manuel mª mazo vega
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TRANSPLANTATION OF MESENCHYMAL STEM CELLS EXERTS A GREATER LONG-TERM EFFECT
THAN BM-MNC IN CHRONIC MYOCARDIAL INFARCTION IN RAT
MANUEL Mª MAZO VEGA
U n i v e r s i d a d d e N a v a r r a
CENTRO DE INVESTIGACIÓN MÉDICA APLICADA
MYOCARDIAL INFARCTION
The world health report 2004, World Health Organization
Cardiovascular diseases:
-First cause of mortality
-Myocardial infarction: 12,6%
CARDIOVASCULAR DISEASES
30%
CANCER+RESP DISEAS +DIABETES
22%
MATERNAL AND PERINATAL COND, NUTRITIONAL STATE
30%
OTHER CHRONIC DISEAS. 9%
INJURIES 9%
Nitrates
Aspirin
ACEi
ARB
Aldosterone antagonists
Estatins
Beta-Blockers
Inflammatory cytokines antagonists
Neutral endopeptidase inhibitors
PHARMACOLOGICAL SURGICAL
Reperfusion
Transplant
REGENERATIVE
Gene Therapy
Cell Therapy
MYOCARDIAL INFARCTION: TREATMENTS
STEM CELL THERAPY
STEM CELL THERAPY
EXPERIMENTAL DESIGN
SPRAGUE-DAWLEY RAT (+Cyclosporin)
GFP+ S-D RAT
BM-MNC GFP+ MSC GFP+
CD73+
CD45- CD90+
CD44+
RT1A+
RT1B-
CD31-
CH
ON
DR
OC
YTE
AD
IPO
CYT
EO
STEO
CYT
EPhenotype Differentiation
Implant (106 cell)
+0 d
Infarct
Eco
microPET
-30 dEco
+30 d+14 d+7 d
Histological Analysis
Eco
microPET
+90 d
5-6 weeks
% L
VEF
MEDIUM BM-MNC MSCPRE-IMPLANT 3 MONTHS
* *
0
10
20
30
40
50
60
RESULTS: CARDIAC FUNCTION
% 18
F-FD
G U
PTA
KE
(ALL
SEG
MEN
TS)
% 18
F-FD
G U
PTA
KE
(INF.
SEG
MEN
TS)
MEDIUM BM-MNC MSC
MEDIUM BM-MNC MSC
A**
*B
C
MED
IUM
MSC
BM
-MN
C
PRE-IMPL 3 MONTHS
60
65
70
75
80
85
35
40
45
50
55
60
RESULTS: TISSUE METABOLISM
A B D
E F H
I J L
1 WEEK 2 WEEKS 3 MONTHSM
EDIU
MB
M-M
NC
MSC
C
G
K
1 MONTH
RESULTS: ENGRAFTMENT
RESULTS: INFLAMMATION
0
500
1000
1500
2000
2500
INFA
RC
T
CD
68+/
mm
2
A CB DPE
RI-I
NFA
RC
T C
D68
+/m
m2
1 WEEK 2 WEEKS 1 MONTH
E GF
MEDIUM BM-MNC MSC
H
TOPRO3 GFP CD68 MERGEDLK MJI MERGED
MEDIUM
BM-MNC
MSC
1 WEEK 2 WEEKS 1 MONTH
MEDIUM
BM-MNC
MSC
**
**
** ****
**
0
100
200
300
400CD68 TOPRO3 CD68 TOPRO3
GFP CD68 TOPRO3 GFP CD68 TOPRO3
CD68 TOPRO3
GFP CD68 TOPRO3
MEDIUM BM-MNC MSC
A B
* *
*
RESULTS: INFLAMMATION
50
55
60
65
70
75
% IN
FAR
CTE
D L
V
*
MEDIUM BM-MNC MSC
KJ
MEDIUM BM-MNC MSC
LI
% C
VF *
MEDIUM BM-MNC MSC
ON
MEDIUM BM-MNC MSC
PM
0
5
10
15
20
25
% S
M-P
OSI
TIVE
AR
EA
0
300
600
900
1200
00,5
11,5
22,5
3G
B
MEDIUM BM-MNC
C
MSC
D
MEDIUM BM-MNC MSC
*
****
**
MEDIUM BM-MNC MSC
A
F
MEDIUM BM-MNC MSC
HE
CAV1 DAPI CAV1 DAPI CAV1 DAPI
αSMA DAPI αSMA DAPI αSMA DAPI
CA
PILL
AR
IES/
mm
2
RESULTS: MECHANISMS OF ACTION
01020304050
01020304050
0
50
100
150
050
100150200
0
50100150200
0
50
100
150
####
PCN
A+C
AV1
+/m
m2
1 WEEK 2 WEEKS
**** ****
****
*
****
#
****
1 WEEK 2 WEEKS
####
****
1 WEEK 2 WEEKS
1 WEEK 2 WEEKS
1 WEEK 2 WEEKS
1 WEEK 2 WEEKS
BM-MNC MSC
PCN
A+C
AV1
+/m
m2
A PERI-INFARCT INFARCT
BM
-MN
CM
SCB
M-M
NC
MSC
BM
-MN
CM
SC
B
CA
V1+P
CN
A+
GFP PCNA CAV1 TOPRO3
GFP PCNA CAV1 TOPRO3
GFP PCNA CAV1 TOPRO3
GFP PCNA CAV1 TOPRO3
GFP PCNA αSMA TOPRO3
GFP PCNA αSMA TOPRO3
GFP PCNA αSMA TOPRO3
GFP PCNA αSMA TOPRO3
GFP PCNA αSMA TOPRO3
GFP PCNA αSMA TOPRO3
GFP PCNA αSMA TOPRO3
GFP PCNA αSMA TOPRO3
PCNA CAV1 TOPRO3
PCNA CAV1 TOPRO3
PCNA CAV1 TOPRO3
PCNA CAV1 TOPRO3
PCNA αSMA TOPRO3
PCNA αSMA TOPRO3
PCNA αSMA TOPRO3
PCNA αSMA TOPRO3
PCNA αSMA TOPRO3
PCNA αSMA TOPRO3
PCNA αSMA TOPRO3
PCNA αSMA TOPRO3
1 WEEK 1 WEEK2 WEEKS 2 WEEKSPERI-INFARCT INFARCT
MYO
FIB
(αSM
A+)
PC
NA
+
PCN
A+α
SMA
+ (M
YOFI
B)/m
m2
SMC
(αSM
A+)
PC
NA
+
PCN
A+α
SMA
+ (M
YOFI
B)/m
m2
PCN
A+α
SMA
+ (S
MC
)/mm
2
PCN
A+α
SMA
+ (S
MC
)/mm
2
RESULTS: MECHANISMS OF ACTION
•Treatment with bone marrow stem cells (BM-MNC or MSC) induced a long-lasting (3 months) improvement in cardiac function. Moreover, animals injected with MSC showed an increase of tissue metabolism, which was associated with a decreased infarct size and collagen content and a higher degree of revascularization.
•The benefits observed after bone marrow stem cell transplantation were possibly due to paracrine mechanisms involved in angiogenesis and host cell proliferation and not through direct cell contribution.
CONCLUSIONS
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