DASAR STEM CELL DAN
PENGEMBANGAN TERAPI
ORGAN
Prof. Dr. Marlina, MS, Apt
Seminar Nasional Farmasi
Rocky Hotel, Padang, 23 Juni 2012
STEM CELL RESEARCH WHAT IS IT ALL ABOUT?
http://stemcells.nih.gov/info/basics/
"Image courtesy of NIH resource for stem cell research"
What are stem cells?

Stem cells are undifferentiated cells that have many
potential scientific uses:
 Cell based therapies
 Often referred to as regenerative or reparative
medicine
 Therapeutic cloning
 Gene therapy
 Cancer research
 Basic research
Two types of stem cells


Embryonic Stem Cells (ESC): received from:
 Embryos created in vitro fertilization
 Aborted embryos
Adult Stem Cells (ASC): can be received from:
 Limited tissues (bone marrow, muscle, brain)
 Discrete populations of adult stem cells generate
replacements for cells that are lost through normal
wear and tear, injury or disease
 Placental cord
“ADULT” STEM CELLS ARE OBTAINED
IN A VARIETY OF WAYS
Illustration by Matt Bohan, 2007
STEM CELLS HAVE ALSO BEEN
FOUND IN “MATURE” ORGANS
Illustration by Matt Bohan, 2007
Source of ESC


Blastocyst
 3-5 day old embryo
 Stem cells give rise to multiple specialized cell types
that make up the heart, lung, skin, and other tissues
Human ESC were only studied since 1998
 It took scientists 20 years to learn how to grow
human ESC following studies with mouse ESC
How are embryonic stem cells
harvested?


Human ES cells are derived from 4-5 day old blastocyst
Blastocyst structures include:



Trophoblast: outer layer of cells that surrounds the blastocyst &
forms the placenta
Blastocoel: (“blastoseel”) the hollow cavity inside the blastocyst
that will form body cavity
Inner cell mass: a group of approx. 30 cells at one end of the
blastocoel:

Forms 3 germ layers that form all embryonic tissues (endoderm,
mesoderm, ectoderm)
Blastocyst
http://www.ivf-infertility.com/infertility/infertility5.php
Unique characteristics of Stem Cells


Stem cells can regenerate
 Unlimited self renewal through cell division
Stem cells can specialize
 Under certain physiologic or experimental conditions
 Stem cells then become cells with special functions such
as:
 Beating cells of the heart muscle
 Insulin-producing cells of the pancreas
Self - Renewal (Regeneration)

Stem cells are capable of dividing & renewing
themselves for long periods
 This is unlike muscle, blood or nerve cells –
which do not normally replicate themselves
 In the lab, a starting population of SCs that
proliferate for many months yields millions of
cells that continue to be unspecialized
 These cells are capable of long-term selfrenewal
Specialization of Stem Cells:
Differentiation

Differentiation: unspecialized stem cells give rise to
specialized (differentiated) cells in response to
external and internal chemical signals
 Internal signals: turn on specific genes causing
differential gene expression
 External signals include:
 Chemicals secreted by other cells such as
growth factors, cytokines, etc.
 Physical contact with neighboring cells
Potential of Stem Cells

Totipotent (total):
 Total
potential to differentiate into any adult
cell type
 Total potential to form specialized tissue
needed for embryonic development

Pluripotent (plural):
 Potential
to form most or all 210
differentiated adult cell types

Multipotent (multiple):
 Limited
potential
 Forms only multiple adult cell types
 Chondrocyte
 Neurons
Unipotent – these cells only produce one cell
type., but have the property of self renewal
which distinguishes them from the non stem
cells.
http://www.stemcellresearch.org/testimony/20040929prentice.htm Reprinted with permission of Do No Harm.
Adult Stem Cells
 Adult
or somatic stem cells have
unknown origin in mature tissues
 Unlike embryonic stem cells, which
are defined by their origin (inner cell
mass of the blastocyst)
Potential of Adult Stem Cells
Adult stem cells continued

Adult stem cells typically generate the cell types of
the tissue in which they reside
 Stem cells that reside in bone marrow give rise to
RBC, WBC and platelets
 Recent experiments have raised the possibility
that stem cells from one tissue can give rise to
other cell types
 This is known as PLASTICITY
Adult Stem Cell Plasticity Examples




Blood cells becoming neurons
Liver cells stimulated to produce insulin
Hematopoietic (blood cell producing) stem cells that
become heart cells
CONCLUSION: Exploring the use of adult stem cells
for cell-based therapies has become a very important
(and rapidly increasing) area of investigation by research
scientists!
Adult stem cells: A brief
history


Adult stem cell research began about 40 years ago
Stem cell discoveries in 1960s:
 Bone marrow contains 2 populations of stem cells
 Hematopoietic stem cells – forms all blood cell types
 Bone marrow stromal cells – mixed cell population
that generates bone, cartilage, fat and fibrous
connective tissue
 Rat brain contains two regions of dividing cells, which
become nerve cells
History Cont.

Stem Cell Discoveries in
the 1990s

Neural stem cells in brain
are able to generate the
brain’s three major cell
types



Astrocytes
Oligodendroglial cells
Neurons
http://www.alsa.org/images/cms/Research/Topics/cell_targets.jpg
Potential Uses of Stem
Cells

Basic research – clarification of complex
events that occur during human
development & understanding molecular
basis of cancer
 Molecular mechanisms for gene control
 Role of signals in gene expression &
differentiation of the stem cell
 Stem cell theory of cancer
Potential uses cont.

Biotechnology(drug discovery & development) – stem
cells can provide specific cell types to test new drugs
 Safety testing of new drugs on differentiated cell
lines
 Screening of potential drugs
 Cancer cell lines are already being used to screen
potential anti-tumor drugs
 Availability of pluripotent stem cells would allow
drug testing in a wider range of cell types & to
reduce animal testing
Potential uses cont.

Cell based therapies:
 Regenerative therapy to treat Parkinson’s,
Alzheimer’s, ALS, spinal cord injury, stroke, severe
burns, heart disease, diabetes, osteoarthritis, and
rheumatoid arthritis
 Stem cells in gene therapy
 Stem cells as vehicles after they have been
genetically manipulated
 Stem cells in therapeutic cloning
 Stem cells in cancer




Embryonic vs Adult Stem
Cells
Totipotent
 Differentiation into
ANY cell type
Known Source
Large numbers can be
harvested from embryos
May cause immune
rejection
 Rejection of ES cells by
recipient has not been
shown yet

Multi or pluripotent




Differentiation into some cell
types, limited outcomes
Unknown source
Limited numbers, more
difficult to isolate
Less likely to cause immune
rejection, since the patient’s
own cells can be used
Application of stem cells
 Stem
cell research:
1. It provides an ideal model for the
study of development of organisms
2. It replaces damaged cells of the body
3. It also aids in drug discovery
 Regenerative
medicine
and
 Therapeutic issues
Bone marrow transplant:
Example of adult stem cell-based therapy
Haematopoeitic stem cells
 Derived
from bone marrow in adults
and umbilical cord blood
 Option given to the parents regarding
stem cell banking during antenatal
visits
 25% chance that sibling also can have
a perfect match
The Nobel Prize, 1990
E. Donnall Thomas
first succsessful HSCT in treatment of acute leukemias
Thomas ED, Lochte HL, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation
and chemotherapy. N. Engl. J. Med. 1957; 257: 491.



Blood is collected
from umb cord
immediately after
delivery about 100150cc
The number of cells in
1 ml is 40,000
They are stored in
blood banks at
-196deg celsius in a
state of suspended
animation and restart
their activity on
thawing
Hematopoietic and Stromal Adult
Stem Cell Differentiation
stemcells.nih.gov/.../images/figure2_lg.jpg
Ailments for which stem cells
are being used now






Acute leukemias
Chronic leukemias
Myelodysplastic
syndromes
Marrow failure
Myeloproliferative
disorders
Lymphoproliferative
disorders
Trials underway
Cardiac disease
 Diabetes
 Multiple Sclerosis
 Muscular Dystrophy
 Parkinson’s disease
 Spinal cord injury
 Stroke

Cell Therapy in Failing Heart

GOAL










Transfer of functional myocytes to heart – Improve its function
The DEALS “ Homing of grafted cells”
Engraft into non functional scar
Electromechanical coupling and synchronisation
Neo angiogenesis and myogenesis
Good craft survival
Low immunogenecity
Ethical acceptance
Low oncogenicity
Case of application
Stem cells for myocardial regeneration
HETEROLOGOUS
AUTOLOGOUS
•Fetal cardiomyocytes
•Skeletal myoblast
•Embryonal stem cells
•Endothelial progenitors
•Bone marrow stem cells
Stem cells therapy




Cardiovascular note
Infarct repair
Cardiomyopathy treatment
End stage coronary artery disease
Bone marrow stem cells
Hemapoeitic Stem cells
Endothelial Progenitor cells <0.05%
(Stromal stem cells)
T-2%
(Lin – c Kit (+ve) ; AC 133+)
CD 34+
Transplantation
HEART
Translocation
(Endogenous stem cell mobilization)
G – CSF
CARDIOMYOCYTES
Endothelium sm cells
GM - CSF
Diabetes Research
What is known

cells are not generated from adult stem
cells in the pancreas.

It is unlikely that a cure for diabetes will
come from adult stem cells.

Embryonic stem cells have been shown to
generate insulin-producing cells.
What Has Been Tried:
Whole organ pancreas transplants
 Problem:
not enough organs to meet the
demand
 Problem: must take powerful
immunosuppressants
What Has Been Tried:
Injections of pancreatic islet cells
 Problem:
less than 8% of these
transplants have been successful
 Problem: immunosuppressants are
required
Possible Next Step:
Inject  cells into the patient’s pancreas
 Problem:
There is much work to be
done before this technique will be
ready—if it is ever ready.
Possible Next Step:
Activate  cells in the patient’s
own pancreas
 Problem: There may be no cells left in
the pancreas of a patient to activate.
Possible Next Step
Provide type l diabetics with
transplants of cells derived from
embryonic stem cells.
What We Need to Know
 What
properties make embryonic stem
cells unique?
 Where do these cells come from?
 How are they involved in the formation of
the pancreas, cells, and other tissues?
What makes them unique?

can regenerate an infinite
number of times

can be grown in culture
indefinitely

are classified as
pluripotent

are able to differentiate
into specialized cells as
needed
Germ Layer Differentiation
Forming Specialized Cells
Growth factors and other signals tell a stem cell when to
differentiate and what type of cell to become.
Forming Specialized Cells
The same growth factors and signals could be used to direct the
differentiation of human embryonic stem cells grown in culture.
What is Known