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Figure legends
Fig. 1. Experimental scheme.
a. The construction of HSVtk model. TK-NOG mouse is a transgenic mouse with NOG background, in
which the mouse albumin enhancer/promoter (mAlb E/P), the chimeric intron, HSVtk cDNA, and the
3’-UTR of the human growth hormone gene with a polyadenylation signal (hGH pA) are integrated in
its genome, and expresses HSV-TK only in the liver. We established an immunocompetent mice by
backcrossing TK-NOG mice to C57BL/6 or BALB/c mice 9-10 times or more (designated as
HSVtk/BL6 and HSVtk/Balb).
b. Method of hepatocytes transplantation. GCV was intraperitoneally injected to HSVtk/BL6 or
HSVtk/Balb, and primary hepatocytes (PHs) isolated from GFP-tg were transplanted after the ALT level
reached 500 U/L (Auto or Allo model). HSVtk/BL6 administered with PBS after administered of GCV
was used a control (Sham).
c. Treatment model for immune rejection against allogenic hepatocytes. HSVtk/Balb after GCV
administration was transplanted with PHs isolated from GFP-tg with BL/6 background (Allo model).
FK506 was intraperitoneally administered every day from the day before transplantation until the day of
sacrifice (FK-treated model). ASCs were intravenously administered three times on the day of
transplantation, 3 days and 6 days after transplantation (ASC-treated model). Allo model without
treatment was used as control. All the mice were sacrificed for analyses two weeks after transplantation.
Fig. 2. Changes of BW and ALT levels.
a. Sequential changes of BW ratios in Sham, Auto, Allo models. The BW ratio (the ratio of BW at each time
point to BW just before PH transplantation) was calculated for each week until 8 weeks after PH
transplantation. 0 w means the time point before PH transplantation. All the data are expressed as mean
± SD. *p < 0.05 (Auto vs Sham on same week), †p < 0.05 (Allo vs Auto on same week). n = 3 in each
group.
b. Sequential changes of ALT levels in Sham, Auto, Allo models. ALT levels were measured every week
from 0 to 8 weeks after PH transplantation. All the data are expressed as mean ± SD. *p < 0.05 (Auto vs
Sham on same week), †p < 0.05 (Allo vs Auto on same week). n = 3 in each group.
Fig. 3. Engraftment of transplanted PHs.
a. GFP-immunostaining in the liver of Auto model. Representative histological images of GFPimmunostained liver sections from the mice sacrificed at each time point (time after PH transplantation)
are presented. From left to right, the liver images of the mice 1, 2, 4, 8 weeks after transplantation,
respectively. 2 × objective’s scale bar: 200 µm, 20 × objective’s scale bar: 20 µm.
b. Average values (%) of hepatocyte replacement indecies (RIs). GFP-positive areas of the tissue samples
were calculated using ImageJ. All the data are expressed as mean ± SD. *p < 0.05. n = 3 in each group.
c. Hepatic GFP mRNA expression in Auto and Allo models. Hepatic mRNA expression levels were
- 17 -
measured by qRT-PCR. Expression levels of the respective mRNAs were normalized to that of GAPDH
and the data were presented as fold change compared with the average of Auto model at 1 week after
PH transplantation. All the data are expressed as mean ± SD. *p < 0.05 n = 3 in each group.
Fig. 4. Liver histology.
a. Histological analysis with H&E staining at day 0, 0 w (upper row) and each time point after PH
transplantation in Sham (second row), Auto (third row), and Allo (lower row) models. Arrowheads (↑)
indicate the apoptosis-like cells. Magnification of objective × 20 (scale bar: 20 µm).
b. Histological analysis stained with Azan at day0 (upper row), 0w(second row) and 8 weeks after
transplantation in Sham (third row), Auto (fourth row), and Allo (lower row) models. 4 × objective’s
scale bar: 200 µm, 20 × objective’s scale bar: 20 µm. The graph shows the Azan-positive area measured
by the Image J software. *p < 0.05. n = 3 in each group.
c. Histological analysis stained with PCNA at day0 (upper row), 0w(second row) and 8 weeks after
transplantation in Sham (third row), Auto (fourth row), and Allo (lower row) models. 4 × objective’s
scale bar: 200 µm, 20 × objective’s scale bar: 20 µm.
Fig. 5. Hepatic mRNA expressions.
Intrahepatic mRNA expression levels were measured by qRT-PCR. Expression levels of the respective
mRNAs were normalized to that of GAPDH. The normalized data were presented as fold change
compared with HSVtk/BL6 at day 0 for Sham and Auto models, and HSVtk/Balb at day 0 for Allo
model (* p <0.05, †p<0.05 in comparison of the values between Sham and Auto models at the same
time point) . All the items were listed in the order of upper graph, that of Sham, Auto and Allo model.
All the data are expressed as mean ± SD. n = 3~5 in each group.
a-c. The mRNA expression of inflammatory cytokines(a), cell surface lineage makers (b), growth factors
(c), fibrosis makers (d).
Fig. 6. The effect of the treatment against immue rejection.
a. Liver histology in treatment models against immune rejection. H&E (upper row) and GFP
immunostaining (lower row) of representative liver sections from each group of mice. From left to right,
Allo, FK-treated, and ASC-treated models, respectively. Magnification of objective × 20 (scale bar: 20
µm).
b. Hepatic mRNA expressions in the treatment models. Hepatic mRNA expression levels were measured by
qRT-PCR. Expression levels of the respective mRNAs were normalized to that of GAPDH, and
presented as fold change compared with HSVtk/Balb day 0 for Allo model. All the data are expressed as
mean ± SD. *p < 0.05. n = 3~5 in each group.
- 18 -
Figure1
（a）
（b）
（c）
- 19 -
Figure2
（a）
（b）
Figure3
（a）
（b）
（c）
- 20 -
Figure4
（a）
（b）
（c）
- 21 -
Figure5
（a）
（b）
（c）
（d）
- 22 -
Figure6
（a）
（b）
- 23 -
Suppl. Fig. 1. Histology analysis of GFP immunostaining in Auto 8 weeks model.
a. Histology of whole liver immunostained with GFP antibody (Auto model at 8 weeks after PH
transplantation with RI of 54.7%). Scale bar: 200 µl.
b. Histological analysis with H&E staining at 8weeks after PH transplantation in Sham (upper row), Allo
(lower row).The area enclosed by lines indicate small hepatocytes. 4× objective’s scale bar: 200 µm, 20×
objective’s scale bar: 20 µm.
Suppl. Fig. 2. Analysis of the sizes of the nuclei.
a,b. The sizes of the nuclei in the liver sections with H&E staining were analyzed by using BZ-X800 and
shown as histograms. The liver sections were observed at original magnification × 20, and five random
points were analyzed. The numbers indicate each median. a; Day 0 (left column) and 0 w (right
column). b; Sham (upper row), Auto (middle row), and Allo (lower row) models. n = 3~5 in each group.
Suppl. Fig. 3. Hepatic mRNA expression in Sham, Auto, and Allo models.
Intrahepatic mRNA expression levels were measured by qRT-PCR. Expression levels of the respective
mRNAs were normalized to that of GAPDH. In Sham and Auto model, the normalized data were
presented as fold change compared with HSVtk/BL6 at day 0 for Sham and Auto models, and
HSVtk/Balb at day 0 for Allo model (* p <0.05, †p<0.05 in comparison of the values between Sham
and Auto models at the same time point) . All the items were listed in the order of upper graph, that of
Sham, Auto and Allo model. All the data are expressed as mean ± SD. n = 3~5 in each group.
a,b: The mRNA expressions of chemokines (a) and growth factors (b).
Suppl. Fig. 4. The influence and effect of the treatment against immue rejection.
a. Sequential changes of BW rations in Allo, FK- and ASC-treated models. The Body weight ratio (the ratio
of BW just before PH transplantation) was calculated for each week until 2 weeks after PH
transplantation. n = 3~5 in each group.
b. Sequential changes of ALT levels in Allo, FK- and ASC-treated models. ALT levels were measured every
week from 0 to 2weeks after PH transplantation. n = 3~5 in each group.
c,d. Analysis of hepatocyte replacement rate in the treated models. GFP-positive areas of the tissue samples
were calculated using ImageJ and average values (%) of hepatocyte replacement indecies (RIs) were
presented (c); hepatic mRNA expression levels of GFP mRNA were measured by qRT-PCR, expression
levels of the mRNAs were normalized to that of GAPDH, and the values were presented as fold change
compared with the those of Auto model at 1week after transplantation (d). All the data are expressed as
mean ± SD. n = 3~5 in each group.
- 24 -
Suppl.Fig.1
（a）
（b）
Suppl.Fig.2
（a）
（b）
- 25 -
Suppl.Fig.3
（a）
（b）
（c）
- 26 -
Suppl.Fig.4
（a）
（c）
（b）
（d）
- 27 -
Suppl. Table 1. The combination of recipient and donor mice in each model.
Recipient
Donor
Sham
HSVtk/BL6
Auto
HSVtk/BL6
GFPtg (BL6)
Allo
HSVtk/Balb
GFPtg (BL6)
FK
HSVtk/Balb
GFPtg (BL6)
ASC
HSVtk/Balb
GFPtg (BL6)
FK model (FK506-treated Allo model) and ASC model (ASC-treated Allo model) used the same recipientdonor combination as Allo model.
Suppl. Table 2. Primers used for qRT-PCR analysis in the study.
Gene
Forward primer sequences (5'--3')
Reverse primer sequences (5'--3')
Ccl1
CAGCAAGAGCATGCTTACGG
TTGAGGCGCAGCTTTCTCTA
Ccl2
GTGCTGAAGACCTTAGGGCAGA
AGCAGCAGGTGTCCCAAAGA
Ccl3
CATGACACTCTGCAACCAAGTCTTC
GAGCAAAGGCTGCTGGTTTCA
Ccl4
GGAGCTGCTCAGTTCAACTCCA
GAGACCAGCAGTCTTTGCTCCA
Ccl5
GGCTAGGACTAGAGCAAGCAATGAC
GGAGTATTTCTACACCAGCAGCAAG
Cd3
CTGGGCAACAATGCCAAAGA
AGCCGGATATGGTGCCTATGTTTA
Cd4
CAACCTGACTCTGACTCTGGACAA
AGGTAGGTCCCATCACCTCACA
Cd8
GTACTTCAGTTCTGTCGTGCCAGTC
TCGCAGCACTGGCTTGGTA
Cd11b
CCACTCATTGTGGGCAGCTC
GGGCAGCTTCATTCATCATGTC
Cd11c
AGGTCTGCTGCTGCTGGCTA
GGTCCCGTCTGAGACAAACTG
Cd19
CAACCAGTTGGCAGGATGATG
ATGACTGGGACCGGACTGAA
Cdk2
TCCGGATCTTTCGGACTCTG
ACAAGCTCCGTCCATCTTCA
Cdk4
CCAGGCAGGCTTTTCATTCA
AGGTCCTGGAAGTATGGGTG
Cx3cl1
TCATGTGCGACAAGATGACC
GTGTCGTCTCCAGGACAATG
Cxcl1
CCGAAGTCATAGCCACACTCAA
GCAGTCTGTCTTCTTTCTCCGTTA
Cxcl2
GAAGTCATAGCCACTCTCAAGG
CCTCCTTTCCAGGTCAGTTAGC
Cxcl9
TTCCTGAGCAGTCCCAAATATCC
CTTCAGACATCTTCAGCGCACA
Cxcl10
TGTCCATCCATCGCAGCAC
ATCATCCCTGCGAGCCTATCC
Cyclind
GGGGACAACTCTTAAGTCTCAC
CCAATAAAAGACCAATCTCTC
Cyclind1
AGGCGGATGAGAACAAGCAGA
CAGGCTTGACTCCAGAAGGG
Cycline
GAGCTTGAATACCCTAGGACTG
CGTCTCTCTGTGGAGCTTATAGAC
Cytoglobin
TCTGGAGGAGATCGCCGAGGAAT
CTTCTGCCCAAAGTGCTGCCAG
Egf
AGCATACTCAGCGTCACAGC
GCAGGACCGGCACAAGTC
Egfr
CTGCCAAGGCACAAGTAACA
ATTGGGACAGCTTGGATCAC
F4/80
TCACTGTCTGCTCAACCGTC
TGCCATCAACTCATGATACCCT
- 28 -
Gapdh
TGTGTCCGTCGTGGATCTGA
TTGCTGTTGAAGTCGCAGGAG
Gfp
AACTCCAGCAGGACCATGTGAT
CACATGAAGCAGCACGACTTCT
Hgf
GGCCCACTCATTTGTGAAC
CATCCACGACCAGGAAC
Ifn-γ
CGGCACAGTCATTGAAAGCCTA
GTTGCTGATGGCCTGATTGTC
Il1α
TGGTTAAATGACCTGCAACAGGAA
AGGTCGGTCTCACTACCTGTGATG
Il1β
GAACGTCACACACCAGCAGGTTA
TCCAGGATGAGGACATGAGCAC
Il6
CCACTTCACAAGTCGGAGGCTTA
CCAGTTTGGTAGCATCCATCATTTC
Il10
GCCAGAGCCACATGCTCCTA
GATAAGGCTTGGCAACCCAAGTAA
Ly6c
TGCCTGCAACCTTGTCTGAG
GCTGGGCAGGAAGTCTCAAT
Ly6g
TTGCAAAGTCCTGTGTGCTC
GTCCAGAGTAGTGGGGCAGA
Nkp46
GACTAGGGCTCACAGAGGGACA
AAGAAGTAGGGTCGGTAGGTGC
P16
CGCAGGTTCTTGGTCACTGT
TGTTCACGAAAGCCAGAGCG
P21
CCTGGTGATGTCCGACCTG
CCATGAGCGCATCGCAATC
Procollagen1
TGGTGCCAAGGGTGATACTG
CAATGGGACCAGTCAGACCA
Sma
TGGGTGACGAAGCACAGAGC
CTTCAGGGGCAACACGAAGC
Tgfα
CTCTGCTAGCGCTGGGTATC
TGGGCACTTGTTGAAGTGAG
Tgfβ
GTGTGGAGCAACATGTGGAACTCTA
CGCTGAATCGAAAGCCCTGTA
Tnfα
TATGGCCCAGACCCTCACA
GGAGTAGACAAGGTACAACCCATC
Vegf
CTGCTGTAACGATGAAGCCCTG
GCTGTAGGAAGCTCATCTCTCC
Vegfr
GGCGGTGGTGACAGTATCTT
TCTCCGGCAAGCTCAAT
Suppl. Table 3. Sequential changes of body weight (BW) ratios and ALT levels.
a. BW ratios
0w
1w
2w
4w
8w
Sham
1.0±0.0
0.97±0.03
1.02±0.04
1.04±0.06
1.02±0.07
Auto
1.0±0.0
0.96±0.05
0.95±0.08
1.00±0.12
1.18±0.06
Allo
1.0±0.0
1.01±0.02
1.07±0.05
1.06±0.05
1.05±0.06
Treat-
FK
1.0±0.0
0.75±0.07
0.69±0.05
ment
ASC
1.0±0.0
0.91±0.06
0.88±0.14
b. ALT levels
0w
1w
2w
4w
8w
Sham
494±119
208±58
321±21
268±135
425±175
Auto
456±98
160±61
192±41
216±127
82±61
Allo
869±439
246±105
344±209
402±136
507±211
Treat-
FK
918±111
760±300
365±53
ment
ASC
660±167
319±27
237±107
- 29 -
...
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