Cardiac Stem Cells

The adult heart is among the least regenerative organ in the

human body

Millions of people around the globe die each year of HF

Heart failure caused by inadequate number and loss
cardiomyocytes

Surviving cardiomyocytes have to adapt placed under greater
work load can lead to cardiac hypertrophy


Conventional beliefs stated that heart is a post mitotic organ

This dogma has been challenged discovery of CPC

The mammalian heart possesses intrinsic albeit linited
regenerative capacity

The field of cardiac regeneration is replete with contradictory
findings

Limited availability of technical factors to precisely monitor
development of newly formed cardiomyocytes.

The fetal myocardium grows normally by cardiomyocyte
proliferation/hyperplasia

After birth the myocardium grows by hypertrophy/inc in CM
volume

This transition from hyperplasia to hypertrophy occurs 3 days
postnatally in rats although exact transition period in humans
remains unknown

The cardiomyocyte volume in rodents increased 2.5 fold between
postnatal day 3 and day 12

Between P3 and P12 cardiomyocytes underwent karyokinesis in the
absence of cell division acytokinetic mitosis

Increase in ploidy also occurs through Endomitosis






Cardiomyocyte expression of cell cycle regulators are
carefully regulated different profiles during different phases

PRENATAL HEART UNDERGOING HYPERPLASIA






This pattern is reversed after birth cardiomyocyte
hypertrophy occurs leading to cell cycle exit postnatally.
Cyclins (A,B,D1/D2/D3)
CDKs
E2F

CDK inhibitors P21 and
p27
Cyclin A protein in rat heart during development

Disapearance of Cyclin A correlates with permanent withdrawal of
cardiomyocytes from the cell cycle in human and rat hearts ; Masao
Yoshizumi et al.
Lower vertebrates such as zebrafish and newts display cardiac
regeneration

Cardiac regeneration has been extensively studied in the
zebrafish

Regeneration without scarring mechanisms yet to be
elucidated

Successful regeneration was displayed after amputation of
20% of the heart ventricle in zebrafish

Amputation of
ventricular
apex

Blastema
formation
around
amputation site
Expression of
pre-cardiac
markers
(GATA-4)
Complete
differentiation
and
regeneration
Seminal Principles
1. Multipotent cardiac progenitor cells exist in the heart

2. After birth, there is a limited number of creation of new
heart cells

3. Lower vertebrates (newt,zebrafish) and neonatal mice exhibit
myocardial regeneration following injury
EXISTENCE OF MULTIPOTENT CARDIAC STEM CELLS
The heart contains a compartment of primitive cells with
stem cell like features Cardiac stem cells

Identification of CSC in heart has been controversial since it is
relatively rare

1 c-kit-positive CSC for every 30,000 cells (myocytes and
nonmyocytes)this frequency remains constant across species

CSC are stored in niches that control their
proliferation,migration and differentiation

CSC in these niches are thought to replace dying
cardiomyocytes and other cells

C-kit-positive cardiac stem cells in culture
Cardiac Stem Cell Niches
Niche constitutes a microenvironment in which the stem cells
divide and differentiate protection from damaging stimuli

Stem cells do not survive in the absence of the niche and each
niche is tailored to specifically meet the requirements of its
resident stem cells

The niche controls and maintains the slow-cycling and self
renewal of stem cells

Niches in each self renewing organ vary in architechtural
organization and composition


CSC interaction with cardiomyocytes and fibroblast
Studies provide definitive evidence for the presence of CSC
Common CSC markers are :
A. C-kit
B. NKX2.5
C. ISL1+

These cells have been shown to undergoe multilineage
differentation into myocytes, fibroblasts,smooth muscle cells
and endothelial cells
Postnatal cardiomyocyte renewal occurs in mammals including humans

Isotope dating studies were used to provide evidence that cardiomyocyte
turnover occurs in mammals as well as humans

A team led by Jonas frisen from the karolinska institute in stockholm has
shown that human hearts make new muscle cells albeit very slowly

People born before 1955 before the most intense period of bomb testing
had higher levles of C14 in their cardiomyocytes than at the time of their
birth

A 50 yr old heart still has more than half the cells it had at birth revealed
by mathematical modeling studies

A 25yr old heart replaces 1% of all cardiomyocytes over a year.
EMBRYONIC STEM CELLS
Embryonic stem cells ( ESC) are capable of differentiating into
cardiomyocytes.

During the last decade, protocols to differentiate human ESC
into cardiomyocytes have been developed successful
isolations of cardiomyocytes from differentiating ESC have
been reported.






Advantages of using ESC:
ESC derived cardiomyocytes exhibit all major molecular,
structural,mechanical and electrophysiological
characteristics of primary cariomyocytes

Grafted cells in animal models survive and mature for at
least 12 weeks

Grafted cells couple electrically with the host
cardiomyocytes
DISADVANTAGES:
ESC derived cardiomyocytes resemble fetal rather than adult
cardiomyocytes

Risk of teratoma formation

Immunologic mismatch immune rejection

No beneficial effects observed 12 weeks after transplantation
Bone marrow derived cells
Bone marrow represents a source of HSC and MSC

Isolated from the peripheral circulation or by bone marrow
aspiration

BMSCs are among the best charaterized and potentially
clinically accepted

Their isolation protocols,delivery to patient methods,safety
and therapeutic efficiency has already been evaluated and
established in treatment of hematologic diseases


BMSCs affect the myocardial regeneration process via:
1. potentiating neovascularization
2. reduction in apoptosis
3. inhibit synthesis of proinflammatory cytokines
4. Promote synthesis of antiinflammatory molecules

The first liscenced treatment using BMSC was
Hearticellgram-AMI approved by the korean FDA
Used in treating acute MI
Improvement in left ventricular function was found