Download Adipose-derived stem cell

Regeneration and stem cells
= self renewal
Definition
1) Self-renewing capability 
Clonal expansion
2) Differentiation into various types
of cells, multipotent
Why stem cell research in CV medicine?
Rising Mortality from cardiovascular diseases
100
30
Ischemic heart disease mortality per 100,000
Poor prognosis of cardiovascular diseases
25
Survival curve of
advanced gastric cancer
80
20
60
TNF-α
15
10
40
5
Survival curve of heart failure
20
0
1986
1988 1990 1992 1994 1996
1998 2000 2002
Mortality in Korea due to ischemic heart disease
(Korea National Statistical Office, 2003)
0
2
4
6
8
Why stem cell research in CV medicine?
Effects on
Mechanism of Action
Loss of myocardium
Inadequate blood supply
May prevent further loss
+
Medical Treatment
Inhibit neurohumoral
response
Cardiac resynchronization
therapy
Resynchronize
contraction
-
+/-
Surgical ventricular
restoration
Restoring geometry
-
+/-
Ventricular assist device
Unloading cardiac load
-
+/-
Artificial heart
New mechanical
contractile apparatus
+++
Not indicated
Heart Transplantation
New heart
+++
+++
Stem cell therapy
Regeneration of
myocardium and
blood vessels
++
++
Earlier Clinical Trials of Cell Therapy for IHD in recent 10 yrs
N
Method of delivery (Underling disease)
LVEF
Follow-up Period
Donor cell
Hamano et al
5
Myocardial injection during CABG (OMI)
NA
Up to 1 y
Bone marrow cells
None
Strauer et al
10
Intracoronary infusion after PCI (AMI)
57%
3 mo
Bone marrow cells
None
Assmus et al
20
Intracoronary infusion after PCI (AMI)
51%
4 mo
Bone marrow cells/
Progenitor cells
None
Menasché et al
10
Myocardial injection during CABG (OMI)
24%
10.9 mo
Skeletal myoblasts
Death, VT
Stamm et al
12
Myocardial injection during CABG (OMI)
36%
3-9 mo
Bone marrow cells
SVT
Pagani et al
5
Myocardial injection during LVAD (OM)
NA
68-191 d
Skeletal myoblasts
Arrhythmia, LVAD
death
Tse et al
8
Myocardial injection during catheterization
(angina)
58%
3 mo
Bone marrow cells
None
Perin et al
14
Myocardial injection during catheterization (OMI)
30%
4 mo
Bone marrow cells
Death
Galinaes et al
21
Myocardial injection during CABG (OMI)
NA
10 mo
Bone marrow cells
None
BOOSTl
65
Intracoronary infusion after PCI (AMI)
50%
6 mo
Bone marrow cells
None
Smits et al
5
Myocardial injection during catheterization
36%
6 mo
Skeletal myoblasts
VT
MAGIC 1,2
42
Intracoronary infusion after PCI (AMI+OMI)
49%
1y
Aviles et al
5
Intracoronary infusion after PCI (AMI)
53%
6 mo
Bone marrow cells
Heart attack
Chen et al
34
Intracoronary infusion after PCI (AMI)
49%
6 mo
Bone marrow cells
None
Peripheral blood
cells
Complications
Restenosis
Later Clinical Trials of Cell Therapy for IHD in recent 10 yrs
Name
N
Underling
disease
Method of
delivery
Change of
LVEF
Follow-up
Period
Donor cell
Complication
REPAIR
217
AMI
IC
2.5%
4M
BM
none
MAGIC-3-DES
150
AMI/OMI
IC
5.9% (AMI)
6M
PBSC
none
TOPCARE-DCM
20
DCM
ICLAD
2.8%
3M
BM
none
TOPCARE-CHD
109
OMI
IC
4.8% vs.
2.8%
4M
BM,CPC
none
TOPCARECrossover
48
ICMP
IC
2% vs. 0%
2M
BM/CPC
none
ASTAMI
100
Ant. AMI
IC
None
6M
BM
none
Hendrikx et al
20
OMI
CABG
None
4M
BM
none
Herbots et al
67
AMI
IC
None
4M
BM
none
Hambrecht et al
26
OMI CTO
IC
8%
3M
CPC
none
IACT/Strauer
18
OMI
IC
7%
3M
BM
restenosis (6%)
Erbs et al
26
OMI CTO
IC
7.1%
3M
CPC
none
Zbinden et a
14
Angina
none
-
2wk
GMCSF only
2 ACS
Hill et al
16
Angina
none
-
1M
GCSF only
2MI
Scheme of Clinical Trials
for CardioVascular Regeneration Therapy
Source of Stem Cells
Delivery Strategy
Skeletal Myoblast (Genetic
Engineering)
Bone Marrow Stem Cells
Peripheral Blood Stem Cells
Adipose Tissue Stem Cells
In-situ Cardiac Stem Cells
Surgical Ecto-Myo injection
X
Trans-catheter Endo-Myo injection
Intracoronary Infusion
Skeletal myoblast: MyoCellTM program in SNUH
intramyocardial cell injection
patient muscle biopsy
ICD
cell selection & expansion
final 50 million cells/cc
x x x
x x x
x x x
x
injection
catheter
25 million cells/site x 10 sites
Bone marrow-derived stem cell
NIH Stem Cell Book 2006, Cho et al 2006 Regenerative Medicine
Adipose-derived stem cell: ASC
Gimble et al, Circ Res 2004 Gimble et al, Circulation 2007
Cardiac stem/progenitor cell
nucleus
α-sarcomeric actin
c-kit
Nkx2.5
Beltrami A et al Cell 2003, Barile L et al NCPC 2007
Umbilical cord blood-derived stem cell
UCB Harvest
Separation
of MNCs
Seeding & Incubation
Monolayer
of cultured cells
- Prolonged proliferation
- Multi-potential differentiation
- Immunological privilege (allogeneic source)


HLA II 음성
T cell co-stimulatory molecules 음성
(B7-1, B7-2, CD40, CD40L 음성)

MLR inhibition

fail to induce allogenic T cell response in vivo
MAGIC cell program:
Myocardial Regeneration and Angiogenesis in Patient with Myocardial
Infarction using G-CSF mobilization and Intra-Coronary Stem Cell Infusion
MobPBSCs
G-CSF injection
for 3days
Intracoronary infusion
of stem cells
Apheresis
Kang HJ, Kim HS, et al. Lancet 2004
Kang HJ,,,, Kim HS. Circulation 2006
Kang HJ,,,, Kim HS. Heart 2007
Chang SA,,,, Kang HJ, Kim HS. Heart 2008
Park KW,,,, Kim HS. JMCC 2008
Chang SA, Kang HJ,,,, Kim HS. Heart 2009
Kang HJ,,, Kim HS. Cell Transplantation 2012
Kang HJ, Kim HS, et al. Can Med Asso J 2004
Kang HJ,,,, Kim HS. Am Heart J 2007
Kang JH & Kim HS. Exp Rev Card Thr 2008
Kang HJ & Kim HS. EHJ Supp 2008
Kim YJ,,,, Kim HS. Heart 2009
Kang HJ ,,,, Kim HS. Trials 2011
Kang HJ,,, Kim HS. Euro Heart J 2012
MAGIC Cell program in SNUH
[Seoul National University Hospital, Korea]
2003
2004
MAGIC Cell-1
MAGIC Cell-2
2006
2005
2007
2008
2009
2010
: G-CSF vs. Cell infusion vs. control in elective PCI
: G-CSF vs. control in AMI who underwent primary PCI
MAGIC Cell-3-DES
: Cell infusion vs. control in AMI and OMI with DES
G-CSF and endothelial function
Effect of Cell infusion on LV dyssynchrony
G-CSF and Restenosis, coronary remodeling
1st generation stem cell therapy
1.5th generation stem cell therapy
2nd generation stem cell therapy
MAGIC Cell-4-ICMP
: Cell infusion in ischemic CMP without PCI
MAGIC Cell-5
: cell infusion with combicytokine vs.
G-CSF
MAGIC Cell-6
: waiting for agent
SNUH MAGIC Cell Program
MAGIC Cell-1,2 trial
from Dec 2002
Additional cell infusion is better than G-CSF
alone.
NIH may be a concern of G-CSF.
MAGIC Cell-3-DES & 4-ICMP trial
from Feb 2004
DES solved restenosis problem of G-CSF.
Additional cell infusion is better than control in AMI rather than OMI
MAGIC Cell-5-CombiCyto trial
from April 2007
To enhance homing rate and therapeutic efficacy