STEM CELLS AND CELLULAR THERAPY: POTENTIAL TREATMENT FOR CARDIOVASCULAR DISEASES

STEM CELLS AND CELLULAR THERAPY: POTENTIAL TREATMENT FOR CARDIOVASCULAR DISEASES

Professor Panos Zavos, Ed.S., Ph.D.Professor Panos Zavos, Ed.S., Ph.D.Professor Emeritus of Reproductive Physiology/Andrology,

University of Kentucky Director, Andrology Institute of AmericaAssociate Director, Kentucky Center for Reproductive Medicine & IVF, Lexington, KY, USA

Historical Event:How Two Friends Met

Historical Event:How Two Friends Met

What is a Stem Cell?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?

What is meant by Self Renewal?

Stem Cells: Scientific Progress and Future Research Directions (2001)http://www.nih.gov/news/stemcell/scireport.htm

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

Where can we find Stem Cells?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

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 Totipotent – potential to develop into any cell /

tissue type (over 200 different cells types described)

derived from embryo’s and foetal tissue

Embryonic Stem Cells Totipotent – potential to develop into any cell /

tissue type (over 200 different cells types described)

derived from embryo’s and foetal tissue

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Adult Stem Cells Pluripotent – develop into the specialized tissue

from which they originated and some closely related specialized tissues.

derived from differentiated (specialized) tissues

Adult Stem Cells Pluripotent – develop into the specialized tissue

from which they originated and some closely related specialized tissues.

derived from differentiated (specialized) tissues

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What do Stem Cells do?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

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Embryonic Stem Cells are Totipotent

Embryonic Stem Cells are Totipotent

Adult Stem Cells are PluripotentAdult Stem Cells are Pluripotent

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Specific Tissues can be grown from Stem cells under special

conditions

Specific Tissues can be grown from Stem cells under special

conditions

Stem Cells: A Primer (2000) http://www.nih.gov/news/stemcell/primer.htm

Tissue Engineering

True Multi-disciplinary Science

Requires 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

Materials Science

Mathematical ModellingClinicians

PhysiologyMedical

Engineering

Cell Biology

Genomics

Molecular Biology

Biochemistry

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Tissue Engineering

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

Tissue Engineering - Mesothelia Collect patients own progenitor cells and grow

them in test tubes Incorrect balance of hormones may cause scarring

Leavesley et al. NDT 14:1208 (1999)

+EGF - EGF

Human peritoneal mesothelial progenitor cellsgrown in vitro for 7 days, ±EGF

Tissue Engineering – epithelia Collect patient progenitor cells, grow them in ex

vivo Transplant

SkinCornea

Tissue Engineering – bone & cartilage

Use 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

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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!!

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

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

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.

Wow… Is this a miracle?Wow… Is this a miracle?

Stem Cell Therapy for Myocardial Repair

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.

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

Mechanisms of Action of Stem Cells for the Treatment of Heart DiseasesMechanisms of Action of Stem Cells for the Treatment of Heart Diseases

Many questions remain about the safety and mechanisms of action of stem cells for the treatment of heart diseases.

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?

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

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:

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

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

Stem Cell Delivery Methods and DevicesStem Cell Delivery Methods and Devices

Texas Heart Institute Physicians and ScientistsDiscuss 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,"

"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.

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.

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.

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 utilizing donated preimplantation embryos from in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) programs

Therapeutic cloning may be performed by utilizing donated preimplantation embryos from in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) programs

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.

Therapeutic cloning may be performed by creating embryos via nuclear transfer from

patients’ somatic cells into enucleated oocytes

Therapeutic cloning may be performed by creating embryos via nuclear transfer from

patients’ somatic cells into enucleated oocytes

donorsomatic cells

Biopsie

donoregg cells

enucleatedegg cell

THERAPEUTIC CLONING

cloned embryo

nucleartransplantation

immunologically compatible transplantation

Cellular Therapy to Treat Heart DiseaseCellular 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: 

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

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 cloningInterspecies cloningDevelopment of an interspecies-specific bioassay using the bovine

oocyte model to evaluate the potential of SCNT in humans: Possible Embryonic Stem Cell Source 

World DNA and Genome Day, China, April 25-30, 2005: Submitted for Publication

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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

K. Illmensee, M. Levanduski, and P. M. Zavos 

Can Science Fix Hearts via Stem Cell Transfer?

We are working on and we’ll soon be there!!

Can Science Fix Hearts via Stem Cell Transfer?

We are working on and we’ll soon be there!!

Salamanders can fix themselves!We can almost fix mice

Salamanders can fix themselves!We can almost fix mice

“That’s all Folk’s”“That’s all Folk’s”2005 Prof. Dr. Panos Zavos

This presentation is available @ http://www.zavos.org

The stem cells and the heart?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.

People is our Business and the World is Our Market!

People is our Business and the World is Our Market!