Stem cell therapy shows promise for treating heart disease but requires more research. While early studies found bone marrow stem cells could differentiate into heart cells, recent studies dispute this. Stem cells may improve heart function through paracrine effects like stimulating angiogenesis rather than regeneration. Safety concerns include arrhythmias and need addressing. Larger trials had mixed results, so more basic research is needed to optimize stem cell type, delivery methods, and tracking before further large clinical trials.

1. Stem cell ther apy
A new per spective for the
tr eatment of ischemic hear t
diseases
Dr . Md . Arifur Rahman
MD (Cardiology)

2. Cell technologies – Medicine of 21st century

“All diseases begin at cell level” proclaimed the famous German scientist Rudolf
Virchov in the 19th. Century.

The 21st. Century is a century of cells ,biomedicine, cell biology and molecular
medicine.

Stem cells could be used to replace missing or damaged cells in important diseases.

Today, donated organs and tissues are often used to replace those that are diseased
or destroyed. Unfortunately, the number of people needing a transplant far exceeds
the number of organs available for transplantation.

3. HISTORY

Georges Mathé, a French oncologist, performed the first European bone marrow
transplant in 1959 on five Yugoslavian nuclear workers whose own marrow had
been damaged by irradiation caused by a Criticality accident at the Vinča Nuclear
Institute, but all of these transplants were rejected.

Stem cell transplantation was pioneered using bone-marrow-derived stem cells
(1950 -1970) by E. Donnall Thomas, whose work was later recognized with a
Nobel Prize in Medicine.

4. HISTORY

In 2001, Menasche, et.al. described the successful implantation of autologous
skeletal myoblasts into the post-infarction scar of a patient with severe ischemic
heart failure.

Following the procedure, the researchers used imaging techniques to observe the
heart’s muscular wall and to assess its ability to beat. When they examined patients
5 months after treatment, they concluded that treated hearts pumped blood more
efficiently and improved tissue health.

5. Background

Coronary artery disease is a growing problem worldwide. Early treatment with stabilizing
drugs and revascularization by percutaneous coronary intervention or by-pass surgery has
reduced the mortality significantly, but it is still the most common cause of death and a major
cause of hospital admissions.

Treatment with stem cells with the potential to regenerate the damaged myocardium is a
relatively new approach.

However, the results from clinical studies on stem cell therapy for cardiac regeneration have
been inconsistent. Some of the discrepancy could be due differences in study designs or
patient selection.

6. Stem cells for clinical treatment

Stem cells are self-replicating and have the capacity to differentiate into at least one
highly terminally differentiated specialized cell type .

In cardiology most focus has been on bone marrow derived hematopoietic stem
cells, which have the potential to differentiate into endothelial cells and myocardial
vasculogenesis.

7. Stem cells for clinical treatment

Stem cells can be classified into three categories which specifies their
differentiation potential:
1. embryonic stem cells (ESC)- derived from inner cell mass of the
blastocyte
stage of the developing embryo
2. adult stem cells- bone marrow. MNCs and MSCs -peripheral blood ,
umbilical cord blood and from adipose tissue
3. induced pluripotent stem cells (iPS cells)- transcriptional reprogramming,
somatic cells such as fibroblasts.

8. Bone marrow derived mononuclear cells

This is the most frequent source of cells used in clinical cardiac regeneration,
because they are the most easily accessible source of autologous cells for use in
reparative transplantation. MNCs can easily be harvested from bone marrow
aspirate and can be isolated using markers on the cell surface.

The potential disadvantage of using MNCs, is that the percentage of stem cells that
are therapeutically useful may potentially be small.

9. Mesenchymal stromal cells

MSCs require substantial culture expansion for weeks prior to most
experimental applications .

MSCs can differentiate into endothelial progenitor cells by stimulating
with vascular endothelial growth factor (VEGF) and into cardiomyocytes
by a cocktail of growth factors, chemicals or by microenvironment in vivo.

10. Induced pluripotent stem cells

These are adult somatic cells reprogrammed into pluripotent stem cells, by
introducing pluripotency-associated transcription factors. The iPS cells
acquire properties similar to those of ESCs . This technology could
potentially eliminate : immune rejection after transplantation and the
ethical concerns regarding the use of human embryos. But there are also
other problems One of these is teratoma formation identical to what is seen
with ESCs.

11. Mechanisms ofAction
The mechanism remains controversial, and it is likely that the cells
regenerate myocardium through several pathways.

Transplanted cells differentiated into cardiac cells, blood vessels, or
other cells damaged by CVD.

transplanted stem cells release growth factors and other molecules
that promote blood vessel formation (angiogenesis) or stimulate
“resident” cardiac stem cells to repair damage.

strengthening of the post-infarct scar and the fusion of donor cells
with host cardiomyocytes.

12. Cardiac stem cells- Can the heart regenerate?

The ability of the cardiomyocytes to replicate is controversial . Increases in cardiac
mass in mammals during fetal life occur mainly due to cardiomyocyte proliferation.
During the perinatal period, mammalian cardiomyocytes are withdraw from the cell
cycle, thus limiting their ability to divide and increase in number .

Thus, normal postnatal growth and adaptive increases in cardiac mass in adults as a
result of hemodynamic burden are achieved mainly through increase in cell size
known as hypertrophy . The human heart contains cycling myocytes undergoing
mitosis under normal and pathological conditions .

13. Methods of Stem Cell Delivery
Transvascular Route
This approach is particularly for acutely infarcted and reperfused myocardium.

Stem cells can be infused directly into the coronary arteries and have a greater
likelihood of remaining in the injured myocardium as a result of the activation of
adhesion molecules and chemokines.

The advantage of an intracoronary infusion is that the cells can be directed to a
particular territory.

An alternative approach is to inject stem cells intravenously.

14. Direct Injection Into the Ventricular Wall

Direct injection of stem cells is used in patients in whom a transvascular approach
may not be possible because of total occlusion or poor flow within the vessel of the
affected territory.
There are 3 different approaches to direct injection
A transendocardial approach can be used in which a needle catheter is
advanced across the aortic valve and positioned against the endocardial surface.
Cells can then be injected directly into the left ventricle. Electrophysiological
mapping can be used to differentiate sites of viable, ischemic, or scarred
myocardium.

15. Direct Injection Into the Ventricular Wall

In a transepicardial approach, cells are injected during open heart surgery. The
advantage of this approach is that it allows direct visualization of the myocardium
and easier identification of regions of scar and border zones of infarcted tissues.

A third approach involves the delivery of cells through one of the cardiac veins
directly into the myocardium. The limitation of this approach is that positioning the
catheter within a particular coronary vein may be considerably more time
consuming and technically challenging.

16. Mobilization and homing of stem cells

Little is known about the signals involved in the mobilization and homing of stem
cells to the injured myocardium. It is currently believed that the cytokines CSF, GCSF, and stromal-cell–derived factor-1 (SDF-1) and their receptors play a major
role.

Despite their relatively high efficiency, all of the above-mentioned delivery
methods are hampered by a major limitation of cell cardiomyoplasty, namely, cell
death.

17. Mobilization and homing of stem cells

As many as 90% of transplanted cells die shortly after implantation as a result of
physical stress from the implantation procedure itself, myocardial inflammation, or
myocardial hypoxia. This suggest ways to improve the timing of cell
cardiomyoplasty.

Therapy too soon after an ischemic episode, when the damaged tissue is still
inflamed, may increase the risk of cell death; therapy too late may decrease the
chances of reverse myocardial remodeling.

18. Safety Concerns
Arrhythmia –

Increased frequency of nonsustained ventricular tachycardia in patients treated
with skeletal myoblasts, peaking 11 to 30 days after stem cell transplantation.

Mechanism - the injected stem cells do not communicate electrically with
neighboring cardiac myocytes and/or result in slowed conduction, thereby
promoting reentrant arrhythmias.

It has recently been suggested that skeletal myoblasts that have been genetically
engineered to express gap junction protein connexin 43 exhibited decreased
arrhythmogenicity.

19. Restenosis, Accelerated Atherosclerosis, and Coronary
Obstruction

Stem cell transplantation may promote the formation of de novo lesions or
atherosclerotic plaque progression,

CD133+ cells delivered via intracoronary injection in the setting of myocardial
infarction, with in-stent restenosis rates of 37% and reocclusion rates of 11%

It is also possible that if the cells are delivered at a high enough concentration via
the coronary circulation, they may adhere to each other, form aggregates, and
thereby lead to the occlusion of microvessels

20. Abnormal Cellular Differentiation

Fortunately, no clinical trials to date that have used stem cells to promote cardiac
tissue regeneration have demonstrated an increased frequency of tumor formation.

However, most of the clinical trials have been conducted on small numbers of
patients. Furthermore, it is not clear how adequate testing would be conducted to
monitor for this potential side effect. Because stem cells are known to migrate to
several other organs after delivery to the heart, it is conceivable that aberrant
cellular differentiation with the potential of tumor formation could occur in any of
these organs.

21. Tracking of Stem Cells

One of the major concerns regarding the delivery of stem cells is determining
which cells remain in the heart and which cells ultimately end up in other organs as
a result of a washout effect.

Within a few hours after transplantation, stem cells injected locally within the heart
also are observed within the lungs, spleen, liver, and kidney. only 24% of the
originally injected cells remained in the heart.

Methods to label and track stem cells in animal models, including scintigraphy,
PET, and MRI. PET scanning and MRI also have been tested recently in humans to
track stem cells.

22. Evidence for Tissue Regeneration

The ultimate goal of stem cell therapy is to promote cardiac tissue regeneration to
improvements in cardiac function that is synchronized with the rest of the
functioning heart in the absence of proarrhythmic or other adverse effects.

There is evidence that stem cells may lead to improvements in cardiac function that
are independent of tissue regeneration. Although early studies supported the ability
of bone marrow–derived mononuclear cells to differentiate into cardiac myocytes,
subsequent studies failed to support these initial observations.

23. Evidence for Tissue Regeneration

It has been suggested that the locally injected cells can act in a paracrine fashion to
improve ventricular function through the release of growth factors or other
paracrine mediators. These mediators may act to directly augment systolic function,
prevent apoptosis of ischemic myocardial cells, or limit injury by promoting
angiogenesis.

These paracrine effects are more likely to be useful in patients with acute
myocardial ischemia or with hibernating myocardium and less likely to be
beneficial in patients with chronically infarcted myocardium with significant scar
formation.

24. Questions need to be addressed ?

First, have we identified which stem cell type to use?

Second, have we determined the mechanisms by which stem cells promote
myocardial function or repair? At present, there is limited evidence to support that
stem cells used thus far in patients promote significant cardiac tissue regeneration.
Third, can the stem cell be retained efficiently within the heart?

Finally, can clinical trials be done in such a way that important safety issues will be
adequately addressed? What methods will be used to monitor the development of
life-threatening arrhythmias and to track injected stem cells throughout the body?

25. Conclusions



Stem cells remain a highly promising therapeutic modality that could address the
large, unmet clinical need of treating patients throughout the world with significant
cardiac dysfunction that cannot be adequately treated with conventional therapeutic
approaches or cardiac transplantation because of the limited availability of this
resource.
On the basis of the mixed results of more recent larger clinical trials, we should err
on the side of caution before committing precious resources to conduct additional
large clinical trials.
It is clear that additional basic research is needed to optimize ways to promote
cardiac tissue regeneration, to improve methods by which delivered stem cells will
remain in the heart, and to optimize the way in which stem cells are tracked after
delivery.