Download to view Dr. Zavos` slide presentation

STEM CELLS AND CELLULAR
THERAPY: POTENTIAL TREATMENT
FOR CARDIOVASCULAR DISEASES
Professor Panos Zavos, Ed.S., Ph.D.
Professor Emeritus of Reproductive Physiology/Andrology,
University of Kentucky
Director, Andrology Institute of America
Associate Director, Kentucky Center for Reproductive
Medicine & IVF, Lexington, KY, USA
Historical Event:
How Two Friends Met
What is a Stem Cell?
A
Stem Cell is a special kind of cell that has a unique
capacity to (i) renew itself indefinitely and (ii)
produce specialized cells and tissue types
A
Stem cell is not committed to a specific function
– until it receives a signal to differentiate into a
specialized cell
 Stem
Cell’s capacity to proliferate (generate more
cells) indefinitely, combined with their ability to
specialize (differentiate) into many different cell
types, makes them unique
Stem Cells: Scientific Progress and Future Research Directions (2001)
http://www.nih.gov/news/stemcell/scireport.htm
What is meant by Self Renewal?


Cell division is usually symmetrical – daughter cells
are identical to each other and to the parent
Stem cell division is asymmetrical – daughter cells
are non-identical, only one is identical to parent
Stem Cells: Scientific Progress and Future Research Directions (2001)
http://www.nih.gov/news/stemcell/scireport.htm
Where can we find Stem Cells?
 Stem
Cells have been isolated from the embryo, foetus
or adult in various organs including the heart.
 Embryonic
stem cells – derived from inner cell mass of
blastocyst (very early stage embryo; 4 to 5 day old)
 Adult
stem cells – derived from adult tissue,
undifferentiated progenitor (precursor) cells which
mature (differentiate) into functional cell types
characteristic of the original tissue
Stem Cells: Scientific Progress and Future Research Directions (2001)
http://www.nih.gov/news/stemcell/scireport.htm
Stem Cells Found in the Heart
A cluster
of cardiac stem cells (blue) between heart
muscle cells (red) in human heart tissue.
Image courtesy National Academy of Sciences, U.S.A.
Embryonic Stem Cells
Science Magazine (2001)
– potential to develop into any cell / tissue
type (over 200 different cells types described)
 derived from embryo’s and foetal tissue
Gilbert, S (2002) http://www.devbio.com/
 Totipotent
Adult Stem Cells
Time Magazine (1999)
– develop into the specialized tissue from
which they originated and some closely related
specialized tissues.
 derived from differentiated (specialized) tissues
The Scientist, Inc (2001)
 Pluripotent
What do Stem Cells do?
 Stem
Cells produce progenitor (precursor)
cells which, in turn, differentiate through a
maturation cascade into specialized cells,
creating tissues and organs
 Adult
Stem Cells are quiescent (dormant) –
until they receive a signal to reproduce and
differentiate to repopulate and replace
damaged, exhausted and aged cells
Thus, Stem Cells maintain functional integrity
Stem Cells: Scientific Progress and Future Research Directions (2001)
http://www.nih.gov/news/stemcell/scireport.htm
Stem Cells: Scientific Progress and Future Research Directions (2001)
http://www.nih.gov/news/stemcell/scireport.htm
Embryonic Stem Cells are Totipotent
Stem Cells: Scientific Progress and Future Research Directions (2001)
http://www.nih.gov/news/stemcell/scireport.htm
Adult Stem Cells are Pluripotent
Specific Tissues can be grown from Stem
cells under special conditions
Stem Cells: A Primer (2000) http://www.nih.gov/news/stemcell/primer.htm
Medical
Engineering
Tissue Engineering
 True
Multi-disciplinary Science
Materials
Science
Clinicians
Genomics
Molecular
Biology
Biochemistry
 Requires
Physiology
Cell
Biology
Mathematical
Modelling
contributions from many specialities;
physicists, chemists, materials engineers,
mathematicians, computational biologists, biochemists,
biomedical engineers, molecular biologists,
immunologists, cell physiologists, clinicians
 Required
to guide cell growth and differentiation,
connections, communication, functional integration
 Stem
cells may be a source
to ‘grow-your-own’ cells and
tissues to replace trauma- &
disease-damaged tissue
 Not
rejected as non-self
Regenerative Medicine
Stem Cells: Scientific Progress and Future Research Directions (2001)
http://www.nih.gov/news/stemcell/scireport.htm
Tissue Engineering
Tissue Engineering - Mesothelia
 Collect
patients own progenitor cells and grow them in
test tubes
 Incorrect balance of hormones may cause scarring
+EGF
- EGF
Human peritoneal mesothelial progenitor cells
grown in vitro for 7 days, ±EGF
Leavesley et al. NDT 14:1208 (1999)
Tissue Engineering – epithelia
 Collect
patient progenitor cells, grow them in ex vivo
 Transplant
Cornea
Skin
Tissue Engineering – bone & cartilage
http://www.orthovita.com/
scaffold to guide ‘new’ tissue growth, provide strength
and shape, connect and integrate with healthy patient
tissues
 ‘Seed’ with patients own cells prevents ‘non-self’ rejection
http://www.eng.hull.ac.uk/
 Use
Promise of Stem Cell Therapy
 Living
cells can be manipulated outside the body for
therapeutic applications:

correct defective gene(s) – gene therapy

treating cardiovascular diseases & infarcts

provide committed progenitors for a specific tissue (eg. platelets)

grow replacement tissue (eg. corneas, skin)

cochlear implants

grow new nerves (eg. spinal-cord injury)

‘off-the-shelf,’ pre-fabricated body parts?
http://www.probes.com/
Scientists Repair the Heart!!
Group at Düsseldorf University
Cardiac Unit in Germany used
mononuclear bone marrow cells
isolated from the patient were
transplanted six days after incubation
into artery supplying the heart.
RESULTS:
Ten weeks later the infarcted area
had been substantially reduced and
the pumping activity of the heart had
also improved significantly.
Internist, 2002;43:S96-S98
Wow… Is this a miracle?
A study showed that adult mouse bone marrow cells could also
develop into heart cells and vascular structures, resulting in the
substantial replacement of damaged heart tissue within 2 weeks.
Regeneration of the infarcted heart in mice injected with hematopoietic stem
cells. Arrows indicate newly formed myocardium in the infarcted region of the
ventricular wall (VM is viable myocardium). Another study showed that adult
mouse bone marrow cells could develop into neuronal (brain) cells.
http://www.niapublications.org/pubs/portfolio/html/biology.htm
Stem Cell Therapy for Myocardial Repair
Transplantation of both skeletal myoblasts and stem cells into the
region of infarcted myocardium results in improved myocardial
function in both the murine and porcine infarct models.
Intravenous injection of stem cells and bone marrow stimulating
cytokines also improves cardiac function.
In order for cell therapy to be widely clinically applicable, the
optimal cell has to be compatible both mechanically and electrically
with the host myocardium.
Mechanisms of Action of Stem Cells
for the Treatment of Heart Diseases
Pre-clinical studies provide toxicity data,
and may also provide useful data regarding
the cellular product’s mechanism of action.
Certain in vitro studies have shown that
non-heart cells may be manipulated to take
on functional characteristics of heart cells.
These transplanted cells may acquire the
ability to revascularize, regenerate muscle
and conduct electrical impulses in the
heart
Many questions remain about the safety
and mechanisms of action of stem cells
for the treatment of heart diseases.
Stem Cell Therapy for Myocardial Repair
Is it Arrhythmogenic?
Although it remains possible that these arrhythmias reflect
the natural history of myocardial infarction rather than the
introduction of the new stem cells, it seems clear that one
must consider the potential mechanisms of arrhythmias
and strategies to control or eliminate them.
The nature and the type of cells used for therapy could be
a source of variation in the morphologic heterogeneity of
action potentials generated by the repaired myocardium
Proarrhythmias Before Stem Cell
Therapy might be attributed to one or
more of the following reasons:
1. Heterogeneity of action potentials between the native and
the transplanted stem cells,
2. Intrinsic arrhythmic potential of injected stem cells
3. Increased sprouting induced by stem cell injection; and
4. Local injury or edema induced by intramyocardial injection
Stem Cell Delivery Methods and Devices
Heart catheterization methods and devices are being investigated
as a way to deliver cellular products. Current research in this area
is focused on development of heart catheters and methods that
can provide targeted delivery of high concentrations of cells to
specific regions of the heart muscle.
Issues related to the safety and effectiveness of the medical
devices used to deliver stem cells to a patient are still under
investigation. For example, more understanding is needed
regarding the safety and effectiveness associated with the
delivery of cells by coronary artery balloon catheter devices
Texas Heart Institute Physicians and Scientists
Discuss Advances in Stem Cell Research
With the NOGA system, a specially designed catheter helps map the interior of the left ventricle.
"When we harvest the bone marrow, we can select out the
population of stem cells that we expect will develop into the
physiological structures that we want. We process the bone marrow
cells for about three hours and then inject them into the heart,"
Texas Heart Institute Physicians and scientists….continues
The same catheter-based system allows doctors to inject stem cells directly into the heart
muscle, in sites identified as damaged by the NOGA technology.
"The process is somewhat like a video game. The NOGA gives us a real-time,
three-dimensional, color-coded image so we can target the treatment sites
within a millimeter of precision," says Dr. Perin.
The doctors use a number of parameters and algorithms to verify placement
before they begin the stem cell injections. Although only a tiny quantity is
injected into the heart muscle, that injection contains millions of stem cells.
RESULTS: In the canine animal model, the research team has found the
treatment results in a 30% reduction in scar tissue within the first two weeks.
Therapeutic cloning may be performed by utilizing donated
preimplantation embryos from in vitro fertilization (IVF) and
intracytoplasmic sperm injection (ICSI) programs
Preimplantation-stage embryos
from IVF and ICSI programs in
assisted reproductive technologies
(ART) may be used for isolation,
selection, and expansion of
embryonic stem cells derived from
the inner cell mass (ICM) of
blastocysts cultured in vitro and
that may serve for heterologous
transplantation therapies.
Therapeutic cloning may be performed by creating
embryos via nuclear transfer from patients’ somatic
cells into enucleated oocytes
Biopsied tissue from patients may be cultured
in vitro for somatic donor cells used in
nuclear transfers into enucleated recipient
oocytes. The resulting cloned blastocysts
genetically derived from the respective
nuclear cell donor may be taken for
embryonic stem cell culture and autologous
transplantation therapies.
This concept would offer a unique opportunity
to establish patient-specific stem cells for
regenerative therapies.
Cellular Therapy to Treat Heart Disease
Despite many recent advances in medical therapy
and interventional techniques, ischemic heart
disease and congestive heart failure (CHF) remain
the major causes of morbidity and mortality in the
United States. Cellular therapy for treating these and
other heart conditions is a growing field of clinical
research. Potential cell treatments for patients with
congestive heart failure (CHF) and ischemic heart
disease are of great interest to medical researchers
and treating physicians.
Research to date for Myocardial Repair
has involved cells from:
1. Autologous (donors who are also the recipients of the cellular
therapy) skeletal muscle (myoblasts),
2. Hematopoietic stem cells from autologous peripheral blood, and
3. Unspecialized mesenchymal or hematopoietic stem cells from
bone marrow.
They have been administered through catheters into the coronary
arteries, transendocardially through injection catheters into the left
ventricular myocardium, or transepicardially through a needle
during coronary artery bypass graft.
Stem Cells Found in the Heart
The Adult cardiac stem cells are multipotent and support myocardial regeneration
They
are self-renewing, clonogenic, and multipotent, giving rise to myocytes,
smooth muscle, and endothelial cells.
When injected into an ischemic heart, these cells or their clonal progeny
reconstitute well-differentiated myocardium, formed by blood-carrying new
vessels and myocytes with the characteristics of young cells.
Thus, the adult heart, like the brain, is mainly composed of terminally
differentiated cells, but is not a terminally differentiated organ because it
contains stem cells supporting its regeneration.
The existence of these cells opens new opportunities for myocardial repair.
Interspecies cloning
Development of an interspecies-specific bioassay using the bovine
oocyte model to evaluate the potential of SCNT in humans:
Possible Embryonic Stem Cell Source
K. Illmensee, M. Levanduski, and P. M. Zavos
Reprogen Organization, Limassol, Cyprus; Andrology Institute of America and the Kentucky Center for Reproductive
Medicine and IVF, Lexington, KY, USA; Embryoserve Corporation, New York, NY, USA
A
B
C
D
World DNA and Genome Day, China, April 25-30, 2005: Submitted for Publication
Salamanders can fix themselves!
We can almost fix mice
Can Science Fix Hearts via Stem
Cell Transfer?
We
are working on and
we’ll soon be there!
The stem cells and the heart?
"The possibility to regenerate and to restore function of
the heart after myocardial infarction with stem cell
transplantation holds great promise for treating heart
failure,"
Dr. David Stern, Dean of the Medical College of Georgia.
“That’s all Folk’s”
2005
Prof. Dr. Panos Zavos
This presentation is available @ http://www.zavos.org
People is our
Business and
the World is
Our Market!