Advances in Cardiac Regenerative Medicine Using Stem Cells

Curriculum Vitae
IDI (Indonesian Medical Association)
PAPDI (Indonesian Association of Internal Medicine)
PERKI (Indonesian Heart Association)
PUSKI (Indonesian Society of Medical
Ultrasonography)
PERKAVI (Indonesian Society of Heart Research)
ASE (American Society of Echocardiography)
ASNC (American Society of Nuclear Cardiology)
AHA (American Heart Association
SCCT (Society of Cardiac Computerized Tomography)
ASFC (ASEAN Society & Federation of Cardiology)
ISFC (International Society & Federation of
Cardiology)
WHL (World Hypertension League)
Membership :
National
International

Formal Training
1976
1981
1985
2004
MD
Faculty of Medicine /Airlangga University, Surabaya
Internist
Faculty of Medicine / Airlangga University,
Surabaya
Cardiologist
Faculty of Medicine / Airlangga University,
Surabaya
PhD
Faculty of Medicine / Airlangga University Surabaya
2R3esearch Interests
Basic Science
Clinical Science
1
2
3
4
1
2
3
Oxidant & Antioxidant in
Atherosclerosis
Atherosclerosic Regression
Stem Cell in Cardiovascular Diseases
Cardiovascular Imaging in
Atherosclerosis
Cardiovascular Imaging in Heart Failure
Stem Cell Treatment in Cardiovascular
Diseases

Curriculum Vitae
Sept-Oct 1992 Nuclear Cardiology. Royal Adelaide Hospital. University of Adelaide.
South Australia. Australia.
Nov 1992-February 1993 Nuclear Cardiology & Other Cardiac Imaging. Academische
Zijkenhuijs Leiden. Netherland.
Jan 1995 Stress Echocardiography. Hunter-Hill Clinic Cardiology. Sydney. New
South Wales. Australia.
April – June 2000 Research on Antioxidant Effect of Garlic Extract on Copper and
Lypoxygenase-catalyzed oxidation of LDL. Institute of Biochemistry.
University Clinic Charite. Humboldt University. Berlin. Germany.
Sept – Oct 2003 Research on the effect of Garlic Extract on Cholesterol Efflux from
Lipid-loaded J-774 Macrophages. Institute of Biochemistry.
University Clinic Charite. Humboldt University. Berlin. Germany.
Jan 2007 Advanced Course on Tissue Doppler Imaging. Chinese University.
Hong Kong.
May 2007 Advanced Course (Level 2 Certification) on Cardiovascular Computed
Tomography, Albany, New York, USA
May 2011 (Level 1 Certification) on Cardiovascular Magnetic Resonance
Imaging, Kualalumpur, Malaysia.
Additional Courses and Training
:

Curriculum Vitae
1. Effects of Onion on Diabetic patients. 15th International Congress of
Internal Medicine. Hamburg, (WEST GERMANY) : 18th - 22nd 1980.
2. Hypertension in the Critical Area of East Java. Singapore: 8th ASEAN
Congress of Cardiology. 7-11 December 1990.
3. Blood glucose and other coronary risk factors in critical areas of East
Java. Jakarta : 6th Congress of ASEAN Federation of Endocrinology, 2-4
July 1992.
4. The Effect of Garlic extracts (DDS, SAC) on Oxidized-LDL. Measurement
of HETE, HODE and its isomeres by HPLC. 1st National,Congress of
Indonesian Society of Heart Research. Jakarta : July 2002.
5. The Effect of Garlic extracts (DDS, SAC) on the Efflux of Cholesterol from
Acetylated-LDL-loaded J-774 Macrophages. Asian Pacific Congress of
Atherosclerosis. Nusadua, Bali 2004.
6. Effects of Garlic & its metabiolites on Atherosclerosis. Focus on
Atherosclerotic Regression. Keynote Speaker. International Organization
for Chemical Sciences in Development (IOCD). Working Group on Plant
Chemistry. Surabaya : April 09-11,2007.
7. Reversin increase plasticity of Bone Marrow-derived Mesenchymal Stem
Cell to generate Cardiomyocyte. Act Med Indon 2012;44:22-27
8. 3 Other International Publications
9. > 100 National Publications and Papers
Publications
:

CARDIOVASCULAR EMERGENCIES COURSE
Bumi Surabaya Hotel, November 7-8th, 2015
IMPROVEMENT IN
CARDIAC
REGENERATIVE
MEDICINE
Prof Budi Susetyo Pikir MD PhD
Department of Cardiology & Vascular Medicine /
Medical Faculty –
Dr.Soetomo Hospital /Airlangga University Hospital
Stem Cell Centre / Institute of Tropical Disease
Airlangga University
S U R A B A Y A

CARDIOVASCULAR EMERGENCIES COURSE
Bumi Surabaya Hotel, November 7-8th, 2015
Spontaneous iPS

Primary Goals of Stem Cell Treatments
I. Biological Revascularization
II. Tissue Regeneration
III. In Vitro Organ / Apparatus development :
a) Vascular vessel
b) Vascularized Myocardial Patch
c) Valves
d) Bronchus
e) Epidermis / Dermis
f) Liver
g) etc
I. Paracrine Effect
Secondary Goals of Stem Cell Treatments

 Good Retention
 Favourable Growth of New Myocardial Tissue
 Good Engraftment (Integration) with Native
Myocardium
STEM CELL for MYOCARDIAL
REGENERATION
Fully Functioning Myocardium
GOAL :
Electrophysiologic Function
Pump Function

Strategies for Improvement of
Stem Cell Treatment in
Myocardial Regeneration
I. Stem Cell Processing :
1. Cellular Engineering
2. Epigenetic Engineering
3. Genetic Engineering
II. Evaluation of Treatment :
1. Stem Cell Tracking
2. Myocardial Revascuklarization / Perfusion
3. Myocardial Viability

II. Scaffold
III. Evaluation of Treatment :

Choosing the right Source
of Stem Cells
 The best source : Cardiac Resident
Stem Cells located at Subepicardiac
Fat of RV, etc.
 Problems :
 Difficult to obtain this cell
 Limited in number in Cardiac
Diseases

Choosing the right Source
of Stem Cells
 Extracardiac “Cardiac Stem Cells” :
– Natural Occuring SC
 Adipose-MSC
 Dental Stem Cells
– Cell/Genetic Enginering
 iPS
 Genetic Editing

NATURALLY
OCCURRING STEM
CELLS
ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG2.GIF
TOTIPOTENT
CELL (ZYGOTE)
PLURIPOTENT
STEM CELLS
(EMBRYONIC STEM CELLS)
EPC VSM-SC.
WHITE BLOOD
CELLSPLATELETS
RED BLOOD
CELLS
BLOOD STEM CELLS
POLYPOTENT
(ECTODERM)
POLYPOTEN
(MESODERM)
POLYPOTEN
(ENODERM)
HEMANGIOBLAST
CARDIO-HEMANGIOBLAST
CARDIOMYOCYTE
VALVULAR CELL
CARDIAC PROGENITOR CELL
CARDIAC SC
COMMON HARD TISSUE STEM CELL
CHONDRBLAST
OSTEOBLAST
ODONTOOBLAST
CEMENTOBLAST
MYOSKELETOBLAST
differentiation dedifferentiation
transdifferentiation
?

Embryonal Stem Cell Marker of
Adult Pluripotent Stem Cell
ESC Marker HPS
(Hemopoietic SC)
MSC
(Mesenchymal SC)
PDLSC
(Periodontic Ligament
SC)
SSC
Spermatogonial SC)
SOX-2 + + + +
OCT-4 + + + +
NANOG + + + +
KLF-4 + + + +
LIN28 + + +
SSEA-1 + + + +
SSEA-3 + + +
SSEA-4 + + + +
TRA-1-60 + + +
TRA-1-81 + + + +
Ng TK et al. Pluripotent Adult Stem Cells : A potential revolution in Regenerative Medicine and
Tissue Engineering. In : Deepa Bhartiya and Nibedita Lenka. Ed. Pluripotent Stem Cells. Intech, 2013.

Cardiovascular Stem / Progenitor Cells
Pluripotent
Stem Cells
Cardiomyocytes
Hemopoietic
Cells
Vascular Cells
Flk-1 &
Brachyuri

Hierarchy of Cardiovascular Lineage SC
iPS
(pluripotent SC)
General Mesoderm
(polypotent SC)
Cardiohemangioblast
(multipotent SC)
Primitive Hemangioblast
(multipotent SC)
Cardiac SC
(oligopotent SC)
HPSC
(oligopotent SC)
Simple Hemangioblast
(oligopotent SC)
Cardiomyocyte Endocardial CellWBC
Megakaryoc
yteRBC Vascular Cells
Common Hard Tissue SC
(multipotent SC)
Common Ancestor SC
Myoskeletoblast
General Ectoderm
(polypotent SC)
General Endoderm
(polypotent SC)

Progress in In Stem Cell
Treatments
Embryonal
Stem Cell for
All Diseases
Bone-Marrow
Stem Cell for
All Diseases
Induced-
Pluripotent
Stem Cell for
All Diseases Spesific /
Resident Stem
Cell for Specific
DiseasesEarly Era New Era
Adipose-
derived MSCS
for All
Diseases

Unwanted Tissue in
Stem Cell Treatment :
ESC iPS MSC
(BM-MSC)
MSC
(Adipose-
derived
SC)
Resident
SC
Teratoma Teratoma
Other Tissue Other Tissue Bone
Fat
Fat

Unwanted Tissue in
Stem Cell Treatment :
Makino et al (1999) :
BM-MSC by 25 passaging  spontaneous dedifferentiation
30 % Differentiation into beating Cardiomyocyte
KE Hatzistergos, A Blum, TA Ince, JM Grichnik, JM Hare. What Is the Oncologic Risk of Stem Cell
Treatment for Heart Disease? Circ Res. 2011;108:1300-1303
Hatzistergoset al (2011) :
Mouse MSC by 65 passaging  Genetic Aberration ?
Differentiation into Multiple Organ FibroSarcoma

Progress in In Stem Cell
Treatments
Embryonal
Stem Cell for
All Diseases
Bone-Marrow
Stem Cell for
All Diseases
Induced-
Pluripotent
Stem Cell for
All Diseases
Resident
Stem Cell for
Specific
Diseases
Early Era
New Era
Adipose-
derived MSCS
for All
Diseases

Early vs New Era of SC Tx
Early Era of SC Tx
(not at the right track)
New Era of SC Tx
(at the right track)
Concept The best source –
• Embryonal SC or iPS
The best source –
Myocard Regeneration
• Flk-1 & Brachyuria SC or
• Cardiac Resident SC
• Combination of Cardiac Progenitor
Cell& EPC
• Myocardial Patch
Angiogenesis
• EPC for Biological
Revascularization
Animal Study • ESC, iPS
• Skeletal Myoblast
• BM-MSC
• Adipocyte-MSC
• Endoth Progenitor Cell
• Flk-1 SC
Clinical Aplication • BM-MNC
• BM-MSC
• Adipocyte-MSC
• EPC
• Extracardiac-derived ”Card SC”

Extracardiac Sources of
“Cardiac Stem/Progenitor Cells”
Adipose-MSC
 1 % Spontaneous beating
cardiomyocytes (Planat-Benard V et al 2004)
 10 % Spontaneous beating
cardiomyocytes (Jumabey et al, 2010)
Planat-Benard V, Menard C, Andre M, et al. Spontaneous Cardiomyocyte differentiation
from Adipose Tissue Stroma Cells. Circ Res. 2004;94:223-9.

Differentiation of PDL-SC
(Periodontic Ligament Stem Cells)
 Neurogenic differentiation (Ectoderm)
 Insulin-producing cell (Endoderm)
 Hepatic cells differentiation (Endoderm)
 Cardiomyogenic differentiaton (mesoderm) within 8
days
 Osteogenic differentiation (mesoderm)
 Chondrogenic differentiation (mesoderm)
23
Has many subpopulations of Stem Cells

After Stem Cell Treatment
using Dental Stem Cell
for Myocardial Regeneration

3. Genetic Engineeri8ng
II. Evaluation of Treatment :

Can we use BM-MSC as source for
Myocardial Regeneration ?
Makino et al (1999)
 Spontanenous dedifferentiation after subcultures for > 4 months
 24 hours Azacytidine-induced cardiomyocyte differentiation  30 %
of Stem Cell became
– individual beating cardiomyocyte after 2 weeks of culture
– synchronized beating cardiomyocyte after 3 weeks of culture
Pikir et al (2010)
 20 nM Reversin was given for 24 hours to induce dediferentiation, followed
by
 9 μM 5-aza-2-deoxycytidine for 24 hours,
 Cardiac Progenitor Cell (GATA +, CD34 and ckit +) formation after 21 days of
culture.
BM-MSC should be induced to Cardiac
Progenitor Cell (CPC) before can be used for

Cardiomyocyte-inducing Agent :
5-aza-2-deoxycytidine
Budi S Pikir & Fedik Acta Med Indones. 2012 Jan;44(1):23-7
Genetic Expression of Cardiomyocyte-lineage
1 2 M 3
219 bp
RT-PCR : c-kit+
Lane 1-2 : Reversin plus 5-AZT
Lane M : Marker
Lane 3 : 5-AZT only
RT-PCR : CD34+
Lane M : Marker
Lane 1-2 : Reversin & 5-AZT
Lane 3 : Reversin only
Lane 4 : 5 AZT only
M 1 2 3 4
235 bp

Cardiomyocyte-inducing Agent :
5-aza-2-deoxycytidine
Budi S Pikir & Fedik Abdulrantam Acta Med Indones. 2012 Jan;44(1):23-7
Genetic Expression of Cardiomyocyte-lineage
1 2 3 4 5 6 M
1 2 3 4 5 6 M
286 bp
RT-PCR : MLC-2
Lane 1-6 : Reversin plus 5-AZT
Lane M : Marker
M 1 2 3
275 bp
RT-PCR : GATA-4
Lane M : Marker
Lane 1 : Reversin only
Lane 2 : 5 AZT only
Lane 3 : Reversin plus 5-AZT

Simple Epigenetic Reprogramming
Makino et al 1999
Budi S Pikir, Fedik A Rantam et al 2010
Spontaneous
Dedifferentiation
Differentiation
DifferentiationDedifferentiation
(24 hrs Reversin)
30 % Adult
Cardiomyocyte
BM-MSC
Cardiac
Progenitor
Cell
BM-MSC
4 months
passaging
3 weeks

Common Ancestor
Stem Cells :
 CD-34 EPC for
Leukocyte or Vascular
Endothelial Cell
Regeneration
 Flk-1 & Brachyuri SC for
Cardiovascular
Regeneration
Closest Family of
Stem Cells :
• BM-MSC for Dentin
Regeneration
• Dental SC for Bone
Regeneration
• Olfactory SC for
Paraplegia
• Ectodermal type of
Dental SC for Nerve
Regeneration
• Subpopulation of
Epidermal SC or Hair
Follicle SC for Nerve
Regeneration
Strategy to select
Correct Source of Stem Cells

Strategy to select
Correct Source of Stem Cells
Empirical Study:
Adipose SC for Bone
or Dentasl
Regeneration
• Olfactory SC for
Paraplegia
• Ectodermal type of
Dental SC for Nerve
Regeneration
Empirical Study:
Adipose SC for
Myocardial
Regeneration
Dental SC for
Insuline-producing
cell (Beta-pancreas
cell)
Adipose SC for Nerve
Regenefation

EXAMPLES OF NATURALLY OCCURRING
STEM CELLS
ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG2.GIF
TOTIPOTENT
CELL (ZYGOTE)
PLURIPOTENT
STEM CELLS
(EMBRYONIC STEM CELLS)
EPC VSM-SC.
WHITE BLOOD
CELLSPLATELETS
RED BLOOD
CELLS
SPECIALIZED
CELLS:
BLOOD STEM CELLS
“ADULT”
STEM CELLS
POLYPOTENT
(ECTODERM)
POLYPOTEN
(MESODERM) POLYPOTEN
(ENODERM)
HEMANGIOBLAST
CARDIO-HEMANGIOBLAST
CARDIOMYOCYTE
VALVULAR CELL
CARDIAC PROGENITOR CELL
CARDIAC SC
COMMON HARD TISSUE STEM CELL
CHONDRBLAST
OSTEOBLAST
ODONTOOBLAST
CEMENTOBLAST
SKELETOBLAST

New Strategy using Stem Cell for
Myocardial Regenetration
1. Using Correct Sources of Stem Cell
a. Resident Cardiac Stem / Progenitor Cell or
b. Extracardiac Cardiac Stem / Progenitor
Cells
2. Using Purified Cardiac Stem / Progenitor
Cell
3. Using Scaffold for CPC attachment &
temporary nutrition
4. Adding Vascular Stem Cell (?)  VSMPC
(?) & EPC

Different strategies for an improved
cell therapy of Myocardial Infarction.
Different strategies for an improved cell therapy of MI. After MI, albeit significantly preventing acute death and transiently
increasing contractile capacity, conventional medical treatment does not restore organ architecture. MSC transplantation is
able to induce a partial recovery of cardiac function and limit infarct expansion. However, low engraftment and differentiation
impair the therapy. Four systems aim at improving this situation and manage total tissue regeneration: tissue engineering,
genetic modification of cells, pretreatment with protective molecules and in vitro predifferentiation towards the desired
lineages.
Manuel Mazo, Miriam Araña, Beatriz Pelacho and Felipe Prosper. Chapter 1 Mesenchymal Stem Cells for Cardiac Repair:
Preclinical Models of Disease. In : Jürgen Hescheler · Erhard Hofer eds. Adult and Pluripotent Stem Cells. Potential for
Regenerative Medicine of the Cardiovascular System. Springer Dordrecht Heidelberg New York London. 2014.

3. Genetic Engineering :
1. iPS
2. Genetic Editing
II. Scaffold

iPS-derived models of
Diabetic Cardiomyopathy

Flk-1 Progenitor Stem Cell in mouse
model of Acute Myocardial Infarction
 AMI by LAD ligation on Immunodeficient SCID beige mice
 Flk-1 was purified by FACS (Fluorescence Activated cell Sorting)
 Placebo (13) injection of PBS intramyocardially
 Flk-1neg Progenitor SC injection of 5 x 105 cells
intramyocardially
 Flk-1pos Progenitor SC injection of 5 x 105 cells
intramyocardially
Mauritz C, Martens A, Rojas SV, et al. Induced pluuripotent stem cell (iPSC)-derived
Flk-1 progenitor cell engraft, differentiate, and improve heart function in a mouse
model of Acyte Myocadial Infarction. Europ Hesrt J 2011;32 :2634-2641.

Flk-1 Progenitor Stem Cell in mouse
model of Acute Myocardial Infarction
Flk-1 was progenitor for Cardiomyocyte
and Vascular Cell Types
 Engraft and Differentiate into New
Myocardium and Vascular Cell.
 Improve LV Function
Mauritz C, Martens A, Rojas SV, et al. Induced pkuripotent stem cell (iPSC)-derived Flk-
1 progenitor cell engraft, differentiate, and improve heart function in a mouse model of
Acyte Myocadial Infarction. Europ Hesrt J 2011;32 :2634-2641.

Induced Pluripotent Cell (iPS) &
Dedifferentation from Somatic Cells.
42
Genetic
Reprogramming
Epigenetic
Reprogramming
Genetic Transfer :
Transfer Factors (TF)
Epigenetic Modification :
Enzymatic DNA/Histone /Ribosome
methylation/acetylation &
demethylation/deacetylation
1. Small Molecule :
• Reversin
2. Embryonal Cell Extract :
• Free cell extract Embryo, etc.
3. Small Protein :
• Oct4, Sox2, Klf4, c-Myc
• Oct3/4
• Sox2
• Klf4
• c-Myc
• Oct4
• Sox2
• Nanog
• Lin28
• Oct4
• Complicated procedures • Simple procedures
• More stable • Less stable
• Low Efficiency (< 1 %) • Very Low Efficiency (0.001-0.03 %)
• High-risk for side-effect • Low risk

Genetic
Reprogramming
Flk-1 SC
iPS
Differentiation
Fibroblast
Epigenetic
Reprogramming
Flk-1 SC
More
Multipotent SC
Differentiation
Multipotent SC

Genetic Editing
45
Xiu-ling XU1, #, *, Fei YI 2, #, Hui-ze PAN 1, Shun-lei DUAN 1, Zhi-chao DING1, Guo-
hong YUAN 1, Jing QU1, Hai-chen ZHANG1, Guang-hui LIU1. Progress and prospects
in stem cell therapy. Acta Pharmacologica Sinica (2013) 34: 741–746.

Scaffold in Stem Cell Tx
I. Natural Scaffold
II. Synthetic Scaffold
1. Non Biodegradable
Scaffold
2. Biodegradable Scaffold

The major roles for supporting matrices
(scaffold)
1. It serves as a framework, which maintains the shape of
the defect. It provides physical support for the healing
area so that there is no collapse of the surrounding
tissue into the wound site.
2. It serves as a 3D substratum for cellular adhesion,
migration, proliferation and production of
extracellular matrix.
3. It serves as a barrier to restrict cellular migration in
a selective manner.
4. It potentially serves as a delivery vehicle for growth
factors.
5. Temporary Nutrition
48

Natural Scaffold :
Extracellular Matrix
 Decellularized Bone
 Decellularized Bronchial Tree from corpse
 Decellularized Cardiac Valves from corpse
 Etc. 49
Natural Scaffold for Bone tissue
engineering :
the extracellular matrix (ECM) of bone, the
unique microenvironmental niche for bone
morphogenesis

Scaffold for Myocardial Regeneration –
in the form of sheet
1. It serves as a framework, which maintains the shape of
the defect. It provides physical support for the healing
area so that there is no collapse of the surrounding
tissue into the wound site.
2. It serves as a 3D substratum for cellular adhesion,
migration, proliferation and production of
extracellular matrix.
3. It serves as a barrier to restrict cellular migration in
a selective manner.
4. It potentially serves as a delivery vehicle for growth
factors.
5. Temporary Nutrition
50

II. Scaffold
2. Myocardial Revascularization / Perfusion

EVALUATION BY CARDIAC IMAGING
Stem Cell Transplantation
LV Function
LV Wall Motion
Myocardial Perfusion
Myocardial Viability
Due to stem cell ?
Due to paracrine effect ?
Cardiac
MRI

Cardiac
MRI
Stem Cell Transplantation
LV Function
LV Wall Motion
Myocardial Perfusion
Myocardial Viability
Due to stem cell ?
Due to paracrine effect ?
Stem Cell Tracking
Cardiac
MRI
EVALUATION BY CARDIAC MRI

Contrast Agent for Stem Cell Tracking
 SPIO (Superparamagnetic Iron Oxide) Nano
Particle :
– Magnetitite Fe3O4 or Maghemite Fe2O3
 Ferumoxide (Endorem in Europe) and Feridex in USA) 120-180 nm
 Ferucarbotran (Resovist) diameter 62 nm
 Ferumoxtrane-10 (Combidex in USA and Sinerem in Europe)
 Ferumoxytol (Feraheme)
– Preparation of Stem Cell labelling
 Surface labelling
 Internalization of contrast into stem cell before transplantation :
– Cross-linked with a membrane-translocaqting signal peptide (e.g. HIV-1 Tat protein)
– Incubated in comnibination with transfection agentsa

EVALUATION BY CARDIAC MRI
• T1 Contrast Agent (bright positive signal ) :
• Gadolimnium (Gd-) containing NP (e.g. Gd-chelated NP and Gd-chelated
dextran NP) – GadoCellTrack
• Gadolinium oxide NP
• T2 Contrast Agent (negative signal or dark spot) :
• SPIO NP bimetallic ferrite NP (e.g. CoFe2O4, MnFe2O4 and NiFe2O4)
• Hybrid magnetic NP such Fe3O4, Au dumbbell
Contrast Agent can be detected ultil several month
after stem cell transplantation

Limitation of SPIO Contrast Agent
 Extracellular deposition in tissue :
– Active exocytosis by viable stem cells
– Passive release due to death of transplanted cells
 Immunocompetent animal:
– infiltrating leukocyte and microglia surrounding dead
stem cells and to internalize superparamagnetic iron-
oxide clusters
 Immunodefficient animal :
– contrast clear at a faster rate – due to proliferation of
surviving transplanted cell and associated
labeldiffusion

Cardiac MRI
Perfusion Defect
Rest-stress MPI (a–f) in a patient with
severe proximal stenosis (90%
luminal narrowing) of the
osterolateral branch of the left
circumflex CA (arrow, g). First-pass
MPI during stress (a–c), and during
rest (d–f) showing 3 short-axis levels
(basal, mid, apical). While LV
myocardial nhancement is
homogeneous during rest, an
extensive perfusion defect (arrows, a–
c) is visible during adenosine stress
MPI involving the entire LV lateral
wall

Cardiac MRI
Perfusion & Viability Test

Ischemic Dilated Cardiomyopathy
Cardiac MRI
Perfusion & Viability Test

CONCLUSIONS :
with Current Practice of Stem Cell Tx
(BM-MNC , BM-MSC or Adipose-MSC) :
 Short-term moderate improvement of LV
function (6%) – due to Paracrine Effet ?
 Long-term ?
With Stem Cell Injection :
• I.V Injection - < 2 % reside in area of
target
• Intracoronary injection – 5 % reside in
area of target
• Intramyocardial injection – 25 % reside in
area of target.

FUTURE DIRECTION
Correct Source of Stem Cell :
 Resident Cardiac Stem Cells
 Extracardiac Source of Cardiac Mesoderm
(Brachyuri, Flk-1) or Cardiac Stem Cell
– Isolation directly from Adipose-MSC or Dental
Stem Cells
– “Transdifferentiation” from Closest Family of
Stem Cells (by epigenetic reprogramming before
differentiation)
Purified it before can be used for clinical application

 Optimal preparation of STEM CELLS
– Correct source of STEM CELLS
– Optimal stage of development of STEM CELLS (Cardiac
Mesoderm, Cardiac Stem Cell, Cardiac Progenitor Cells)
– Purified it
– Add Vascular Smooth Muscle Progenitor Cells (?) and
Endothelial Progenitor Cell for Cardiac Progenitor Cells
 Optimal Route of Injection (Intramyocardial –
subendocardial or subepicardial)
FUTURE DIRECTION

CONCLUSIONS :
to achieve the best result :
TISSUE ENGINEERING
(Patch or Injectable Scaffold)
(It is not possible to regenerate large
infarction with Cell Tx alone)

Tehran Arrhythmia Center
Challenge : Knowledge Explosion
“We are drowning in information but
starved for knowledge.”
— Naisbitt, ‘82

Advances in Cardiac Regenerative Medicine Using Stem Cells

Recommended

Recommended

More Related Content

What's hot

What's hot (19)

Similar to Advances in Cardiac Regenerative Medicine Using Stem Cells

Similar to Advances in Cardiac Regenerative Medicine Using Stem Cells (20)

Recently uploaded

Recently uploaded (20)

Advances in Cardiac Regenerative Medicine Using Stem Cells