Đánh giá hiệu quả điều trị xơ gan của việc ghép tế bào gốc trung mô tủy xương trên mô hình chuột

Khoa hoc Y - Duo°

Danh gia hiOu qua dieu tri xd gan cua vi0c ghep to bao goc trung ma
tuy xu'Ong tren mo hinh chuEit
Twang Hai Nhungu', Le Van Trinh', Nguyen Hai Nam', NO Quac Data, Le Minh Huy'
Huynh Nghia', Nguyen Van Thanh4, Pliant Van Phficil, Phan Kim NgW.
Thong thi nghi Nghien cent va ang dung to bcio goc, Trwang Dgi hoc Khoa hpc Ty. nhien, Doi hpc Qudc gia TP lid Chi Minh
:Khoa Sinh hpc, Trzterng Dgi hoc Khoa hoc Tv nhien, Doi hoc Quac gia TP Ho Chi Minh
3Tnrong Doi hoc Y &tor TP He, Chi Minh
'Tryon Dgi hoc Nguyin Thcinh, TP Ho Chi Minh

NO), nhan bai 3.11.2015, ngsly chuyen phin bien 10.11.2015, ugly nhan phin bien 11.12.2015, ngay chip nhan dang 21.12.2015

Tren the giel, lieu phi!) to bac, gOc cho duly tiem nang lan trong cac nghien cuu dieu tri benh xa gan. Tay
nhien, hien nay yin chin thong nhit phic do dieu tri ve ngutin 4 bac), phucrng phi') trim, ding thei ir nu&
ta china ce cac ding bo ve linh vyc nay. Nham myc dich nghien cuu phut trien lieu phap mai trong dieu tri
xcr gan a lurk ta, ale tfic gia tien hinh gay to mo hinh chuOt xor gan bang CCI4 va thu nghiem dem 106 4
bko goc trung mo tay string de melt tri. Ket qua cho thiy, sau 21 ngily tiem 106 to bko vao tinh mach duoi
ciia chuOt bi benh xa gan, nh6m chuOt dieu tri phyc hOi chi se Albumin tir 1,7531-0,042 len 2,1161-0,120,
grim 9 din bieu hien cac gen xa h6a nhv TGF, giam 13 din Procollagen, giam 3000 lAn Integrin, giam sir
bieu hien ciia collagen-1, SMAa ve giam dien tich cac dui xoo teen hinh thai mo hyc so voi nh6m doi chirng.
Tit khoa: benh xo. gan, lige phap to boo gbc, mo hinh chubt gan, d bao goc trung me, to boo giic tuy xtrang.
Chi so plain logi 3.5

CUM thileu
Xa gan là tinh trang ton thuang gan mon tinh, dAn
tori hinh thanh nhUng m6 xa xam chiem kh8ng gian cua
to bao gan. Theo se lieu thong ke cua Mokdad va Ong
six [I], chi trong num 2010, xa gan IA nguyen nhan gay
tir vong cho,hcm mOt trieu ngtrai. Deng thei, xa gan
con IA yeu to nguy ca cao cua ung thu gan [2]. Hien

nay, y hoc van chua ce lieu pita!) dieu tri khei benh xa
gan vi: (1) xa h6a gan IA qua trinh Ice° dui va rat kh6
phoc hoi khi m8 gan xufit hien dui xa [3]; (2) lieu phap
hea tri phai duy tri sir dong lau dii NIA kitting mang lai
hieu quA cao do dung thuoc giup irc the qua trinh xa
hea (anti-TGF, anti-PDGF) thi hog (king chirc 'tang
gan khb hei phoc, dung thutic co tic dung irc the mien
dich bao v'e gan thi kh6 ngan chin so tien trien cua xa
hea [4], va dung ca hai loai thu6c ten van chua cho
thay hieu qua [5]; (3) ghep gan van chua giai quyet
duTic do tinh trang thieu but nguZin me, nguy ca thai
loai sau ghep cao, chi phi dieu tri cao va gay xam Ifin
[6].

ce, the thay the cac phtrcmg phap dieu tri xa gan truyen
thong nhtr ten vi: (1) to bao etc co the thu nhin tir
nhieu nguon nhu m6 ma, my xuang, mau day rem [7];
(2) ghep to bao gOc tix than giam nguy ca thai loai mien
dich; (3) to bao g6c khi ghep giup irc the qufi trinh
xa hoa nhe tier cac cytokine, cal thien hog deng chirc
fling gan vi to bao goc da duqc chimg minh kha nang
biet hi:5a thanh to bao chirc nang ging to bio gan, kich
thich sv phan chia cua to bao gan truong thanh [8-12].
Do do, to bio goc dangsduqc sir dung nhieu trong cac
nghien dm lam sang dieu tri benh xa gan va mang lai
hieu qua tich cor [4, 13]. Te bao etc trung mo tir toy
xuang (BM-MSC) dang dyer sir dung nhieu tren lam
sang (26/31 nghien cim sir dung to bao g8c) de dieu tri
xa gan [14]. Ket qua ghi nh'in, ghep BM-MSC giap
benh nhan cii thien chirc Wang gan va chi so MELD

[14, 15]. Deng thei, BM-MSC a thu nhin va c6 the
cay ghep tir than. Do de, BM-MSC là met ngulin to bao
tiem nang Ion trong dieu tri benh xa gan.

Viet Nam là yang c6 ty le benh gan rat cao [16].
Nham gap phan nghien ciru tim ra lieu phip hieu qua
Ghep 4 bac* g6c là lieu phap moi dang dtrqc nghien cho dieu tri benh xa gan, cung cap ca se cin lam sang
ciru trong dieu tri benh xa gan. Lieu pita') to bac) gee cho cac nghien ciru xa han tren lam sang, chting toi
*Mc gia lien he: Email:

WHOA HOC\
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55


Khoa hoc Y - Duoc

Effectiveness of the treatment of
liver cirrhosis by using bone marrow
mesenchymal stem cell in a mouse model
Summary

In the world, stem cell therapy has shown a
potential in liver cirrhosis treatment. Up to now,
we have not found out the best regimen of cell
types, injection methods, while Vietnam has not
yet published any result in this field. For that

reason, this research aims to developing a new
therapy for liver cirrhosis treatment in Vietnam.
The authors conducted experiments using bone
marrow mesenchymal stem cell for treatment in
the mouse model with liver cirrhosis by CCI4.
The result showed that 21 days after injected
106 stem cells into tail vein, the treatment group
was improved with the Albumin index from
1.7531-0.042 to 2.1161-0.120; the expression
of genes related to fibrosis was decreased
such as TGF (by 9 times), Procollagen (by 13
times), Integrin (by 3000 times); and the result
also showed the reduction in the presence of
collagen-1, SMA-a and the smaller fibrotic areas
in histology compared with the control group.

musculus var, albino)duc, 4 tan tuoi, can nang khoang
5 g, khee manh duqc mua tir Vien Pasteur TP He Chi
Minh. Tien hinh thu dui chuOt, loci be phan ca dui,
thu toy ttlr xuang dui va xuang tang chin chutt, nuoi
cay tang sinh va chen lqc BM-MSC trong mei trueng
DMEM/F12 (Gibco) be sung 10% FBS (Sigma) va 1%
Antibiotic (Gibco), trong dieu Icien 37°C, 5% CO2.
Chip ti bit o: chi* mo hinh benh xa gan dtrqc chia
ngau nhien thanh 2 nhom: nhem doi cluing (n=5) tiem
0,15 ml PBS, nhom thi nghiem (n=5) tiem 106 huyen
phit 4 bao dan trong 0,15 ml PBS-/con qua tinh mach
duoi, chuOt binh thueng duqc sir dung lam doi chimg
&mg. Sau 21 ngay ghep, hieu qua dieu tri benh se
duqc dinh gia dua tren cac chi tieu:

Men gan: thu 0,2 ml huyet Ming, do cac chi tieu
nhu AST/ALT bang KIT GOT(ASAT)/GPT(ALAT)
IFCC Mod.liquiUV test (GERMANY), Albumin va
Billirubin bAng Kit QuantiChrom BCG Albumin/
Billirubin Assay (Bioassay Systems, CA, USA) theo
quy trinh cua nha san xuat.
Danh gia mik de) bi& hien cac gen xa hoas bang
qRT-PCR: sinh thief mo gan chu6t, tach mRNA tong tir
me gan bang b45 Kit Easy-BLUE Total RNA Extraction
(iNtON Biotechnology, Korea). Dinh gia mirc de bieu
hien gen bang qRT-PCR (qRT-PCR Master Mix Kit,
1-Step Agilent, CA, USA), Om cac gen:
Bang trinh tK cac mo' sri dang trong phan sing qRT-PCR ciia nghien mitt

Keywords: bone marrow derived stem cells,
liver cirhosis, mouse model of liver cirrhosis,
mesenchymal stem cells, stem cell therapy.

Ten m6i
Fibronectin

3'-TGAAGAGGGGCACATGCTGA-5'
5.-GTGGGAGTTGGGCTGACTCG-3'

Procollagen

3'-CCTGGACGCCATCAAGGTCTAC-5'
5'-CAAGTTCCGGTGTGACTCG-3'

Integrin

3'-GCCAGGGCTGGTTATACAGA-5'
5'-TCACAATGGCACACAGGTTT-3'

Nt5e

3'-TTTGGAAGGTGGATTTCCTG-5'
5'-CCTCTCAAATCCAGGGACAA3-'

TGF-6

3'-CTTCAGCTCCACAGAGAAGAACTGC-5.
5'-CACAATCATGITGGACAACTGCTCC-3'

GAPDH (ch(mg nÂi)

3'-AAGTTGTCATGGATGACC-5'
5'-ATCACCATCTTCCAGGAGC-3'

Classification numbers 3.5

tor

4101P-n1111111111111111111111101.1111111111111.1.1ã111111=1.0

tien hanh thir nghiem dieu tri benh xa gan bang BMMSC tren mo hinh chuOt bj xa gan bei
VOt hOu Ira phuung phap
MO hinh chu'Ot xa gan: thuc hien theo quy trinh
cua Tnrcmg Hai Nhung va tong su [17], chuet duqc
ming CC14 bang cach pha yeti dau olive (3:7 v/v), thong

qua duCmg thuc quan, lieu lucmg 1 ml CC14/kg, 3 lin/
tuan trong 11 tuan. Danh gia cac chi tieu thuc hien m6
hinh gem men (AST, ALT, Albumin, Bilirubin), bleu
hien gen (Fibronectin, Integrin, TGF, Procollagen,
Nt5e), mo hpc nhuOm H&E va Trichrome, bieu hien
collagen-1 va SMA-a.
Chutin bj BM-MSC: chuOt nhat tang (Mus

Danh gia mo hoc: ce dinh me gan trong
Parafolmardehyde 4% (Merck Millipore, Germany),
nhuOm H&E va Trichrome theo quy trinh cua Benh
vien Chq Ray (TP He Chi Minh).
Danh gia bi"juhien collagen-1 va SMA-a bang
nhuOm hew ma mien dich: mo gan duqc có dinh trong

TAP 011

WA HOC .
LNG1■KAIEVIet am

4(4) 4.2016

Tani' tkr

56


Khoa hoc Y - Ducc

4% paraformaldehyde (Merck Millipore, Dar). Lat cat

(slide) paraffin duqc kilt paraffin va tai hydrate h6a
bing sodium citrate (10mM, pH 6) a 95-100°C trong
20 phitt. Cac slide duqc lam lanh xuang khoang 20-30
phut a nhiat d4 phong. Sau do, cac slide duqc block
trong 30 phut a nhiat dO phong vai blocking buffer
(2% huyet thanh de, 1% BSA, 0,1% Triton X100,
0,05% Tween 20, 0,01M PBS pH 7,2-7,4, 0,05%
sodium azide). Slides duqc nhuOm khang the khang
collagen I (Santa Cruz Biotechnology, Inc) hoc antisma-Anfa (Santa Cruz Biotechnology, Inc) vai ding
dO pha bang 1:100 trong TBS 1% BSA qua dem
4°C. Peroxidase nal sinh duqc block bang peroxidase
blocking buffer (3% H202 trong PBS) trong 10 phut
a nhiat dO ph6ng. Horseradish peroxidase-conjugated
secondary goat-anti-rabbit antibody trong TBS 1%
BSA duqc nhuOm trong 1 gia a nhiat dO ph6ng. Ket
qua nhuOm khang the duqc kiem tra bang cach sir dung
ACE kit (Sigma-Aldrich, St Louis, MO) theo hiking
dAn. Nhan to bao ducx nhuOm bing herrratoxylin-Gill

eoo

su giam nang dO Albumin huyet tuang so yeti chi*
thuong (p<0,05). So sanh cac chi tieu sinh hoa nhom
chuOt xa gan duqc diau tri bang to bao va nhOm doi
chtng (tiem PBS): chuOt xa gan giam tinh trang ton
thuang gan thong qua cac chi so AST, ALT, Bilirubin
giam Nit mirc birth thuang. Tuy nhien, chirc nang san
xuat Albumin ten nh6m duqc dieu tri bang BM-MSC
duqc phuc hoi ve mtc binh thuong va cao hcm nh6m
d6i chimg (p<0,05).

Kat qua chi tieu mar dO bieu hien gen gay xa hoa
(hinh 1c): chuOt me, hinh tang bieu hien manh cac gen
xa h6a (mac dO bieu hien cac gen cita chuOt thuang la
2°), clan tai hinh thanh mo xa a chuat mo hinh. Sau khi
duqc thin nghiam dieu tri bang BM-MSC chuOt tang
bleu hien Fibronectin (ket qua tuang tkr a nh6m doi
chimg), giam bieu hien manh cac gen Integrin, TFG,
Procollagen va Nt5e khi so vai chuOt mo hinh va chuOt
doi chirng (p<0,05). Do do, ghep to bao lam giam su
san xuat mo xa a chuOt xa gan.

Nonni
cm Mode
-PBS
BM

400

mo Normal
ELI Mode
ME PBS
BN

BM
2 ,3

Model
PBS-Tar
BMMSC-Tail

(

ZOO

cc
oc
Quo

Hinh 1: biiu do so mini, chi tieu sinh hod va bieu hien gen tren cite nhom chuet
(a) Bieu do so stinh gici tri AST va ALT.- (b) Bleu d6 so scinh gia tri Albumin via Bilirubin:(c) Bldu do so sankmirc Wu
. hien gen
model: nhom ma hinh xugan, PBS-tail: idiom tient gut Ayr PBS. BMMSC tail: nhom ghep to boo

III (Merck Millipore, Dire). Slides duqc dra sach bAng
Tween 20 TBS (2-3 'An) gifra mai buck.
1y thdng
kiam dinh thong ke
student t-test, phan tich kat qua bang Microsoft Excel
2010 va Prism 6.
Phwang phap zit

Mgt quit
Kat qua chi tieu sinh h6a (hinh 1 a, 1 b) dm cac nhom
chuOt sau theri gian gay mo hinh the hien tinh trang gan
bi ton thuang Ong bai su gia tang manh cac chi so
nhu AST (tang 5 lan), ALT (tang 10 lan) va Bilirubin
(2 lArt) trong huyet tuang so vori chuOt thuang. 136ng
thai, hoot dOng chirc nang gan suy giam the hien qua

1110A HOC

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Kat qua chi fiat, hinh thai mo hoc: danh gia su,khac
bit ye tinh trang banh giva cac nhOm chuOt a cap dO
mo hoc (hinh 2): chuOt mo hinh dual tac Clang oh
CCL, mai gan bieu hien tinh tang ton thuang manh
nhu viem, can tritc mo thay dai, nhiau to bao gan chat
hoAc nhiern ma (nhuOm H&E) so vai nhom dai chimg.
XuAt hien cac dai xa, thanh ph'An chinh la collagen bao
quanh mach, khu vkxc cira va xa bac cau (noi litn hai
khu vuc eta) khi nhuOm Trichrome. Trong cau ft-6c mei
xa collagen type-1 chiam mgt Itrqng lan [18], the hien
tren hinh thai mo hoc khi nhuOm vai khang the khang
collagen type-1. Ngoai ra, chuOt mo hinh con cho thAy

51


Khoe hQc Y - Dug=
ChuOi Ihtrons

M6 hinh

BM-MSC

PBS

Hinh 2: kdt qua nhuoM ma gan vett H&E, Trichrome, collagen-!. SMA-a
(X100)
Mil ten chi cac vi tri viem, xa vd during tinh khing the

so Wong lan SMA-a IA diu hieu tren be mat to bao
nguyen bao sqi ca [19].
Sau thoi gian duqc dieu tri INS BM-MSC, au vac
m8 gan chuOt m8 hinh duqc hOi phuc nhanh han nhom
doi chimg the hien qua cac dac diem: au trac m8
hoc on dinh (nhuOm H&E, Trichrome), giam to bao
chet va nhiem ma, giam sir bat mau vai thuOc nhuOm
Trichrome, dOng nghia vai viec cac dai xa tren mo hoc
da tieu bien din, Wang ding vai hinh anh nhuOm h6a
m8 mien dich collagen type 1 va SMA-a.
Theo Iii*n
bang CCI4
.ChuOt duqc gay mo hinh benh xa
bieu hien firth tang ton thucrng gan cap tinh the hien
qua cac chi s8 sinh haa, tang bieu hien manh cac gen
gay xa h6a, xuit hien cac dai xa tren cau trite mo.
Trong thai gian dieu tri bang cay ghep to bio, chuOt
khong bi gay dOc bai CCI4, nen chuOt co the to cai
thien tinh tang benh nhu: phuc hOi chi so AST, ALT,
Bilirubin, giam bleu hien cac gen xa h6a Integrin,
TFG, Procollagen va NtSe. Ket qua nay ghi nhan
twang dOng vai Kuo va cOng sir, Carvalho va cOng sir
[8, 20]. Thy nhien, mac dp phuc hOi la khk biet gicra
hai nhem duqc dieu tri to bao va nhem chfmg.
TAP CAT

WHOA HOCV.
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Mac di) phuc hOi 6 18 chuOt duqc dieu tri bang
BM-MSC la tot han so vai nhom doi chang vi: khac
Met ye chi so Albumin nham dieu tri cao han so vai
nh6m dOi chang cho thiy hoat dOng chac !tang gan
18 doi chimg van chtra hOi phuc, ghi nhOn twang dung
ve cal thien chi so Albumin a benh nhan sau ghep BMMSC trong bao cao cua Terai va cOng sir [21]. Cac gen
xa h6a nhu TGF, Procollagen, Integrin giam manh
nham dieu tri so vai dOi chung, clan ten ket qua giim
manh bieu hien m8 xa tren cau true m8 hoc nhuOm
Trichrome, collagen type 1 a nhom dieu tri so veil nham
doi chang. Ket qua nhuOm SMA-a cho thay nham dieu
tri giam manh chi s8 nay. SMA-a bieu hien dac trong
ten nguyen bao sqi Co. Trong xa gan, nguyen bao sqi
co, clang vai tr6 chinh trong viec san xuit m8 xa [18,
22]. Do da, nhom chuOt dtroc dieu tri bang BM-MSC
khong con bieu hien nguyen bao sqi ca, dan tai giam
bieu hien cac gen xa h6a va giam hinh thanh mo xa
tren hinh thai m8 hoc. Ngoai ra, cac nghien eau khk
nhtr Jang va cOng sir [23] nen hinh ghep BM-MSC
tren mo hinh chuOt Rat xa gan cling ghi nhtn !them
dieu tri giam bieu hien TGF, collagen-1 va SMAa so
dOi chimg.
So sanh vai cac co the da duqc chang minh ve hieu
qua cilia BM-MSC trong viec dieu tri benh xa gan nhu:

to bao
the sir ghat trien
to bao goc g6p phin
hinh sao, la nguon to bao chinh chuyen clang thanh
nguyen bao sqi co [24], lam giam san xuit yeu to gay
xa cua Krizhanovsky va cOng six [25], cai thien chin
nang gan va giam xa thong qua sir tang hoat dOng cilia
enzyme phan giai chat nen ngoai bao haa [26, 27],
dung hop vai 4 bao gan truing thanh gift') 4 bao gan
phan chia trong bao cao dm Wang va cOng sir [28],
ac the phosphoryl h6a Smad2/3, giim san xuat yeu to
xa h6a 6 nguyen bao sqi ca cua Jang va cong sir [23].
Ket qua cita nghien cau nay img hO gia thiet,BM-MSC
gap phan ac the to bao hinh sao va ac the qua trinh
sinh xa bai vi cac ket qua ghi nh4n twang dong vai cac
nghien cuu khk ve sir giam so luong HSC trong gan,
giam bieu hien cac gen gay xa hoa va dai xa ten hinh
thai m8 hoc.
Ket lu4n
Tiem 106 to bao BM-MSC thong qua tinh mach
duoi len m8 hinh chuOt bi xa gan do CC14 cho thay:
BM-MSC gap phin phuc hOi chac nang gan the hien a
chi so Albumin, tang cuing qua trinh phuc hoi mo gan
ton thucmg thong qua sir giam bieu hien nguyen bao


Khoa hgc Y - Ducpc

seri ca, giam qua trinh xa h6a gan.
Lei cam on

Chang toi xin than thanh cam an sir tai tro. kinh phi
tit Doi hoc Qu d' e gia TP HO' Chi Minh, trong khu6n kho
cle tai ma sec B2012-18-07/TD/08.

Tai lieu tham khao
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countries between 1980 and 2010: a systematic analysis", BMC
Aledicine, 12(1), pp.1-24.

[14] Chen G, et al (2015), "Adipose derived stem cell-based
treatment for acute liver failure", Stem Cell Research & Therapy, 6(1),
p.40.
[15] Terai S, et al (2014), "Status and prospects of liver cirrhosis
treatment by using bone marrow-derived cells and mesenchymal
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[16] Toan N.L, et al (2006), "Impact of the hepatitis B virus
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[2] Schuppan D, Afdhal N.H (2008), "Liver cirrhosis", The
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[19] Hinz B (2007), "Formation and Function of the Myofibroblast
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[4] Schuppan D, Kim Y.0 (2013), "Evolving therapies for liver
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[20] Carvalho A.B, et al (2008), "Bone marrow multipotent
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Tissue Eng, 12(12), pp.85-3477.
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the Management of Liver Cirrhosis: A Systematic Review and MetaAnalysis", Current Stem Cell Research & Therapy, 10(2), pp. I 66-180.

ItHOA HQC
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CONG WHO VIO

[21]Terai S, et al (2006), "Improved liver function in patients with
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[24] Mederacke I, et al (2013), "Fate tracing reveals hepatic
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stellate cells limits liver fibrosis", Cell, 134(4), pp.657-667.
[26] Iwamoto T, et al (2013), "Bone-marrow-derived cells
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