chromosomal)-295.7(aberrations)-300.8(if)-294.9(a)-290.4(large)-292.6(DNA)-300(area)]TJ
0 -1.2266 TD
[(is)-466.4(affected.)-467.5(If)-464.2(a)-461.1(small)-467(DNA)-464.3(area)-461.2(\(single)-465.5(gene\))-469.6(is)-460.1(mutated;)]TJ
0 -1.2203 TD
[(however,)-359.7(karyotype)-353.1(making)-354.3(is)-352.6(not)-354.4(sufcient)-354.1(and)-353.7(additional)]TJ
T*
[(molecular)-299(genetic)-301.7(method,)-294.5(such)-296.2(as)-298(SNP)-297(genotyping,)-296.5(shall)-295.8(be)]TJ
0 -1.2266 TD
[(applied.)-508.3(Karyotyping)-502(and)-505.4(SNP)-505.6(genotyping)-502.3(regarded)-504.3(as)-506.7(a)]TJ
0 -1.2203 TD
[(necessary)-294.3(control)-291.1(for)-288.5(the)-288.3(genetic)-289.1(integrity)-292.7(of)-287.8(embryonic)-287.9(stem)]TJ
T*
[(cells)-368(by)-356.6(the)-364.2(International)-364.1(Stem)-363.1(Cell)-361.2(Initiation)-364.1([17].)-363.3(The)-366.7(SNP)]TJ
28.0042 41.2001 TD
[(assay)-322.2(results)-331.1(did)-325.7(not)-329.1(show)-325.2(substantial)-328.6(genotypic)-329.4(differences)]TJ
0 -1.2203 TD
[(regardless)-254.6(of)-256.2(passage)-260.2(number)-260.2(within)-256.2(the)-256.7(same)-257.5(origin)-258.6(\(Fig.)-256(3\).)]TJ
0 -1.2266 TD
[(The)-322.4(call)-322(rates)-330.7(for)-320.1(hAdMSCs)-329(at)-322.5(passages)-331.1(3,)-318.6(6,)-324.9(9,)-324.9(and)-322(12)-321.5(were)]TJ
0 -1.2203 TD
[(99.78%,)-448.1(99.90%,)-441.8(99.91%,)-448.1(and)-448.5(99.93%,)-448.1(respectively,)-454.2(and)-442.2(the)]TJ
T*
[(reproducibility)-336(of)-338.4(each)-330.9(sample)-338.3(was)-331.2(100%.)]TJ
1.1128 -1.2266 TD
[(To)-423.1(evaluate)-428.6(the)-427.4(hAdMSC)-428.9(stability)-425.9(in)-430.6(saline)-428.5(solution)-430.1(de-)]TJ
-1.1128 -1.2203 TD
[(pending)-347.8(on)-347.6(the)-351.5(storage)-350.5(time,)-345.8(the)-351.5(cell)-347.7(number,)-345.4(survival)-352.9(rate,)]TJ
T*
[(and)-347.3(purity)-346.9(were)-349.9(measured)-351(3)-347.3(times)-350.5(at)-347.7(each)-343.5(time)-349.2(point)-352.9(up)-350.5(to)]TJ
0 -1.2266 TD
[(72)-163.4(h.)-322.4(No)-318.9(signicant)-319(decrease)-326(in)-316.7(the)-319.9(survival)-321.3(rate)-323.1(or)-313.3(total)-322.9(cell)]TJ
0 -1.2203 TD
[(number)-336.1(was)-331.2(observed)-341.5(at)-335.1(any)-329.8(time)-336.6(point)-340.3(\(Table)-333.3(3\).)-331.7(Cultured)]TJ
T*
[(hAdMSCs)-392.2(had)-391.6(a)-391.5(survival)-390.8(rate)-392.6(of)]TJ
/F5 1 Tf
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